Prevention of Autoimmune Disease: The Type 1 Diabetes Paradigm

C H A P T E R

70 Prevention of Autoimmune Disease: The Type 1 Diabetes Paradigm Leonard C. Harrison and John M. Wentworth Walter & Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

O U T L I N E Mucosa-Mediated Antigen-Specific Tolerance Trials of Islet Autoantigen-Specific Vaccination in Humans

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Overview of Type 1 Diabetes Autoimmune Pathology Nature and Nurture

1391 1391 1393

Prevention of Type 1 Diabetes

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Epilogue

1406

Primary Prevention Diet and Gut Microbiome Modification Virus Vaccination Antigen-Specific Immunotherapy

1400 1401 1402 1402

Acknowledgments

1407

References

1407

Further Reading

1413

Secondary Prevention

1402

1404

OVERVIEW OF TYPE 1 DIABETES Autoimmune Pathology From the 1970s, it has gradually become clearer that type 1 diabetes (T1D) is an autoimmune disease (Eisenbarth, 1986). The evidence includes infiltration of the islets by immune cells (Gepts, 1965; Foulis et al., 1986), strong genetic risk associated with specific classes I and II human leukocyte antigen (HLA) genes coding for molecules that present peptide antigens to T cells, as well as with the insulin gene and a range of immune genes (Concannon et al., 2009), circulating autoantibodies to beta-cell antigens (Verge et al., 1996; Colman et al., 2000; Bingley et al., 1999; Ziegler et al., 2013), T cells in the blood (Harrison et al., 1993; Mannering et al., 2005) and pancreas (Pathiraja et al., 2015) that recognize insulin and other beta-cell antigens, a report of recurrent immune beta-cell destruction after pancreatic isograft transplantation without immunosuppression between identical twins discordant for T1D (Sutherland et al., 1989), occasional reports of T1D after bone marrow transplantation from a T1D donor (Lampeter et al., 1998a,b) and induction of T1D by immune checkpoint inhibitor antibodies (Kapke et al., 2017). Beta-cell destruction in T1D is mediated by autoreactive T cells, the ultimate effectors being CD8 cytotoxic T cells. The evidence for this is unequivocal in the inbred nonobese mouse (NOD) model of T1D, which shares a number of key features with T1D in outbred humans (Leiter et al., 1987; Adorini et al., 2002). The molecular mechanisms of beta-cell death, gleaned mostly from the NOD mouse, encompass a combination of apoptosis induced by activation of extrinsic (e.g., TNF receptor or Fas ligation) or intrinsic (e.g., endoplasmic reticulum stress) death pathways and necroptosis induced by cytotoxic CD8 T-cell granule components

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70. PREVENTION OF TYPE 1 DIABETES

(granzymes and perforin), reactive oxygen species, or ischemia. The NOD mouse has also served to demonstrate proof-of-principle for preventative therapies that could translate to humans. Two major distinctions between T1D and other autoimmune diseases, that allow those at risk to be identified and, therefore, are requisite for prevention, are the major contribution of HLA genes to risk and the ability to identify children many months to years before eventual loss of most beta-cell function leads to clinical presentation (Fig. 70.1). Birth cohort studies of children with a T1D relative have shown that the development of diabetes by the age of 18 years is almost always associated with the appearance of islet autoantibodies in the first years of life. Of children with two or more islet autoantibodies before the age of 3 years, 57% (95% CI: 51.7% 62.3%) and 74.8% (95% CI: 69.7% 79.9%) progressed to diabetes by 6 and 10 years, respectively; with a single islet autoantibody, 14.5% progressed to diabetes by 10 years (Ziegler et al., 2013). In order to prevent T1D, a paradigm shift is necessary to redefine the disease as an autoimmune beta-cell disorder from the beginning of the asymptomatic phase of islet autoimmunity (Stage 1), rather than as a metabolic disorder of end-stage pathology (Stage 3) (Couper and Harrison, in press). In children, the diagnosis of T1D at clinical presentation is usually based on symptoms and signs, but can be confirmed, and in older individuals established, by detecting circulating islet autoantibodies to beta-cell antigens, to insulin (IAA), glutamic acid decarboxylase 65,000 mol. wt. isoform (GADA), insulinoma-like antigen-2 (IA-2A), and zinc transporter-8. One or more autoantibody specificities is present in at least 90% of Caucasian children with T1D compared to B1% of the general population, but in only B50% of the Hispanic-American and AfricanAmerican children diagnosed with T1D. IAA are more often the first sign of islet autoimmunity in children followed from birth and is the most predictive autoantibody. A family history of T1D in close relatives is present in only 10% 15% of newly diagnosed cases. However, affected families have provided major insights into the genetics and natural history of T1D. In T1D relatives the rate of progression to clinical diabetes is positively associated with the number and titer of islet autoantibodies (Verge et al., 1996; Bingley et al., 1999; Colman et al., 2000; Ziegler et al., 2013), the number and type of HLA classes I and II risk alleles (Honeyman et al., 1995; Tait et al., 1995) and the degree of insulin resistance (Fourlanos et al, 2004) and is negatively associated with age (Table 70.1).

FIGURE 70.1 Stages in the natural history of type 1 diabetes. TABLE 70.1 Markers of Risk for Diabetes in Islet Autoantibody-Positive Relatives Number of antigen specificities of islet autoantibodies Antigen specificity of islet autoantibody Level of islet autoantibody Age at detection of islet autoantibody FPIR to i.v. glucose Insulin resistance, for example, estimated as HOMA-R HLA alleles for risk or protection HLA haplotype sharing with proband Kinship with proband Body mass index FPIR, First phase insulin response; HOMA-R, Homeostatic model assessment-insulin resistance.

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Nature and Nurture The incidence of T1D is highest in Caucasian northwest Europeans. This reflects the distribution of specific risk HLA genes, which account for up to 50% of the lifetime risk for T1D (Table 70.2). However, the incidence of T1D has been rising on a background of lower risk HLA alleles. In Western European societies, the incidence in childhood has more than doubled since the 1980s and has been rising at B3% annually, particularly in younger children (Gale, 2002). The same trend is beginning to be seen in countries such as Kuwait and Saudi Arabia, and areas of India and China that have adopted Western lifestyles, but where the prevalence of high-risk HLA genotypes for T1D is much lower. Environmental factors may increase the penetrance of risk genes for T1D. In the case of HLA genes, the increasing incidence of T1D is accounted for by children with intermediate (DR 4, 4 or DR 3, 3) or low (DR 4, X or DR 3, X) risk phenotypes, not the highest risk HLA phenotypes (DR 3, 4; DQ 2, 8) (Fourlanos et al., 2008). Interestingly, these lower risk HLA phenotypes are the ones seen in non-Caucasians and in adults presenting with T1D. The environment in Western societies has changed dramatically during the last century including in ways that have been associated either epidemiologically or in animal studies with a rising incidence of T1D (Wentworth et al., 2009). A marker of the modern “exposome” is obesity, associated with insulin resistance and type 2 diabetes, and with alterations in the gut microbiome. When children at increased genetic risk for T1D (with an affected first-degree relative) were monitored from birth, weight gain in the first 2 3 years of life was a risk factor for islet autoimmunity (Couper et al., 2009). In at-risk children who developed islet autoantibodies, insulin resistance was an independent marker of those who progressed most rapidly to clinical diabetes (Fourlanos et al., 2004). Whether insulin resistance promotes the development of islet autoimmunity is an important question that can be answered by an ongoing pregnancy birth cohort study (Penno et al., 2013). Thus, insulin resistance associated with obesity could synergize with impaired beta-cell function to accelerate the development of T1D, justifying attention to environment lifestyle factors to forestall or prevent T1D. Obesity is the outcome of increased energy consumption and changed diet composition, both readily provided by the modern “Western” diet. This diet lacks diversity of components, lacks plant-derived prebiotics and complex carbohydrates (starches and fiber), is high in saturated fats, sucrose, and fructose, and contains artificial preservatives, emulsifiers, and sweeteners. All of these alter the composition of the gut microbiome and reduce its diversity, which are features of the gut microbiome in children at risk (Dunne et al., 2014; TABLE 70.2

Lifetime Risks for Type 1 Diabetes

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Knip and Siljander, 2016). Diets containing a diverse range of plant products (cereals, fresh fruits vegetables, nuts, seeds) provide complex carbohydrates for fermentation by colonic bacteria to short-chain fatty acids such as butyrate, propionate, and acetate, and other antiinflammatory products (Thorburn et al., 2014). Microbial colonization of the gut is required for development of a normal immune system and the maintenance of gut epithelial homeostasis and “barrier function” mediated by products such as butyrate and mucins (Yu et al. 2012). It is no surprise therefore that the microbiome—the trillions of microorganisms (bacteria, fungi, archaea, protozoa, viruses) and their millions of genes and proteins that reside within our mucosae, skin, and secretions at the interface with the world—has come under increasing focus as a bellwether of health and disease. In the NOD mouse, the incidence of autoimmune diabetes is markedly altered by changes in the microbiome in combination with diet. The incidence of spontaneous diabetes in NOD mice differs greatly between colonies around the world and is inversely correlated with exposure to microbial infection (Pozzilli et al., 1993). The high incidence of diabetes in NOD mice housed under pathogen-free conditions is reduced by conventional conditions of housing and feeding (Suzuki, 1987). Under such conditions, bacterial colonization of the intestine is accompanied by maturation of mucosal immune function (Kawaguchi-Miyashita et al., 1996). In germ-free on a defined, sterile diet the incidence of disease compared to specific pathogen-free (SPF) mice is accelerated and increased from 70% to 100% (Marin˜o et al., 2017). Provision of a diet high in butyrate and acetate to NOD mice in SPF conditions almost totally prevented diabetes (Marin˜o et al., 2017). The counterpart in humans may be modern Finland and its Russian neighbor Karelia. Finland has the highest incidence of T1D in the world, currently 57.6 cases/100,000 population # 14 years (www.diabetesatlas.org). In 2005, there was a 6-fold difference in the incidence of T1D between Finland and Karelia, despite overlap in ethnic background and a similar distribution of high-risk HLA genotypes (Kondrashova et al., 2005). This marked difference in the incidence of T1D is associated in Finnish children with decreased gut bacterial microbiome diversity, a dominance of the phylum Bacteroidetes over Firmicutes and a deficiency of butyrate- and mucin-producing bacteria (Kostic et al., 2015). These changes were seen after the appearance of autoantibodies, suggesting that they followed rather than preceded the disease process. However, a further small study in Finnish children identified a relative abundance of Bacteroides dorei, which peaked around 7 8 months of age with the introduction of solids and preceded the appearance of islet autoantibodies (Davis-Richardson et al., 2014). Gut Bacteroides species are abundant in Finnish children, including B. dorei, which produces a lipopolysaccharide (LPS) endotoxin that inhibits the immunostimulatory activity of Escherichia coli LPS, known to protect against diabetes development in NOD mice (Vatanen et al., 2016). Individuals with T1D and even those with islet autoantibodies at risk for T1D, have impaired barrier function with increased “leakiness” through intercellular gap junctions (Bosi et al., 2006), consistent with the descriptions of the altered composition and decreased diversity of the microbiome in T1D. We noted some years ago that “gut leakiness,” reflected by increased titers of antibodies to food components, was present even in T1D and celiac disease relatives with the HLA A1-B8-DR3-DQ2 risk haplotype (Harrison and Honeyman, 1999). This is consistent with more recent evidence for a relationship between the microbiome and host genome. The question, does “gut leakiness” precede the development of islet autoimmunity, and how does it relate to the microbiome and to T1D genetics, has not been fully answered. We found that among asymptomatic children with islet autoantibodies those who progressed most rapidly to diabetes had lower gut microbial diversity with deficiency of the Prevotella genus and increased gut permeability (Harbison et al., 2018). The presentation of clinical T1D peaks in winter (Moltchanova et al., 2009), attributed to environmental factors such as increased number of virus infections and a decrease in vitamin D. However, given the long presymptomatic stage of disease, these would appear to represent nonspecific precipitants. Viruses, in particular enteroviruses, are proposed as a cause of T1D but the evidence remains circumstantial (Honeyman 2005; Roivainen and Klingel 2010). Viral mechanisms in T1D could be direct or indirect, for example, infection of β cells, infection of the exocrine pancreas with bystander death of β cells, mimicry between T-cell epitopes in a viral protein and beta-cell autoantigens, or activation of endogenous retroviruses in β cells by environmental agents. If an exogenous virus was clearly identified then protective vaccination in early in life would be an approach to primary prevention. However, if a specific enterovirus strain was shown to be diabetogenic, creating a vaccine may be challenging because among the many thousands of strain variants, the only one for which a vaccine currently exists is poliovirus. The first virus to be associated with T1D was rubella (Forrest et al., 1971). Children with congenital rubella born to mothers who contracted rubella early in pregnancy had evidence of infection in the brain, pancreas, and other tissues and 20% developed insulin-dependent diabetes (Menser et al., 1978). Subsequently, almost twice this proportion was reported to develop islet cell antibodies (ICAs) (Ginsberg-Fellner et al., 1985). Children with congenital rubella and ensuing diabetes had a higher frequency of the T1D susceptibility HLA class I phenotype A1 (Menser et al., 1974), on the risk haplotype HLA A1-B8-[DR3-DQ2]. Rubella vaccine virtually eliminated

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congenital rubella but obviously not T1D; clearly many other environmental factors must be involved, mumps virus epidemics have been associated with T1D onset after 2 4 years and introduction of a mumps vaccine was associated with a plateau in the rising incidence of T1D in Finland, but this was temporary and mumps vaccination has clearly not prevented T1D. Rotavirus (RV) is the commonest cause of gastroenteritis in young children. The discovery of strong sequence similarities between T-cell epitopes in the VP7 protein of rotavirus and GAD and IA-2 islet antigens in autoantibody-positive children led to speculation that mimicry with rotavirus might contribute to islet autoimmunity. Subsequently, in the Australian BabyDiab Study, rotavirus infection was associated with the first appearance of or an increase in islet autoantibodies in children (Honeyman et al., 2000). Moreover, rotavirus infects β cells in islets of mice, pigs, and monkeys, and was recently shown to cause transient involution of the pancreas and hyperglycemia in a toll-like receptor (TLR)-3-dependent manner in mice (Honeyman et al., 2014). Ubiquitous rotavirus infections that drive cross-reactive immunity to islet autoantigens are unlikely to be diabetogenic but could complement and sustain the immune response following direct infection of β cells. Recently, in Australian children aged less than 4 years, it was shown that the number of incident cases of T1D has decreased by 14% (RR 0.86) following the introduction of oral RV vaccine in 2007 (Perrett et al., 2019). As with mumps, the significance of this observation requires ongoing surveillance, and confirmation from an ongoing case control linkage study.

PREVENTION OF TYPE 1 DIABETES Progress in understanding mechanisms of beta-cell destruction, the ability to identify individuals at high risk for T1D, and proof-of-principle for preventative therapies in the NOD mouse model set the scene for preventing or arresting autoimmune beta-cell damage in humans. This goal is relevant not only to individuals at risk but to those with clinical diabetes, in order to preserve residual beta-cell function, permit possible beta-cell regeneration and prevent recurrent autoimmune disease after therapeutic beta-cell replacement or regeneration. It will be eminently more achievable with increasing acceptance that T1D is an autoimmune disease that begins early in life, which is when intervention for primary or secondary prevention should logically begin and not at the time of end-stage pathology and clinical presentation. Newer biologic agents that are disease-sparing in autoimmune diseases such as rheumatoid arthritis would never be expected to reverse end-stage joint pathology. The caveat is that any form of treatment given to asymptomatic, at-risk children must have an excellent safety profile— “Primum non nocere” (first do no harm)—because even in islet autoantibody-positive children prediction of clinical disease is not 100%. Population heterogeneity is a critical consideration in the design and interpretation of clinical trials. In addition to HLA genes, over 50 genetic loci are associated with T1D, but very little is known about how they contribute to disease development in different environments or influence prevention strategies. Although a restricted set of HLA genes is shared among individuals with T1D, HLA-based heterogeneity in age at clinical presentation is well known (Honeyman et al., 1995; Tait et al., 1995). This suggests that T1D comprises disease subtypes and that prevention will most likely require a more “personalized” approach. Indeed, it is known that the natural history of declining beta-cell function after diagnosis depends on age, HLA status, autoimmune status including number and level of islet autoantibodies, residual beta-cell function, and insulin resistance (Greenbaum and Harrison, 2003). Inclusion of T1D relatives in secondary prevention trials has been based on age (,40) and islet autoantibodies ($2), for a predicted 5-year incidence of B40%, but more refinement is possible by building subtype analysis into trial design. Up to 10% of adults presenting with diabetes have what appears to be a slowly progressive form of T1D, associated mainly with GAD65 autoantibodies, which initially is noninsulin-requiring (Gottsater et al., 1995; Hagopian et al., 1993; Tuomi et al., 1993; Turner et al., 1997). They have higher residual beta-cell function at diagnosis than younger patients with classical T1D, which implies a wider and perhaps more penetrable therapeutic window for secondary prevention (Fourlanos et al., 2005). The “personalized” approach requires new robust surrogate assays of disease mechanisms to identify people most likely to benefit from a specific therapy and allow the design of more practical, cheaper, and efficient boutique trials, rather than larger, expensive trials powered on the endpoint of diabetes. The number of candidate agents that fulfill scientific and ethical criteria for primary or secondary prevention trials is limited and recruiting individuals for these trials is a significant logistical exercise. Consequently, of the many clinical trials undertaken for “prevention” of T1D since the 1980s, most have been tertiary trials in individuals with recent-onset clinical T1D. A comprehensive listing of these trials is provided (Table 70.3), in which classification by agent necessitates combining the categories of secondary and tertiary prevention. The primary outcome measure in

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70. PREVENTION OF TYPE 1 DIABETES

Trials for Prevention of Type 1 Diabetes Followup (months) Outcome

Participants (n)

Reference

PRIMARY PREVENTION Cow’s milk elimination (trial to reduce IDDM in the genetically at-risk TRIGR)

FDRs with HLA risk (150)

$ 36

Elimination of bovine insulin from infant formula (FINDIA study)

HLA at-risk infants (1113)

36

Weaning to hydrolyzed casein formula vs cow’s milk 1 20%casein formula (TRIGR study)

HLA at-risk 138 m No change in incidence of islet antibodies or infants (median) of diabetes (2159)

No change in incidence of islet autoantibodies Hummel et al. (2011) or diabetes Decrease in incidence of islet autoantibodies

Vaarala et al. (2012)

Knip et al. (2011), Knip et al. (2014), and Knip et al. (2018)

SECONDARY AND TERTIARY PREVENTION Nonspecific immune suppression Azathioprine (2 mg/kg/day for up to 12 months)

RD (24)

12

Increased basal and glucagon-stimulated Cpeptide, and more remissions

Harrison et al. (1985)

Cyclosporine (7.5 mg/kg/day for up to 9 months)

RD (122)

9

More remissions

Feutren et al. (1986)

Azathioprine (2 mg/kg/day for a year) 1 prednisolone (decreasing dose over 10 weeks)

RD (46)

12

Increased meal-stimulated C-peptide and decreased insulin dose

Silverstein et al. (1988)

Cyclosporine (20 mg/kg/day for 1 year)

RD (188)

12

Increased glucagon-stimulated C-peptide and more remissions, especially in recently diagnosed

Canadian European Randomized Control Trial Group (1988)

Azathioprine (2 mg/kg/day for 1 year)

RD (49)

12

Increased meal-stimulated C-peptide

Cook et al. (1989)

Azathioprine, thymostimulin, or the combination

RD (45)

12

Increased glucagon-stimulated C-peptide and more remissions in combination group

Moncada et al. (1990)

Cyclosporine (10 mg/kg/day for up to 2 years)

RD (219)

24

Increased meal-stimulated C-peptide and more remissions

Assan et al. (1990)

Cyclosporine (10 mg/kg/day for 4 months)

RD (43)

36

No difference in glucagon-stimulated Cpeptide, HbA1C, or insulin dose

Chase et al. (1990a)

Prednisolone (15 mg/day for 8 months) or indomethacin (100 mg/day for 8 months)

RD (25)

24

Decreased insulin dose and increased urine C-peptide in prednisolone group

Secchi et al. (1990)

Cyclosporine (10 mg/kg/day for 1 year)

RD (23)

12

Increased meal—but not glucagon—or glucose-stimulated C-peptide. No difference in insulin dose

Skyler and Rabinovitch, (1992)

Anti-CD5 mAb/ricin A chain anti-T-cell therapy (not blinded)

RD (15)

12

Dose-dependent preservation of mealstimulated C-peptide

Skyler et al. (1993)

Prednisone (1 mg/kg/day tapered over 50 days)

RD (32)

12

Increased glucagon-stimulated C-peptide, but no remissions

Goday et al. (1993)

Anti-CD4 mAb 1 prednisolone

RD (12)

12

No difference in insulin dose, or islet antibody titers

Kohnert et al. (1996)

Methotrexate (5 mg/m2/week; not blinded)

RD (10)

36

No effect on basal or meal-stimulated Cpeptide. Insulin dose increased.

Buckingham and Sandborg (2000)

Teplizumab (OKT3γ1(Ala-Ala) anti-CD3 mAb; not blinded)

RD (18)

12

Increase in meal-stimulated C-peptide in first year. IL-10 detected in serum

Herold et al. (2002)

Teplizumab [OKT3γ1(Ala-Ala) anti-CD3 mAb]

RD (42)

24

Improved C-peptide response to mixed meal, decreased HbA1c and decreased insulin dose

Herold et al. (2005)

(Continued)

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TABLE 70.3

(Continued) Participants (n)

Followup (months) Outcome

Reference

Otelixizumab (CHAgly anti-CD3 mAb)

RD (80)

48

Improved C-peptide response to glucose. Clamp/glucagon up to 36 months. Decreased insulin dose with similar HbA1c

Keymeulen et al. (2005, 2010)

Rituximab (anti-CD20 mAb)

RD (87)

24

Increased C-peptide response to mixed meal at 12 but not 24 months. Decreased HbA1c and insulin dose

Pescovitz et al. (2014) and Pescovitz et al. (2009)

Mycophenolate mofetil 6 daclizumab (anti IL2 receptor mAb)

RD (126)

24

No effect on basal or meal-stimulated Cpeptide. Similar HbA1c and insulin dose

Gottlieb et al. (2010)

Abatacept (CTLA4-Fc fusion protein)

RD (112)

24

Increased C-peptide response to mixed meal. Decreased HbA1c and insulin dose

Orban et al. (2011)

RD (7)

12

Transient decrease in C-peptide response to mixed meal associated with increased numbers of circulating regulatory T cells

Long et al. (2012)

Teplizumab [OKT3γ1 (Ala-Ala) anti-CD3 mAb]

RD (516)

24

Increased C-peptide response to a mixed meal Roep et al. (2013) at 18 and 24 months with decreased insulin and Sherry et al. (2011) use and HbA1c

IL-1 antagonism with canakinumab or anakinra

RD (138)

12

No difference in C-peptide response to a mixed meal, HbA1c or insulin dose

Moran et al. (2013)

Teplizumab [OKT3 γ1 (Ala-Ala) anti-CD3]

RD (52)

24

Increased C-peptide response to mixed meal. Decreased HbA1c and insulin dose

Herold et al. (2013)

Alefacept (anti-CD2)

RD (49)

24

Increased C-peptide response to mixed meal and decreased insulin dose and rate of severe hypoglycemia

Rigby et al. (2013) and Rigby et al. (2015)

Ladarixin (IL-8 antagonist)

RD (72)

12

Ongoing

NCT02814838

Teplizumab [OKT3 γ1 (Ala-Ala) anti-CD3]

AR (170)

48 72

Ongoing

NCT01030861

BCG vaccine

RD (26)

18

No effect on glucagon-stimulated C-peptide, insulin dose, or HbA1C

Elliott et al. (1998)

BCG vaccine

RD (94)

24

No effect on mixed meal-stimulated Cpeptide, insulin dose, or HbA1C

Allen et al. (1999)

Q fever vaccine

RD (39)

12

No effect on glucagon-stimulated C-peptide or insulin dose

Schmidli et al. (unpublished)

Thymopoietin

RD (32)

6

Decreased insulin antibodies and insulin dose. More remissions. No difference in Cpeptide or HbA1c

Giordano et al. (1990)

Gammaglobulin

RD (16)

6

Increased basal C-peptide Decreased insulin dose, unchanged HbA1c

Panto et al. (1990)

Linomide

RD (63)

12

Decreased HbA1c and insulin dose. No difference in glucagon-stimulated C-peptide

Coutant et al. (1998)

HSP60 p277 peptide (DiaPep)

RD (35)

10

Decrease in glucagon-stimulated C-peptide and insulin dose in placebo but not treated group

Raz et al. (2001)

HSP60 p277 peptide (DiaPep)

RD (48 and 99)

18

No effect on C-peptide response to a mixed meal or on insulin requirement

Schloot et al. (2007)

IL-2 1 rapamycin

Nonspecific immune stimulation

Nonspecific immune regulation

(Continued)

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70. PREVENTION OF TYPE 1 DIABETES

(Continued) Participants (n)

Followup (months) Outcome

Reference

1,25-dihydroxy vitamin D3

RD (20)

18

No effect on C-peptide response to a mixed meal or insulin requirement

Walter et al. (2010)

HSP60 p277 peptide (DiaPep)

RD (146)

12

No effect on C-peptide response to a mixed meal

Buzzetti et al. (2011)

Antithymocyte globulin (6.5 mg/kg)

RD (58)

24

No effect on C-peptide response to a mixed meal

Gitelman et al. (2016) and Gitelman et al. (2013)

Antithymocyte globulin (2.5 mg/kg) 1 g-CSF (6 mg fortnightly for 6 doses)

RD (25)

24

Borderline (P 5 .05) improvement in Cpeptide response to a mixed meal at 12 but not 24 months

Haller et al. (2016) and Haller et al. (2015)

Antithymocyte globulin (ATG; 2.5 mg/kg) 6 G-CSF (6 mg fortnightly for 6 doses)

RD (89)

12

Increase in C-peptide response to a mixed meal and decrease in HbA1c; addition of GCSF did not enhance effects

Haller et al. (2018)

Rapamycin 6 vildagliptin

RD (60)

3

Ongoing

NCT02803892

RD (60)

24

Ongoing

NCT03182426

Parenteral insulin (i.v. vs. s.c. 2 weeks)

RD (26)

12

Increased meal-stimulated C-peptide, decreased HbA1c

Shah et al. (1989)

Parenteral (s.c.) insulin

RD (49)

60

Increased glucagon-stimulated C-peptide and improved insulin sensitivity and glycemic control

Linn et al. (1996)

Parenteral (s.c.) insulin and sulfonylurea (glipizide)

RD (27)

12

Increased basal and glucagon-stimulated Cpeptide, more remissions

Selam et al. (1993)

Parenteral (s.c.) insulin

RD (10)

Increased C-peptide response to oral glucose, HbA1c unchanged

Kobayashi et al. (1996)

Parenteral insulin (i.v. vs s.c. 2 weeks)

RD (19)

12

Increased meal and glucagon-stimulated Cpeptide and decreased HbA1c

Schnell et al. (1997)

Parenteral (s.c.) insulin

AR (14)

84

Delay in onset of diabetes. No effect on islet antibody levels

Fu¨chtenbusch et al. (1998)

Oral insulin

RD (80)

12

No effect on basal C-peptide, HbA1c, insulin dose, or insulin antibodies

Pozzilli et al. (2000)

Oral insulin

RD (131)

12

No effect on basal, glucagon-or mealChaillous et al. (2000) stimulated C-peptide, HbA1c, insulin dose, or islet antibody levels

AR (7)

24

No effect on islet antibody levels

Hummel et al. (2002)

Parenteral (s.c.) insulin (DPT-1)

AR (339)

44

No effect on diabetes development

Diabetes Prevention Trial-Type 1 Diabetes Study Group (2002)

Intranasal insulin (Melbourne INIT I)

AR (38)

48

Increased antibody and decreased T-cell responses to insulin

Harrison et al. (2004)

Oral insulin (DPT-1)

AR (372)

52

No effect on diabetes development overall. Post hoc analysis revealed .4-year delay in diabetes onset in participants with insulin autoantibodies

Skyler et al. (2005)

1

CD34 stem cell mobilization with plerixafor (anti-CXCR4, CXCR7 agonist), alemtuzumab (anti-CD52), anakinra (anti-IL-1), etanercept (anti-TNF), liraglutide Antigen-specific immune regulation

Gluten elimination

(Continued)

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TABLE 70.3

(Continued) Participants (n)

Followup (months) Outcome

Reference

Parenteral (s.c.) GAD65-alum

RD (47)

6

Increase in fasting and stimulated plasma Cpeptide with intermediate dose of 20 μg

Agardh et al. (2005)

Intranasal insulin (DIPP)

AR (224)

21

No effect to delay progression to diabetes

Nanto-Salonen et al. (2008)

Parenteral (s.c.) GAD65-alum

RD (70)

30

Delay in loss of C-peptide secretion, in those treated within 6 months of clinical diagnosis

Ludvigsson et al. (2008)

Parenteral (s.c.) insulin B chain 9 23 “altered RD (188) peptide ligand” NBI-6024-0101 (Neurocrine)

25

No effect on C-peptide response to mixed meal

Walter et al. (2009)

Parenteral (s.c.) insulin B chain in incomplete Freund’s adjuvant

RD (12)

24

No effect on C-peptide response to mixed meal. Development of sustained insulinspecific antibody and T-cell responses

Orban et al. (2010)

Intranasal insulin (INIT III)

RD (52)

24

No effect on metabolic parameters. Fourlanos et al. Suppression of T-cell responses to insulin and (2011) antibody responses to subcutaneous insulin

Parenteral (s.c.) GAD65-alum

RD (334)

15

No effect on metabolic parameters

Ludvigsson et al. (2012)

Parenteral (s.c.) GAD65-alum

RD (145)

12

No effect on C-peptide response to mixed meal

Wherrett et al. (2011)

Parenteral (i.m.) proinsulin plasmid DNA

RD (80)

12

Transient improvement in C-peptide response Roep et al. (2013) to mixed meal concomitant with a decrease in the CD8 T-cell response to proinsulin

Oral insulin (TrialNet Study TN07)

AR (560)

72 96

No effect of oral insulin overall, but significant delay in T1D in participants with islet cell antibody and FPIR , 60 μU/mL

Krischer et al. (2017)

Intralymphatic GAD65-alum 1 oral vitamin D RD (6)

15

Stable C-peptide response to mixed meal and decreased HbA1c and insulin dose when compared to historical control group

Ludvigsson et al. (2017)

Intranasal insulin (INIT II)

AR (110)

$ 60

Nasal insulin dose-related insulin antibody response, then suppressed consistent with tolerance induction, but no effect on diabetes incidence

Harrison et al. (2018)

Gluten-free diet

AR (60)

24

Ongoing

NCT02605148

Parenteral (s.c.) GAD65-alum

AR (50)

60

Ongoing

NCT02387164

Nicotinamide

RD (20)

12

Increased glucagon-stimulated C-peptide at 45 days, then decline. No difference in remissions

Mendola et al. (1989)

Nicotinamide

RD (23)

9

Increased basal and glucagon-stimulated Cpeptide

Vague et al. (1989)

Nicotinamide

RD (35)

12

No difference in basal or glucagon-stimulated Chase et al. (1990b) C-peptide

Nicotinamide 6 cyclosporine

RD (90)

12

Decreased insulin dose. No difference in remissions

Pozzilli et al. (1994)

Nicotinamide

RD (56)

12

Increased glucagon-stimulated C-peptide in subjects .15 years old

Pozzilli et al. (1995)

Nicotinamide versus vitamin E (no control group)

RD (84)

12

No difference in basal or glucagon-stimulated Pozzilli et al. (1997) C-peptide, HbA1c, or insulin dose

β-Cell protection

(Continued)

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70. PREVENTION OF TYPE 1 DIABETES

(Continued) Participants (n)

Followup (months) Outcome

Nicotinamide (DENIS)

AR (55)

36

Nicotinamide (ENDIT)

AR (552)

Octreotide

RD (20)

Diazoxide

Reference

No effect on diabetes development

Lampeter et al. (1998a,b)

No effect on diabetes development

Philips et al. (2002)

12

Increased glucagon-stimulated C-peptide at 6 and 12 months; no difference in HbA1c or insulin dose

Grunt et al. (1994)

RD adults (40)

18

Increased basal C-peptide

Bjork et al. (1996)

Nicotinamide 6 parenteral insulin

RD (34)

12

No difference in glucagon-stimulated Cpeptide

Vidal et al. (2000)

Diazoxide

RD children (56)

Increased stimulated C-peptide at 12, not 24, months

Bjork et al. (2001)

Oral antioxidants

RD (46)

30

No difference in meal-stimulated C-peptide, insulin dose or HbA1c

Ludvigsson et al. (2001)

Lansoprazole and sitagliptin

RD (68)

12

No difference in meal-stimulated C-peptide, insulin dose or HbA1c

Griffin et al. (2014)

Liraglutide

AR (42)

12

Ongoing

NCT02611232

Liraglutide

AR (82)

12

Ongoing

NCT02898506

Liraglutide

RD (10)

12

Ongoing

NCT02908087

Albiglutide

RD (67)

12

Ongoing

NCT02284009

Metformin

AR (90)

21

Ongoing

NCT02881528

Imatinib

RD (67)

12

Improved meal-stimulated C-peptide at 12 months

NCT01781975

Hydroxychloroquine

AR (205)

60

Ongoing

NCT03428945

Mechanism uncertain

AR, Islet autoantibody-positive first-degree relative; DENIS, Deutsche Nicotinamide Intervention Study; DIPP, Diabetes Prediction and Prevention Project; DPT-1, Diabetes Prevention Trial Type 1; ENDIT, European Nicotinamide Diabetes Intervention Trial; FDR, first-degree relative; FPIR, first phase insulin response to i.v. glucose; GAD, glutamic acid decarboxylase; IDDM, insulin-dependent diabetes mellitus; INIT, Intranasal Insulin Trial; mAb, monoclonal antibody; RD, person with recently diagnosed diabetes. T1D, type 1 diabetes. Participant numbers are shown in parentheses.

primary and secondary trials is (the absence of) clinical diabetes, in tertiary trials the retention, or increase of residual beta-cell function. Trials of tertiary prevention with more than 70 different agents since the early 1980s (Table 70.3) have failed to demonstrate sustained preservation of residual beta-cell function, although several biologic agents, anti-CD20 (rituximab) and anti-CD3 monoclonal antibodies, anti-thymocyte globulin (ATG) and CTLA-4-Ig (abatacept), slowed the decline of beta-cell function for at least 1 2 years after diagnosis providing hope that earlier intervention might prevent or delay progression to clinical disease. Published randomized primary, secondary, and tertiary trials are summarized in Table 70.4; recent, ongoing trials are registered on ClinicalTrials.gov. In the following we will adhere to the strict definition of prevention and discuss only approaches to prevent clinical T1D.

PRIMARY PREVENTION Evidence for an etiological role of environment in T1D is persuasive and primary prevention could be targeted at environmental factors thought to initiate or promote islet autoimmunity. In countries with a high prevalence of T1D, neonatal screening for the highest risk HLA class II genes can identify over half the children destined to develop T1D (Kimpima¨ki et al., 2001). However, the modest predictive value of genetic testing would justify a primary intervention only if it was safe.

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TABLE 70.4 Comparison of Human Type 1 Diabetes With the NOD Mouse Model Feature

Human

NOD mouse

Preclinical stage

Yes

Yes

Gender

M . F after puberty

F.M

MHC class II aa57 non-Asp

Yes (HLA DQ8)

Yes (I-Ag7)

Polygenic non-MHC

Yes

Yes

Environmental influence on gene penetrance

Yes

Yes

Disease transmission via bone marrow

Yes

Yes

Mononuclear cell infiltration of islets (insulitis)

Moderate

Marked

Other organs

Sometimes

Yes

Impaired immune regulation

Yes

Yes

(Pro)insulin

Yes

Yes

GAD

Yes

Yes

Clinical response to autoantigen-specific therapy

Not yet shown

Yes

Genetic susceptibility

Autoantigens

GAD, Glutamic acid decarboxylase; MHC, major histocompatibility complex.

Diet and Gut Microbiome Modification In the 1980s it was proposed that early exposure of the infant to cow’s milk and/or the lack of breastfeeding predisposed to T1D. Two metaanalyses of multiple studies in which T1D prevalence was associated retrospectively with infant feeding revealed only a marginal increase in relative risk (Gerstein, 1994; Norris and Scott, 1996). In the Denver-based Diabetes Autoimmunity Study in the Young, infant feeding patterns retrospectively analyzed up to 6 months of age were not related to the development of islet autoantibodies up to 7 years of age (Norris et al., 1996). Furthermore, in the Australian BabyDiab Study (Couper et al., 1999) and the German BabyDiab Study (Hummel et al., 2000), no association was found between infant feeding patterns and the development of islet autoantibodies. Nevertheless, to answer whether cow’s milk exposure is a risk, the multicountry Trial to Reduce IDDM in the Genetically At-Risk was initiated. Newborns with a T1D first-degree relative and HLA risk alleles, initially exclusively breast-fed, were randomized to either a casein hydrolysate formula (Neutramigen) comprising milk proteins of reduced complexity or a conventional cow’s milk-based formula until 6 8 months of age and were followed for 10 years. This approach was based on protection from diabetes in NOD mice fed a hydrolyzed casein diet (Lefebvre et al., 2006). Initially, in a preliminary analysis, hydrolyzed casein-based formula was claimed to reduce the rate of islet autoantibody seroconversion (Knip et al., 2010), implying it protected against T1D. However, in the final study report (Knip et al., 2018), this dietary modification was not associated with any change in the incidence of islet autoantibodies or diabetes. Human milk has many components and properties beneficial to the developing infant, including nondigestable human milk oligosaccharides that have a prebiotic effect to promote antiinflammatory Bifidobacteria in the colon (O’Callaghan and van Sinderen, 2016). Breast milk also contains endogenous insulin (Shehadeh et al., 2001), which might induce “oral tolerance” to insulin and so protect against the development of T1D (discussed below). Thus, rather than cow’s milk promoting T1D, human milk may be protective through a variety of mechanisms. As discussed, the gut microbiome differs in composition, diversity, and function between children at risk for T1D and case controls. Microbiome “dysbiosis” may be partly reversible by “un-westernizing” the modern diet to increase the amount and diversity of natural, unprocessed food types known to promote an “antiinflammatory” gut microbiome. This could be boosted by supplementation with prebiotics as demonstrated with butyrate/acetate in the NOD mouse (Marin˜o et al., 2017) and with bespoke probiotics based on knowledge of microbiota known to be deficient in children at risk for T1D. Scientific studies of these approaches are on the drawing board.

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Dietary gluten has also been implicated as an environmental trigger of T1D. Antibodies to wheat gluten proteins are found in a proportion of T1D patients at the time of diagnosis (MacFarlane et al., 2002) and coeliac disease and T1D share the HLA risk haplotype A1-B8-DR3-DQ2 and often coexist. In addition, in individuals with coeliac disease the prevalence of autoimmune diseases including T1D was reported to correlate with duration of exposure to gluten (Ventura et al., 1999). However, the German BABYDIET Study found that delaying the introduction of gluten beyond 12 months of age had no effect on the cumulative incidence of islet autoantibodies or clinical T1D (Hummel et al., 2002). At the population level, compelling evidence links vitamin D deficiency to T1D and other autoimmune diseases. Vitamin D is derived primarily from ultraviolet B light-induced synthesis in the skin and its deficiency is increasingly recognized, not just in populations living furthest from the equator but in people anywhere who avoid sunlight, work and play mainly indoors, are dark-skinned, and living in temperate climes or cover their skin for cultural or religious reasons. The recommended daily allowance of vitamin D has decreased over the past 50 years from 5000 to 400 IU (Hypponen et al., 2001). This is the minimum dose required to prevent rickets following adequate prenatal intake but is inadequate for the physiological immune modulating and antiinflammatory actions of vitamin D (Holick, 2004). Three European studies demonstrated an inverse relationship between vitamin D intake and the incidence of T1D. In a birth cohort study from Northern Finland, an area with only 1900 hours direct sunlight annually and the highest incidence of T1D in the world, T1D status was related to prerecorded data on infants 7 24 months of age given vitamin D in doses below, above, or at the then recommended 2000 IU daily (Hypponen et al., 2001, p. 170). The 2000 IU dose was associated with a low relative risk of 0.12 (95% CI 0.03 0.47). In a multinational European case control study, the odds ratio for T1D was significantly reduced in children given vitamin D (EURODIAB Substudy 2 Study Group, 1999). The risk for T1D in Norwegian children was significantly lower if their mothers had taken cod liver oil (a source of vitamin D) during pregnancy (Stene et al., 2000). Randomized controlled trials of vitamin D supplementation are required in individuals genetically at-risk for T1D but are unlikely to ever be undertaken given the general public awareness of vitamin D deficiency and the widespread availability of vitamin D.

Virus Vaccination As discussed, if a virus or viruses are shown to initiate or promote islet autoimmunity, vaccination would be the means of primary prevention. Enteroviruses and rotavirus remain candidates. However, even though rubella and mumps viruses were implicated vaccination did not alter the incidence of T1D, which either questions the original evidence or indicates that multiple environmental agents in addition to viruses contribute to the etiology of T1D.

Antigen-Specific Immunotherapy This approach employs islet antigens as tools to induce therapeutic immune tolerance, based on extensive proof-of-concept studies in the NOD mouse. Shown to be safe but not yet efficacious for secondary prevention, it is likely to have greater potential in the context of primary prevention, as discussed below.

SECONDARY PREVENTION Secondary prevention has focused on first-degree relatives of a T1D proband, who have autoantibodies against one or more islet antigens. A prerequisite for intervention in asymptomatic individuals is a high likelihood of developing clinical disease. Prediction is determined by measuring autoantibody and metabolic markers of T1D (Table 70.1). In young first-degree relatives, the 5-year risk of diabetes is of the order ,25%, 25% 50%, and .50% if autoantibodies are present to 1, 2, and 3 islet antigens, respectively. For single specificities, autoantibodies to insulin (IAA) are the most predictive. A measure of insulin secretion, first-phase insulin response (FPIR) to intravenous glucose, further refines risk prediction. In addition, in autoantibody-positive relatives with normal FPIR, the highest risk was shown to be independently associated with insulin resistance (Fourlanos et al., 2004). Importantly, stratification of autoantibody-positive individuals based on insulin resistance to better identify “progressors” could improve trial design and power. While detection of autoantibodies is fundamental to preclinical diagnosis and disease prediction, about 10% of new-onset T1D patients of European descent have no detectable antibodies. Moreover, while first-degree relatives who share susceptibility genes and environmental risk factors have at least a 10-fold higher prevalence of T1D

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than the background population, they represent no more than 15% of people diagnosed with T1D. Identifying the other 85% using available predictive tests is more challenging because the lower prevalence of disease in the general population may in turn lower the predictive value of screening tests compared to relatives (Bayes’ theorem). Emerging studies to screen young children in the general population for islet autoantibodies (Ziegler et al., 2016) are based on the fact that preclinical diagnosis averts the classic clinical presentation of life-threatening ketoacidosis (Winkler et al., 2012). The predictive value of islet autoantibodies in the general population has not been widely investigated but will be important if effective means of secondary prevention are found. The ideal prevention strategy in autoimmune disease is autoantigen-based immunotherapy, in which an autoantigen is administered to induce protective immune tolerance; this has been called “negative vaccination” (Harrison, 2008). The rationale is that autoantigen-driven immunoregulatory mechanisms are physiological and can be boosted or restored to prevent pathological autoimmunity. Approaches include administration of an autoantigen by a “tolerogenic” route (e.g., mucosal), cell type (e.g., resting dendritic cell), mode (e.g., with blockade of costimulation molecules) or form (e.g., as an “altered peptide ligand”), all of which have been shown to prevent or suppress experimental autoimmune diseases in rodents (Faria and Weiner, 1999; Harrison and Hafler, 2000; Krause et al., 2000). Mechanisms encompass deletion and/or induction of anergy in potentially pathogenic effector T or induction of regulatory T cells (Tregs) (iTregs). Autoreactive T cells that are activated strongly by antigen may undergo apoptotic cell death and deletion, while those that survive or respond “partially” may become anergic (von Herrath and Harrison, 2003). Of potential importance clinically is the ability of iTreg generated to specific antigen to exert antigen-nonspecific “bystander suppression.” Thus, in response to specific antigen iTreg can, by direct cell contact or release of soluble immunosuppressive factors, impair the ability of antigen-presenting dendritic cells to elicit effector T-cell responses to any antigen locally at the site of the lesion or in the draining lymph nodes. Bystander suppression does not require that the autoantigen used to induce tolerance is necessarily the major or primary pathogenic autoantigen.

Mucosa-Mediated Antigen-Specific Tolerance The mucosal immune system shaped by the microbiome actively generates physiological immune tolerance. Most attempts to induce clinical autoantigen-specific tolerance have been mucosa-based. Numerous studies have shown that NOD mice can be partially protected from diabetes by mucosal administration of islet autoantigens. A large body of evidence indicates that (pro)insulin is a key target antigen driving beta-cell destruction but, paradoxically, can be used as an immunotherapeutic tool (Narendran et al., 2003). Zhang et al. (1991) initially reported protection after oral porcine insulin. Bergerot et al. (1994) then showed that human insulin induced CD4 Tregs that transferred protection to naı¨ve mice. Protection following oral insulin was found to be associated with decreased expression of IFN-γ-secreting Th1 T cells in the pancreas and pancreatic lymph nodes (Hancock et al., 1995; Ploix et al., 1998). Oral insulin-induced CD4 Treg have also been shown to prevent immune-mediated diabetes induced by lymphocytic choriomeningitis virus (LCMV) infection of mice expressing the viral nucleoprotein of LCMV under control of the rat insulin promoter in their β cells (Homann et al., 1999). The majority of T cells in the islets of oral insulin-treated mice without diabetes were shown to secrete Th2 (IL-4, IL-10) and Th3 (TGF-β) cytokines, in contrast to IFN-γ-secreting Th1 cells in islets of mice that developed diabetes. The protective effect of oral insulin was enhanced by simultaneous feeding with IL-10 (Slavin et al., 2001), bacterial component OM-89 (Bellmann et al., 1997; Hartmann et al., 1997), or Schistosome egg antigen (Maron et al., 1998), all of which promote Th2 responses. Fusion of insulin to cholera toxin B-subunit (CTB) significantly improved the ability of oral insulin to prevent diabetes (Bergerot et al., 1997). Oral CTB insulin conjugates in NOD mice induced a shift from a Th1 to a Th2 immunity associated with the induction of regulatory CD4 T cells (Ploix et al., 1999). NOD mice were protected from diabetes by feeding potatoes that transgenically expressed CTB insulin conjugates (Arakawa et al., 1998). Oral GAD65 has also been reported to suppress diabetes development in NOD mice (Ma et al., 1997). Although it is generally believed that neonates are less susceptible to mucosal tolerance induction, oral administration of insulin, insulin B-chain, or GAD65 peptide during the neonatal period suppressed diabetes development in NOD mice (Maron et al., 2001). This suggests that mucosal administration of islet autoantigen in milk could be used to treat very young infants at risk of developing T1D. NOD mice are also protected from diabetes by naso-respiratory administration of islet autoantigens. This route of administration to the mucosa is direct avoids antigen degradation in the stomach. When insulin was administered as an aerosol to NOD mice at 8 weeks of age, after the onset of subclinical disease, insulitis, and diabetes incidence were both significantly reduced (Harrison et al., 1996). Aerosol insulin-induced novel antidiabetic CD8

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γδ T cells that suppressed the adoptive transfer of diabetes to nondiabetic mice by T cells from diabetic mice. The type of Treg induced by (pro)insulin depends on the route and form of antigen. Naso-respiratory insulin, which remains nondegraded and conformationally intact, induces CD8 γδ Treg. On the other hand, oral insulin which is degraded to peptides, or intranasal or oral (pro)insulin peptides, induce CD4 Treg (Ha¨nninen and Harrison, 2000; Martinez et al., 2003). Intranasal administration of the insulin B chain peptide (aa9-23), an epitope recognized by islet-infiltrating CD4 T-cell clones that adoptively transfer diabetes to naı¨ve mice, induce CD4 Treg that protect NOD mice from diabetes (Daniel and Wegmann, 1996). A peptide spanning the B C chain junction in proinsulin also induced CD4 Treg after intranasal administration (Martinez et al., 2003). This peptide, such as insulin B9-23, binds to the NOD mouse class II major histocompatibility complex, I-Ag7 (Harrison et al., 1997), and is a T-cell epitope in NOD mice (Chen et al., 2001) and humans at risk for T1D (Rudy et al., 1995). T-cell epitope peptides from GAD65 administered intranasally are also protective and associated with the induction of regulatory CD4 Treg and with reduced IFN-γ responses to GAD65 (Tian et al., 1996). These “proof-of-principle” studies in the NOD mouse indicate that islet autoantigen proteins or peptides are candidate mucosal “vaccines” for prevention of T1D in humans.

Trials of Islet Autoantigen-Specific Vaccination in Humans The large multicenter Diabetes Prevention Trial (DPT)-1 was launched in the United States in 1994 to determine whether antigen-specific therapy with either systemic or oral insulin would delay or prevent diabetes onset in asymptomatic first-degree relatives with islet autoantibodies. Previously, intensive systemic insulin therapy had been reported to prolong the “honeymoon phase” after diagnosis (Shah et al., 1989) and a pilot study of prophylactic systemic insulin had suggested that this approach might be of benefit in at-risk relatives (Keller et al., 1993). Whether systemic insulin would act only as a hormone to control blood glucose and “rest” β cells (making them less sensitive to immune attack) or also as an antigen to induce immune tolerance was not clear, and read-outs to identify immune mechanisms were not employed. In DPT-1, low-dose systemic insulin (annual intravenous insulin infusions and daily subcutaneous injections) was given to high-risk relatives ( . 50% risk of diabetes over 5 years), matched with an untreated but closely monitored control group, but it had no effect on diabetes incidence (Diabetes Prevention Trial-Type 1 Diabetes Study Group, 2002). In the subsequent randomized controlled DPT-1 trial of oral insulin, islet autoantibody-positive relatives with a 25% 50% 5-year risk of diabetes were given 7.5 mg human insulin or placebo daily for a median of 4.3 years. There was no effect overall, but post hoc hypothesis testing revealed a significant delay of approximately 4 years in diabetes onset in participants who were unequivocally positive for insulin autoantibodies at entry (Skyler et al., 2005) (Fig. 70.2). That oral insulin only benefited participants with insulin autoimmunity suggests that allelism at the insulin gene susceptibility locus (IDDM2) can shape not only the immune response to endogenous insulin as a target autoantigen but to oral insulin as a potential therapeutic tool. To attempt to confirm the post hoc DPT-1 findings,

Proportion diabetes-free

1.0 Oral insulin (n = 63)

0.8

0.6

Placebo (n = 69)

Log-rank P = 0.01 0.4

Hazard ratio 0.41

0.2

0.0 0

1

2

3 Years

4

5

6

FIGURE 70.2 Oral insulin vaccination delays development of diabetes in at-risk T1D relatives. T1D, type 1 diabetes.

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a follow-up international trial of 7.5 mg/d oral insulin was performed by TrialNet between 2007 and 2016. More than 100,000 relatives were screened, of whom 560 met the inclusion criteria, which included the presence of IAA and one or more of GADA, IA-2A, or ICA as measured traditionally by immunofluorescence on pancreas tissue sections. Participants were stratified according to FPIR and presence or absence of ICA. The primary stratum, comprising 389 individuals with ICA and FPIR above threshold, most faithfully represented the post hoc DPT-1 population. The rate of progression to diabetes was highly similar between the placebo groups of the DPT-1 and TrialNet studies. However, oral insulin did not prevent diabetes in the TrialNet primary stratum. Unexpectedly, in the secondary stratum of 55 participants with ICA and low FPIR, oral insulin delayed progression to diabetes by about 2 years. This finding suggests, counterintuitively, that oral insulin might be more effective late rather than early in preclinical T1D. However, given the relatively low number of secondary stratum participants, confirmation of this finding by a dedicated trial will be necessary. Ideally, the TrialNet oral insulin study would have incorporated a higher insulin dose because on a body weight basis the 7.5 mg dose equates to only a few micrograms in the mouse, and milligrams of gavaged insulin were required to induce antidiabetogenic CD4 Treg in NOD mice. Two trials of oral insulin (up to 7.5 mg daily for 12 months) in recently diagnosed patients, attempting tertiary prevention, showed no protective effect on residual beta-cell function (Chaillous et al., 2000; Pozzilli et al., 2000). Why have trials of oral insulin in T1D, as well as oral myelin basic protein in multiple sclerosis (Weiner et al., 1993) and oral collagen in rheumatoid arthritis (McKown et al., 1999; Trentham et al., 1993) failed to show clinical effects? The answer is probably a combination of reasons: relative ineffectiveness of iTreg against effector T cells in established disease; inadequate dose or bioavailability; coinduction of pathogenic T cells; genetic heterogeneity. Antigen-specific tolerance on its own is clinically ineffective in end-stage disease. If a balance between pathogenic and protective T cells determines clinical outcome then antigen-specific tolerance should be most effective in preventing the onset of disease, not after. The question of dose is discussed below but may be related to route of administration. Oral administration may not be optimal for mucosa-mediated tolerance because proteins are degraded after ingestion and the concentration or form of peptide reaching the upper small intestine may be insufficient to induce mucosa-mediated tolerance. Even with a small peptide, mucosal responses occurred after naso-respiratory but not oral administration (Metzler and Wraith, 1993). In the mouse, nasal administration of the model antigen, ovalbumin, elicited antigen-specific T-cell responses in cervical, mediastinal, and mesenteric mucosal lymph nodes, whereas oral administration elicited responses only in the mesenteric nodes (Ha¨nninen et al., 2001). Irrespective of route of administration, antigen presentation in the mucosa may be a “double-edged” sword simultaneously inducing both iTreg and pathogenic cytotoxic CD81 T cells so that a clinical effect is not seen without suppression of the latter, for example, by costimulation blockade with antiCD40 ligand antibody (Ha¨nninen et al., 2002). Insulin contains potentially pathogenic cytotoxic T-cell epitopes but whether mucosal insulin induces cytotoxic CD81 T cells as well as protective Treg is unknown. In the NOD mouse, a proinsulin B-C chain peptide, a “combitope” of CD41 (I-Ag7-restricted) and CD81 (Kd-restricted) T-cell epitopes that induced CD41 Treg, was significantly more protective after nasal administration when the C-terminal p9 anchor residue for binding to Kd was deleted or mutated (Martinez et al., 2003). This indicates that the nature of T-cell epitopes is critical in mucosa-based immunotherapy. None of the oral autoantigen trials sought evidence for an immune effect. There is a pressing need to evaluate immune responses to mucosal autoantigens in human trials; otherwise, it is not possible to know if an antigen dose is bioactive/available. Induction of insulin antibodies was a marker of bioavailability after aerosol insulin in NOD mice (Harrison et al., 1996) or intranasal insulin in humans (Harrison et al., 2004, 2018; Fourlanos et al., 2011). Irrespective of whether or not they are a marker of immunoprotection, induction of insulin antibodies demonstrates the insulin dose was bioactive. Insulin autoantibodies are a risk marker for T1D and an increase in insulin antibodies after naso-respiratory insulin seems counterintuitive. However, in both the NOD mouse and humans at risk for T1D naso-respiratory insulin, although associated with an increase in insulin antibodies, was also associated with a decrease in T-cell responses to insulin. These findings are entirely consistent with the earliest descriptions of mucosal tolerance and with later landmark studies in humans using keyhole limpet hemocyanin (KLH) as a model antigen. When KLH was administered nasally to human volunteers, it elicited a modest antibody response, but after challenge with subcutaneous KLH both antibody and T-cell responses decreased (Waldo et al., 1994). In a recent randomized trial of nasal insulin in people with recent-onset T1D who did not initially require insulin treatment, those who received nasal insulin had blunted insulin antibody responses to subsequent subcutaneous insulin (Fourlanos et al., 2011) (Fig. 70.3). It will be important to determine if nasal insulin induces insulin-specific Treg and to demonstrate that like nasal KLH nasal insulin suppresses T-cell responses to rechallenge indicative of T-cell tolerance.

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30

Insulin antibody (mU/I)

25 Placebo (n = 12)

20 15 p = 0.039 10

Insulin (n = 13)

5 0 0

3

6

9

12

15

18

21

24

Months

Treatment period

FIGURE 70.3 Nasal insulin vaccination suppresses insulin antibody response to subcutaneous insulin.

The evidence for nasal insulin-induced immune tolerance in humans (Fourlanos et al., 2011) cannot necessarily be extrapolated to endogenous “autoantigenic” insulin but provides a mechanistic rationale for randomized trials of nasal insulin vaccination in individuals at-risk for T1D. Two such trials have been performed with progression to clinical diabetes as the primary outcome. In the T1D Prediction and Prevention Project (DIPP) trial in Finland (Nanto-Salonen et al., 2008), nasal insulin (1 U/kg daily) had no effect on progression to diabetes in islet autoantibody-positive children less than 3 years of age. These children were a very high-risk group and many appear to have had borderline beta-cell function judged by low FPIR to i.v. glucose. In the Australian Type 1 DPT, also known as the Intranasal Insulin Trial II (INIT II) (Harrison et al., 2018) nasal insulin at two doses (40 and 440 U) or nasal placebo was administered daily for 7 days and then weekly for a year, with a further 4 years follow-up, in T1D relatives aged 4 30 with autoantibodies to at least two islet antigens (B40% risk of diabetes over 5 years). The insulin dose in INIT II was substantially higher than in the DIPP trial and the participants were older and had less advanced preclinical disease. Again, nasal insulin induced a significant dose-dependent increase in serum insulin antibody concentration, which peaked after several months then dropped to pretreatment concentrations within the treatment year, consistent with immune tolerance to exogenous insulin. However, this bioeffect did not translate into protection against diabetes and, while unexplained, the rate of diabetes development in the placebo group was substantially lower than expected. As reasoned above, antigen-specific vaccination is most likely to be effective before the onset of the disease process and trials of mucosal insulin in islet autoantibody-negative genetically at-risk children are underway (Bonifacio et al., 2015). Based on evidence in the NOD mouse that the incidence of diabetes was lowered by systemic GAD65 (Petersen et al., 1994; Tisch et al., 2001) or nasal GAD65 peptides (Tian et al., 1996), the Swedish company, Diamyd P/L, produced recombinant GAD65, and initiated trials of a subcutaneous GAD65-alum (aluminum hydroxide) vaccine (summarized in Table 70.4). Although the initial trials were encouraging, subsequent larger trials failed to substantiate a clinical effect of the vaccine. Again, it is not surprising that the GAD-alum vaccine had no effect after the onset of clinical diabetes. However, these trials appear to have established the safety of the vaccine and, based on GAD65 antibody responses, its bioactivity, thereby justifying an ongoing secondary prevention trial (DIAPREV-IT) of the vaccine in islet autoantibody-positive at-risk children.

EPILOGUE T1D prevention trials have taught us that treatment should begin as early as possible in the preclinical stage that “magic bullet” monotherapy is unlikely to be successful and that trials would greatly benefit from mechanistic response markers, especially islet autoantigen-reactive T cells, and noninvasive means of evaluating islet pathology and beta-cell function. Progress in preventing T1D is likely to be incremental, analogous to the evolution of combination treatment regimens for cancer or HIV infection, but more constrained by regulatory

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considerations and the relatively slow rate of disease progression. Environmental agents that precipitate or exacerbate autoimmune disease are likely to be ubiquitous and therefore a single strategy, for example, vaccination against a specific virus, is unlikely to be the answer. A prerequisite is the identification of at-risk individuals in early life, for which T1D is a paradigm. Prevention strategies must be safe as well as effective. In this regard, autoantigen-specific vaccination as applied in the oral and nasal insulin trials in T1D provide a glimmer of promise. Lessons learnt from the preclinical diagnosis, prediction, and prevention of T1D should be applicable to other autoimmune diseases.

Acknowledgments This work was supported by the National Health and Medical Research Council of Australia [Program Grant 1037321 and Fellowship 1080887 (LCH)] and made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIIS.

References Adorini, L., Gregori, S., Harrison, L.C., 2002. Understanding autoimmune diabetes: insights from mouse models. Trends Mol. Med. 8, 31 38. Agardh, C.D., Cilio, C.M., Lethagen, A., Lynch, K., Leslie, R.D., Palmer, M., et al., 2005. Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J. Diabetes Complications 19, 238 246. Allen, H.F., Klingensmith, G.J., Jensen, P., Simoes, E., Hayward, A., Chase, H.P., 1999. Effect of bacillus Calmette Guerin vaccination on newonset type 1 diabetes. A randomized clinical study. Diabetes Care 22, 1703 1707. Arakawa, T., Yu, J., Chong, D.K., Hough, J., Engen, P.C., Langridge, W.H., 1998. A plant-based cholera toxin B subunit-insulin fusion protein protects against the development of autoimmune diabetes. Nat. Biotechnol. 16, 934 938. Assan, R., Feutren, G., Sirmai, J., Laborie, C., Boitard, C., Vexiau, P., et al., 1990. Plasma C-peptide levels and clinical remissions in recentonset type I diabetic patients treated with cyclosporin A and insulin. Diabetes 39, 768 774. Bellmann, K., Kolb, H., Hartmann, B., Rothe, H., Rowsell, P., Rastegar, S., et al., 1997. Intervention in autoimmune diabetes by targeting the gut immune system. Int. J. Immunopharmacol. 19, 573 577. Bergerot, I., Fabien, N., Maguer, V., Thivolet, C., 1994. Oral administration of human insulin to NOD mice generates CD4 1 T cells that suppress adoptive transfer of diabetes. J. Autoimmun. 7, 655 663. Bergerot, I., Ploix, C., Petersen, J., Moulin, V., Rask, C., Fabien, N., et al., 1997. A cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes. Proc. Natl. Acad. Sci. U.S.A. 94, 4610 4614. Bingley, P.J., Williams, A.J., Gale, E.A., 1999. Optimized autoantibody-based risk assessment in family members. Implications for future intervention trials. Diabetes Care 22, 1796 1801. Bjork, E., Berne, C., Kampe, O., Wibell, L., Oskarsson, P., Karlsson, F.A., 1996. Diazoxide treatment at onset preserves residual insulin secretion in adults with autoimmune diabetes. Diabetes 45, 1427 1430. Bjork, E., Ortquist, E., Wallensteen, M., Ludvigsson, J., Aman, J., Johansson, C., et al., 2001. Diazoxide treatment at onset in childhood type 1 diabetes. Diabetes 50, A90. Bonifacio, E., Ziegler, A.G., Klingensmith, G., Schober, E., Bingley, P.J., Rottenkolber, M., et al., 2015. Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA 313, 1541 1549. Bosi, E., Molteni, L., Radaelli, M.G., Folini, L., Fermo, I., Bazzigaluppi, E., et al., 2006. Increased intestinal permeability precedes clinical onset of type 1 diabetes. Diabetologia 49, 2824 2827. Buckingham, B.A., Sandborg, C.I., 2000. A randomized trial of methotrexate in newly diagnosed patients with type 1 diabetes mellitus. Clin. Immunol. 96, 86 90. Buzzetti, R., Cernea, S., Petrone, A., Capizzi, M., Spoletini, M., Zampetti, S., et al., 2011. C-peptide response and HLA genotypes in subjects with recent-onset type 1 diabetes after immunotherapy with DiaPep277: an exploratory study. Diabetes 60, 3067 3072. Canadian European Randomized Control Trial Group, 1988. Cyclosporin-induced remission of IDDM after early intervention. Association of 1 yr of cyclosporin treatment with enhanced insulin secretion. Diabetes 37, 1574 1582. Chaillous, L., Lefevre, H., Thivolet, C., Boitard, C., Lahlou, N., Atlan-Gepner, C., et al., 2000. Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale Group. Lancet 356, 545 549. Chase, H.P., Butler-Simon, N., Garg, S.K., Hayward, A., Klingensmith, G.J., Hamman, R.F., et al., 1990a. Cyclosporine A for the treatment of new-onset insulin-dependent diabetes mellitus. Pediatrics 85, 241 245. Chase, H.P., Butler-Simon, N., Garg, S., McDuffie, M., Hoops, S.L., O’Brien, D., 1990b. A trial of nicotinamide in newly diagnosed patients with type 1 (insulin-dependent) diabetes mellitus. Diabetologia 33, 444 446. Chen, W., Bergerot, I., Elliott, J.F., Harrison, L.C., Delovitch, T.L., 2001. Evidence that a peptide spanning the B C junction of proinsulin is a primary autoantigen epitope in the pathogenesis of type 1 diabetes. J. Immunol. 167, 4926 4935. Colman, P.G., Steele, C., Couper, J.J., Beresford, S.J., Powell, T., Kewming, K., et al., 2000. Islet autoimmunity in infants with a type I diabetic relative is common but is frequently restricted to one autoantibody. Diabetologia 43, 203 209. Concannon, P., Rich, S.S., Nepom, G.T., 2009. Genetics of type 1A diabetes. N. Engl. J. Med. 360, 1646 1654. Cook, J.J., Hudson, I., Harrison, L.C., Dean, B., Colman, P.G., Werther, G.A., et al., 1989. A double-blind controlled trial of azathioprine in children with newly-diagnosed type 1 diabetes. Diabetes 38, 779 783. Couper, J.J., Steele, C., Beresford, S., Powell, T., McCaul, K., Pollard, A., et al., 1999. Lack of association between duration of breast-feeding or introduction of cow’s milk and development of islet autoimmunity. Diabetes 48, 2145 2149.

VIII. MANAGEMENT

1408

70. PREVENTION OF TYPE 1 DIABETES

Couper, J.J., Beresford, S., Hirte, C., Baghurst, P., Pollard, A., Tait, B.D., et al., 2009. Weight gain in early life predicts risk of islet autoimmunity in children with a first degree relative with type 1 diabetes. Diabetes Care 32, 94 99. Couper, JJ., Harrison, L.C., Re-defining type 1 diabetes as an autoimmune beta-cell disorder, Med. J. Aust. (in press). Coutant, R., Landais, P., Rosilio, M., Johnsen, C., Lahlou, N., Chatelain, P., et al., 1998. Low dose linomide in type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial. Diabetologia 41, 1040 1046. Daniel, D., Wegmann, D., 1996. Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9 23). Proc. Natl. Acad. Sci. U.S.A. 93, 956 960. Davis-Richardson, A.G., Ardissone, A.N., Dias, R., Simell, V., Leonard, M.T., Kemppainen, K.M., et al., 2014. Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. Front. Microbiol. 5, 678. Available from: https:// doi.org/10.3389/fmicb.2014.00678. Diabetes Prevention Trial-Type 1 Diabetes Study Group, 2002. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N. Engl. J. Med. 346, 1685 1691. Dunne, J.L., Triplett, E.W., Gevers, D., Xavier, R., Insel, R., Danska, J., et al., 2014. The intestinal microbiome in type 1 diabetes. Clin. Exp. Immunol. 177, 30 37. EURODIAB Substudy 2 Study Group, 1999. Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. Diabetologia 42, 51 54. Eisenbarth, G.S., 1986. TypeI diabetes mellitus. A chronic autoimmune disease. N. Engl. J. Med. 314, 1360 1368. Elliott, J.F., Marlin, K.L., Couch, R.M., 1998. Effect of bacille Calmette Guerin vaccination on C-peptide secretion in children newly diagnosed with IDDM. Diabetes Care 21, 1691 1693. Faria, A.M., Weiner, H.L., 1999. Oral tolerance: mechanisms and therapeutic applications. Adv. Immunol. 73, 153 164. Feutren, G., Papoz, L., Assan, R., Vialettes, B., Karsenty, G., Vexiau, P., et al., 1986. Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet 2, 119 124. Forrest, J.M., Menser, M.A., Burgess, J.A., 1971. High frequency of diabetes mellitus in young adults with congenital rubella. Lancet 2, 332 334. Foulis, A.K., Liddle, C.N., Farquharson, M.A., Richmond, J.A., Weir, R.S., 1986. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25-year review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia 29, 267 274. Fourlanos, S., Narendran, P., Byrnes, G., Colman, P., Harrison, L.C., 2004. Insulin resistance is a risk factor for progression to type 1 diabetes. Diabetologia 47, 1661 1667. Fourlanos, S., Dotta, F., Greenbaum, C.K., Palmer, J.P., Rolandsson, O., Colman, P.G., et al., 2005. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 48, 2206 2212. Fourlanos, S., Varney, M., Tait, B.D., Morahan, G., Honeyman, M.C., Colman, P.G., et al., 2008. The rising incidence of type 1 diabetes is accounted for by cases with lower risk HLA genotypes. Diabetes Care 31, 1546 1549. Fourlanos, S., Perry, C., Gellert, S.A., Martinuzzi, E., Mallone, R., Butler, J., et al., 2011. Evidence that nasal insulin induces immune tolerance to insulin in adults with autoimmune diabetes. Diabetes 60, 1237 1245. Fu¨chtenbusch, M., Rabl, W., Grassl, B., Bachmann, W., Standl, E., Ziegler, A.G., 1998. Delay of type I diabetes in high risk, first degree relatives by parenteral antigen administration: the Schwabing Insulin Prophylaxis Pilot Trial. Diabetologia 41, 536 541. Gale, E.A.M., 2002. The rise of childhood type 1 diabetes in the 20th century. Diabetes 51, 3353 3361. Gepts, W., 1965. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14, 619 633. Gerstein, H., 1994. Cow’s milk exposure and type 1 diabetes mellitus. Diabetes Care 17, 13 19. Ginsberg-Fellner, F., Witt, M.E., Fedun, B., Taub, F., Dobersen, M.J., McEvoy, R.C., et al., 1985. Diabetes mellitus and autoimmunity in patients with the congenital rubella syndrome. Rev. Infect. Dis. 7 (Suppl 1), S170 S176. Giordano, C., Panto, F., Amato, M.P., Sapienza, N., Pugliese, A., Galluzzo, A., 1990. Early administration of an immunomodulator and induction of remission in insulin-dependent diabetes mellitus. J. Autoimmun. 3, 611 617. Gitelman, S.E., Gottlieb, P.A., Rigby, M.R., Felner, E.I., Willi, S.M., Fisher, L.K., et al., 2013. Antithymocyte globulin treatment for patients with recent-onset type 1 diabetes: 12-month results of a randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 1, 306 316. Gitelman, S.E., Gottlieb, P.A., Felner, E.I., Willi, S.M., Fisher, L.K., Moran, A., et al., 2016. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomised trial. Diabetologia 59, 1153 1161. Goday, A., Pujol-Borrell, R., Fernandez, J., Casamitjana, R., Rios, M., Vilardell, E., et al., 1993. Effects of a short prednisone regime at clinical onset of type 1 diabetes. Diabetes Res. Clin. Pract. 20, 39 46. Gottlieb, P.A., Quinlan, S., Krause-Steinrauf, H., Greenbaum, C.J., Wilson, D.M., Rodriguez, H., et al., 2010. Failure to preserve beta-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new-onset type 1 diabetes. Diabetes Care 33, 826 832. Gottsater, A., Landin-Olsson, M., Lernmark, A., Fernlund, P., Sundkvist, G., Hagopian, W.A., 1995. Glutamic acid decarboxylase antibody levels predict role of β-cell decline in adult onset diabetes. Diab. Rev. Clin. Prac. 27, 133 140. Greenbaum, C., Harrison, L.C., 2003. Guidelines for intervention trials in subjects with newly-diagnosed type 1 diabetes. Diabetes 52, 1059 1065. Griffin, K.J., Thompson, P.A., Gottschalk, M., Kyllo, J.H., Rabinovitch, A., 2014. Combination therapy with sitagliptin and lansoprazole in patients with recent-onset type 1 diabetes (REPAIR-T1D): 12-month results of a multicentre, randomised, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2, 710 718. Grunt, J.A., al-Hakim, H., Willoughby, L., Howard, C.P., 1994. A randomized trial of a somatostatin analog for preserving beta cell function in children with insulin dependent diabetes mellitus. J. Pediatr. Endocrinol. 7, 331 334. Hagopian, W.A., Karlsen, A.E., Gottsater, A., Landin-Olsson, M., Grubin, C.E., Sundkvist, G., et al., 1993. Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type. J. Clin. Invest. 91, 368 374.

VIII. MANAGEMENT

REFERENCES

1409

Haller, M.J., Gitelman, S.E., Gottlieb, P.A., Michels, A.W., Rosenthal, S.M., Shuster, J.J., et al., 2015. Anti-thymocyte globulin/G-CSF treatment preserves beta cell function in patients with established type 1 diabetes. J. Clin. Invest. 125, 448 455. Haller, M.J., Gitelman, S.E., Gottlieb, P.A., Michels, A.W., Perry, D.J., Schultz, A.R., et al., 2016. Antithymocyte globulin plus G-CSF combination therapy leads to sustained immunomodulatory and metabolic effects in a subset of responders with established type 1 diabetes. Diabetes 65, 3765 3775. Haller, M.J., Schatz, D.A., Skyler, J.S., Krischer, J.P., Bundy, B.N., Miller, J.L., et al., 2018. Low-dose anti-thymocyte globulin (ATG) preserves beta-cell function and improves HbA1c in new-onset type 1 diabetes. Diabetes Care 41, 1917 1925. Hancock, W.W., Polanski, M., Zhang, J., Blogg, N., Weiner, H.L., 1995. Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta and prostaglandin-E. Am. J. Pathol. 147, 1193 1199. Ha¨nninen, A., Harrison, L.C., 2000. Gamma delta T cells as mediators of mucosal tolerance: the autoimmune diabetes model. Immunol. Rev. 173, 109 119. Ha¨nninen, A., Braakhuis, A., Heath, W.R., Harrison, L.C., 2001. Mucosal antigen primes diabetogenic cytotoxic T-lymphocytes regardless of dose or delivery route. Diabetes 50, 771 775. Ha¨nninen, A., Martinez, N.R., Davey, G.M., Heath, W.R., Harrison, L.C., 2002. Transient blockade of CD40 ligand dissociates pathogenic from protective mucosal immunity. J. Clin. Invest. 109, 261 267. Harbison, J.E., Roth-Schulze, A.-J., Barry, S.C., Giles, L.C., Tran, C.D., Ngui, K.M., et al., 2018. Gut microbiome dysbiosis and increased intestinal permeability in Australian children with islet autoimmunity and type 1 diabetes. In: 230-OR ADA Presidents’ Select Abstract. American Diabetes Association 78th Scientific Session, Orlando, FL. Harrison, L.C., 2008. Vaccination against self to prevent autoimmune disease: the type 1 diabetes model. Immunol. Cell Biol. 89, 139 145. Harrison, L.C., Hafler, D.A., 2000. Antigen-specific therapy for autoimmune disease. Curr. Opin. Immunol. 12, 704 711. Harrison, L.C., Honeyman, M.C., 1999. Cow’s milk and type 1 diabetes: the real debate is about mucosal immune function. Diabetes 48, 1501 1507. Harrison, L.C., Colman, P.G., Dean, B., Baxter, R., Martin, F.I., 1985. Increase in remission rate in newly diagnosed type I diabetic subjects treated with azathioprine. Diabetes 34, 1306 1308. Harrison, L.C., Honeyman, M.C., DeAizpurua, H.J., Schmidli, R.S., Tait, B.D., Cram, D.S., et al., 1993. Inverse relationship between humoral and cellular immunity to glutamic acid decarboxylase in humans at-risk for insulin-dependent diabetes. Lancet 341, 1365 1369. Harrison, L.C., Dempsey-Collier, M., Kramer, D.R., Takahashi, K., 1996. Aerosol insulin induces regulatory CD8 gamma delta T cells that prevent murine insulin-dependent diabetes. J. Exp. Med. 184, 2167 2174. Harrison, L.C., Honeyman, M.C., Trembleau, S., Gregori, S., Gallazzi, F., Augstein, P., et al., 1997. A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice. J. Autoimmun. 10, 165 173. Harrison, L.C., Honeyman, M.C., Steele, C.E., Stone, N.L., Sarugeri, E., Bonifacio, E., et al., 2004. Pancreatic beta-cell function and immune responses to insulin after administration of intranasal insulin to humans at risk for type 1 diabetes. Diabetes Care 27, 2348 2355. Harrison, L.C., Hall, C.R., Couper, J.J., Donaghue, K.C., Davis, E.A., Cotterill, A.M., et al., 2018. A randomised controlled trial of intranasal insulin to prevent type 1 diabetes: intranasal insulin trial II (INIT II). In: Proc. Aust. Diab. Congr. Adelaide. Hartmann, B., Bellmann, K., Ghiea, I., Kleemann, R., Kolb, H., 1997. Oral insulin for diabetes prevention in NOD mice: potentiation by enhancing Th2 cytokine expression in the gut through bacterial adjuvant. Diabetologia 40, 902 909. Herold, K.C., Hagopian, W., Auger, J.A., Poumian-Ruiz, E., Taylor, L., Donaldson, D., et al., 2002. Anti-CD3 monoclonal antibody in newonset type 1 diabetes mellitus. N. Engl. J. Med. 346, 1692 1698. Herold, K.C., Gitelman, S.E., Masharani, U., Hagopian, W., Bisikirska, B., Donaldson, D., et al., 2005. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54, 1763 1769. Herold, K.C., Gitelman, S.E., Ehlers, M.R., Gottlieb, P.A., Greenbaum, C.J., Hagopian, W., et al., 2013. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes 62, 3766 3774. von Herrath, M.G., Harrison, L.C., 2003. Antigen-induced regulatory T cells in autoimmunity. Nat. Rev. Immunol. 3, 223 232. Holick, M.F., 2004. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am. J. Clin. Nutr. 79, 362 371. Homann, D., Dyrberg, T., Petersen, J., Oldstone, M.B., von Herrath, M.G., 1999. Insulin in oral immune “tolerance”: a one-amino acid change in the B chain makes the difference. J. Immunol. 163, 1833 1838. Honeyman, M., 2005. How robust is the evidence for viruses in the induction of type 1 diabetes? Curr. Opin. Immunol. 17, 616 623. Honeyman, M.C., Harrison, L.C., Drummond, B., Colman, P.G., Tait, B.D., 1995. Analysis of families at risk for insulin-dependent diabetes reveals that HLA antigens influence progression to preclinical disease. Mol. Med. 1, 576 582. Honeyman, M.C., Coulson, B.S., Stone, N.L., Gellert, S.A., Goldwater, P.N., Steele, C.E., et al., 2000. Association between rotavirus infection and pancreatic islet autoimmunity in children at risk of developing type 1 diabetes. Diabetes 49, 1319 1324. Honeyman, M.C., Laine, D., Londrigan, S., Kirkwood, C., Harrison, L.C., 2014. Rotavirus infection induces transient pancreatic involution and hyperglycemia in weanling mice. PLoS One e106560. Available from: https://doi.org/10.1371/journal.pone.0106560. Hummel, M., Fuchtenbusch, M., Schenker, M., Ziegler, A.G., 2000. No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study. Diabetes Care 23, 969 974. Hummel, M., Bonifacio, E., Naserke, H.E., Ziegler, A.G., 2002. Elimination of dietary gluten does not reduce titers of type 1 diabetesassociated autoantibodies in high-risk subjects. Diabetes Care 25, 1111 1116. Hummel, S., Pfluger, M., Hummel, M., Bonifacio, E., Ziegler, A.G., 2011. Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 34, 1301 1305. Hypponen, E., Laara, E., Reunanen, A., Jarvelin, M.R., Virtanen, S.M., 2001. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 1500 1503.

VIII. MANAGEMENT

1410

70. PREVENTION OF TYPE 1 DIABETES

Kapke, J., Shaheen, Z., Kilari, D., Knudson, P., Wong, S., 2017. Immune checkpoint inhibitor-associated type 1 diabetes mellitus: case series, review of the literature, and optimal management. Case Rep. Oncol. 10, 897 909. Kawaguchi-Miyashita, M., Shimizu, K., Nanno, M., Shimada, S., Watanabe, T., Koga, Y., et al., 1996. Development and cytolytic function of intestinal intraepithelial T lymphocytes in antigen-minimized mice. Immunology 89, 268 273. Keller, R.J., Eisenbarth, G.S., Jackson, R.A., 1993. Insulin prophylaxis in individuals at high risk of type 1 diabetes. Lancet 341, 927 928. Keymeulen, B., Vandemeulebroucke, E., Ziegler, A.G., Mathieu, C., Kaufman, L., Hale, G., et al., 2005. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352, 2598 2608. Keymeulen, B., Walter, M., Mathieu, C., Kaufman, L., Gorus, F., Hilbrands, R., et al., 2010. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 53, 614 623. Kimpima¨ki, T., Kupila, A., Ha¨ma¨la¨inen, A.-M., Kukko, M., Kulmala, P., Savola, K., et al., 2001. The first signs of β-cell autoimmunity appear in infancy in genetically susceptible children from the general population: The Finnish Type 1 Diabetes Prediction and Prevention Study. J. Clin. Endocrinol. Metab. 86, 4782 4788. Knip, M., Siljander, H., 2016. The role of the intestinal microbiota in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 12, 154 167. Knip, M., Virtanen, S.M., Seppa¨, K., Ilonen, J., Savilahti, E., Vaarala, O., et al., 2010. Dietary intervention in infancy and later signs of beta-cell autoimmunity. N. Engl. J. Med. 363, 1900 1908. Knip, M., Virtanen, S.M., Becker, D., Dupre, J., Krischer, J.P., Akerblom, H.K., 2011. Early feeding and risk of type 1 diabetes: experiences from the Trial to Reduce Insulin-dependent diabetes mellitus in the Genetically at Risk (TRIGR). Am. J. Clin. Nutr. 94, 1814S 1820S. Knip, M., Akerblom, H.K., Becker, D., Dosch, H.M., Dupre, J., Fraser, W., et al., 2014. Hydrolyzed infant formula and early beta-cell autoimmunity: a randomized clinical trial. JAMA 311, 2279 2287. ˚ kerblom, H.K., Al Taji, E., Becker, D., Bruining, J., Castano, L., et al., 2018. Effect Writing Group for the TRIGR Study Group, Knip, M., A of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: he TRIGR randomized clinical trial. JAMA 319, 38 48. Kobayashi, T., Nakanishi, K., Murase, T., Kosaka, K., 1996. Small doses of subcutaneous insulin as a strategy for preventing slowly progressive b-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes 45, 622 626. Kohnert, K.D., Hehmke, B., Keilacker, H., Ziegler, M., Emmrich, F., Laube, F., et al., 1996. Antibody response to islet autoantigens in antiCD4/prednisolone immune intervention of type 1 diabetes. Int. J. Clin. Lab. Res. 26, 55 59. Kondrashova, A., Reunanen, A., Romanov, A., Karvonen, A., Viskari, H., Vesikari, T., et al., 2005. A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland. Ann. Med. 37, 67 72. Kostic, A.D., Gevers, D., Siljander, H., Vatanen, T., Hyo¨tyla¨inen, T., Ha¨ma¨la¨inen, A.M., et al., 2015. The dynamics of the human infant gut microbiome in developmentand in progression toward type 1 diabetes. Cell Host Microbe 17, 260 273. Krause, I., Blank, M., Shoenfeld, Y., 2000. Immunomodulation of experimental autoimmune diseases via oral tolerance. Crit. Rev. Immunol. 20, 1 16. Krischer, J.P., Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group, Schatz, D.A., Bundy, B., Skyler, J.S., Greenbaum, C.J., 2017. Effect of oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial. JAMA 318, 1891 1902. Lampeter, E.F., McCann, S.R., Kolb, H., 1998a. Transfer of insulin-dependent diabetes by bone marrow transplantation. Lancet 351, 568 569. Lampeter, E.F., Klinghammer, A., Scherbaum, W.A., Heinze, E., Haastert, B., Giani, G., et al., 1998b. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group. Diabetes 47, 980 984. Lefebvre, D.E., Powell, K.L., Strom, A., Scott, F.W., 2006. Dietary proteins as environmental modifiers of type 1 diabetes mellitus. Ann. Rev. Nutr. 26, 175 202. Leiter, E.H., Prochazka, M., Coleman, D.L., 1987. The non-obese diabetic (NOD) mouse. Am. J. Pathol. 128, 380 383. Linn, T., Ortac, K., Laube, H., Federlin, K., 1996. Intensive therapy in adult insulin-dependent diabetes mellitus is associated with improved insulin sensitivity and reserve: a randomized, controlled, prospective study over 5 years in newly diagnosed patients. Metabolism 45, 1508 1513. Long, S.A., Rieck, M., Sanda, S., Bollyky, J.B., Samuels, P.L., Goland, R., et al., 2012. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes 61, 2340 2348. Ludvigsson, J., Samuelsson, U., Johansson, C., Stenhammar, L., 2001. Treatment with antioxidants at onset of type 1 diabetes in children: a randomized, double-blind placebo-controlled study. Diabetes Metab. Res. Rev. 17, 131 136. Ludvigsson, J., Faresjo, M., Hjorth, M., Axelsson, S., Cheramy, M., Pihl, M., et al., 2008. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N. Engl. J. Med. 359, 1909 1920. Ludvigsson, J., Krisky, D., Casas, R., Battelino, T., Castano, L., Greening, J., et al., 2012. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N. Engl. J. Med. 366, 433 442. Ludvigsson, J., Wahlberg, J., Casas, R., 2017. Intralymphatic injection of autoantigen in type 1 diabetes. N. Engl. J. Med. 376, 697 699. Ma, S.W., Zhao, D.L., Yin, Z.Q., Mukherjee, R., Singh, B., Qin, H.Y., et al., 1997. Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance. Nat. Med. 3, 793 796. MacFarlane, A.J., Burghardt, K.M., Kelly, J., Simell, T., Simell, O., Altosaar, I., et al., 2002. A type 1 diabetes-related protein from wheat (Triticum aestivum): cDNA clone of a wheat storage globulin, Glb1, linked to islet damage. J. Biol. Chem. 278, 54 63. Mannering, S.I., Harrison, L.C., Williamson, N.A., Morris, J.S., Thearle, D.J., Jensen, K.P., et al., 2005. The insulin A-chain epitope recognized by human T cells is post-translationally modified. J. Exp. Med. 202, 1191 1197. Marin˜o, E., Richards, J.L., McLeod, K.H., Yap, Y.A., Stanley, D., Kranich, J., et al., 2017. Gut microbial metabolites limit autoimmune T cell frequencies and protect against type 1 diabetes. Nat. Immunol. 18, 1271. Available from: https://doi.org/10.1038/ni1117-1271c. Maron, R., Palanivel, V., Weiner, H.L., Harn, D.A., 1998. Oral administration of schistosome egg antigens and insulin B-chain generates and enhances Th2-type responses in NOD mice. Clin. Immunol. Immunopathol. 87, 85 92.

VIII. MANAGEMENT

REFERENCES

1411

Maron, R., Guerau-de-Arellano, M., Zhang, X., Weiner, H.L., 2001. Oral administration of insulin to neonates suppresses spontaneous and cyclophosphamide induced diabetes in the NOD mouse. J. Autoimmun. 16, 21 28. Martinez, N.R., Augstein, P., Moustakas, A.K., Papadopoulos, G.K., Gregori, S., Adorini, L., et al., 2003. Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide. J. Clin. Invest. 111, 1365 1371. McKown, K.M., Carbone, L.D., Kaplan, S.B., Aelion, J.A., Lohr, K.M., Cremer, M.A., et al., 1999. Lack of efficacy of oral bovine type II collagen added to existing therapy in rheumatoid arthritis. Arthritis Rheum. 42, 1204 1208. Mendola, G., Casamitjana, R., Gomis, R., 1989. Effect of nicotinamide therapy upon B-cell function in newly diagnosed type 1 (insulin-dependent) diabetic patients. Diabetologia 32, 160 162. Menser, M.A., Forrest, J.M., Honeyman, M.C., Burgess, J.A., 1974. Letter: Diabetes, HL-A antigens, and congenital rubella. Lancet 2, 1508 1509. Menser, M.A., Forrest, J.M., Bransby, R.D., 1978. Rubella infection and diabetes mellitus. Lancet 1, 57 60. Metzler, B., Wraith, D.C., 1993. Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. Int. Immunol. 5, 1159 1165. Moltchanova, E.V., Schreier, N., Lammi, N., Karvonen, M., 2009. Seasonal variation of diagnosis of type 1 diabetes mellitus in children worldwide. Diabetic Med. 26, 673 678. Moncada, E., Subira, M.L., Oleaga, A., Goni, F., Sanchez-Ibarrola, A., Monreal, M., et al., 1990. Insulin requirements and residual beta-cell function 12 months after concluding immunotherapy in type I diabetic patients treated with combined azathioprine and thymostimulin administration for one year. J. Autoimmun. 3, 625 638. Moran, A., Bundy, B., Becker, D.J., DiMeglio, L.A., Gitelman, S.E., Goland, R., et al., 2013. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 381, 1905 1915. Nanto-Salonen, K., Kupila, A., Simell, S., Siljander, H., Salonsaari, T., Hekkala, A., et al., 2008. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 372, 1746 1755. Narendran, P., Mannering, S.I., Harrison, L.C., 2003. Proinsulin a pathogenic autoantigen in type 1 diabetes. Autoimmun. Rev. 2, 204 210. Norris, J.M., Scott, F.W., 1996. A meta analysis of infant diet and insulin-dependent diabetes mellitus: do biases play a role. Epidemiology 7, 87 92. Norris, J.M., Beaty, B., Klingensmith, G., Yu, L., Hoffman, M., Chase, H.P., et al., 1996. Lack of association between early exposure to cow’s milk protein and β cell autoimmunity: Diabetes Autoimmunity Study in the Young (DAISY). JAMA 276, 609 614. O’Callaghan, A., van Sinderen, D., 2016. Bifidobacteria and their role as members of the human gut microbiota. Front. Microbiol. 7, 925. Available from: https://doi.org/10.3389/fmicb.2016.00925. Orban, T., Farkas, K., Jalahej, H., Kis, J., Treszl, A., Falk, B., et al., 2010. Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy. J. Autoimmun. 34, 408 415. Orban, T., Bundy, B., Becker, D.J., DiMeglio, L.A., Gitelman, S.E., Goland, R., et al., 2011. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 378, 412 419. Panto, F., Giordano, C., Amato, M.P., Pugliese, A., Donatelli, M., D’Acquisto, G., et al., 1990. The influence of high dose intravenous immunoglobulins on immunological and metabolic pattern in newly diagnosed type I diabetic patients. J. Autoimmun. 3, 587 592. Pathiraja, V., Kuehlich, J.P., Campbell, P.D., Krishnamurthy, B., Loudovaris, T., Coates, P.T., et al., 2015. Proinsulin-specific, HLA-DQ8 and HLA-DQ8-transdimer-restricted CD41 T cells infiltrate islets in type 1 diabetes. Diabetes 64, 172 182. Penno, M.A.S., Couper, J.J., Craig, M.E., Colman, P.G., Rawlinson, W.D., Cotterill, A.M., et al., 2013. Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes. BMC Pediatr. 13, 124. Available from: https://doi.org/10.1186/1471-2431-13-124. Perrett, K., Jachno, K., Nolan, T., Harrison, L.C., 2019. Rotavirus vaccination and the incidence of type 1 diabetes in children. JAMA Ped. Available from: https://doi:10.1001/jamapediatrics.2018.4578. Pescovitz, M.D., Greenbaum, C.J., Krause-Steinrauf, H., Becker, D.J., Gitelman, S.E., Goland, R., et al., 2009. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N. Engl. J. Med. 361, 2143 2152. Pescovitz, M.D., Greenbaum, C.J., Bundy, B., Becker, D.J., Gitelman, S.E., Goland, R., et al., 2014. B-lymphocyte depletion with rituximab and beta-cell function: two-year results. Diabetes Care 37, 453 459. Petersen, J.S., Karlsen, A.E., Markholst, H., Worsaae, A., Dyrberg, T., Michelsen, B., 1994. Neonatal tolerization with glutamic acid decarboxylase but not with bovine serum albumin delays the onset of diabetes in NOD mice. Diabetes 43, 1478 1484. Philips, J.C., Scheen, A.J., Le Registre Belge du Diabete, 2002. Info-congress. Study of the prevention of type 1 diabetes with nicotinamide: positive lessons of a negative clinical trial (ENDIT). [Article in French]. Rev. Med. Liege 57, 672 675. Ploix, C., Bergerot, I., Fabien, N., Perche, S., Moulin, V., Thivolet, C., 1998. Protection against autoimmune diabetes with oral insulin is associated with the presence of IL-4 type 2 T-cells in the pancreas and pancreatic lymph nodes. Diabetes 47, 39 44. Ploix, C., Bergerot, I., Durand, A., Czerkinsky, C., Holmgren, J., Thivolet, C., 1999. Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4 1 regulatory T-cells. Diabetes 48, 2150 2156. Pozzilli, P., Signore, A., Williams, A.J., Beales, P.E., 1993. NOD mouse colonies around the world--recent facts and figures. Immunol. Today 14, 193 196. Pozzilli, P., Visalli, B., Boccuni, M.L., Baroni, M.G., Buzzetti, R., Fioriti, E., et al., 1994. Randomized trial comparing nicotinamide and nicotinamide plus cyclosporin in recent onset insulin-dependent diabetes (IMDIAB 1). The IMDIAB Study Group. Diabet. Med. 11, 98 104. Pozzilli, P., Visalli, N., Signore, A., Baroni, M.G., Buzzetti, R., Cavallo, M.G., et al., 1995. Double blind trial of nicotinamide in recent-onset IDDM (the IMDIAB III study). Diabetologia 38, 848 852. Pozzilli, P., Visalli, N., Cavallo, M.G., Signore, A., Baroni, M.G., Buzzetti, R., et al., 1997. Vitamin E and nicotinamide have similar effects in maintaining residual beta cell function in recent onset insulin-dependent diabetes (the IMDIAB IV study). Eur. J. Endocrinol. 137, 234 239. Pozzilli, P., Pitocco, D., Visalli, N., Cavallo, M.G., Buzzetti, R., Crino, A., et al., 2000. No effect of oral insulin on residual beta-cell function in recent-onset type 1 diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 43, 1000 1004.

VIII. MANAGEMENT

1412

70. PREVENTION OF TYPE 1 DIABETES

Raz, I., Elias, D., Avron, A., Tamir, M., Metzger, M., Cohen, I.R., 2001. Beta-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial. Lancet 358, 1749 1753. Rigby, M.R., DiMeglio, L.A., Rendell, M.S., Felner, E.I., Dostou, J.M., Gitelman, S.E., et al., 2013. Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Diabetes Endocrinol. 1, 284 294. Rigby, M.R., Harris, K.M., Pinckney, A., DiMeglio, L.A., Rendell, M.S., Felner, E.I., et al., 2015. Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. J. Clin. Invest. 125, 3285 3296. Roep, B.O., Solvason, N., Gottlieb, P.A., Abreu, J.R.F., Harrison, L.C., Eisenbarth, G.S., et al., 2013. Plasmid-encoded proinsulin preserves Cpeptide while specifically reducing proinsulin-specific CD8(1) T cells in type 1 diabetes. Sci. Transl. Med. 5, 191ra182. Roivainen, M., Klingel, K., 2010. Virus infections and type 1 diabetes risk. Curr. Diab. Rep. 10, 350 356. Rudy, G., Stone, N., Harrison, L.C., Colman, P.G., McNair, P., Brusic, V., et al., 1995. Similar peptides from two beta-cell autoantigens, proinsulin and glutamic acid decarboxylase, stimulate T cells of individuals at risk for insulin-dependent diabetes. Mol. Med. 1, 625 633. Schloot, N.C., Meierhoff, G., Lengyel, C., Vandorfi, G., Takacs, J., Panczel, P., et al., 2007. Effect of heat shock protein peptide DiaPep277 on beta-cell function in paediatric and adult patients with recent-onset diabetes mellitus type 1: two prospective, randomized, double-blind phase II trials. Diabetes Metab. Res. Rev. 23, 276 285. Schnell, O., Eisfelder, B., Standl, E., Ziegler, A.G., 1997. High-dose intravenous insulin infusion versus intensive insulin treatment in newly diagnosed IDDM. Diabetes 46, 1607 1611. Secchi, A., Pastore, M.R., Sergi, A., Pontiroli, A.E., Pozza, G., 1990. Prednisone administration in recent onset type I diabetes. J. Autoimmun. 3, 593 600. Selam, J.L., Woertz, L., Lozano, J., Robinson, M., Chan, E., Charles, M.A., 1993. The use of glipizide combined with intensive insulin treatment for the induction of remissions in new onset adult type I diabetes. Autoimmunity 16, 281 288. Shah, S.C., Malone, J.I., Simpson, N.E., 1989. A randomized trial of intensive insulin therapy in newly diagnosed insulin-dependent diabetes mellitus. N. Engl. J. Med. 320, 550 554. Shehadeh, N., Gelertner, L., Blazer, S., Perlman, R., Etzioni, A., 2001. The importance of insulin content in infant diet: suggestion for a new infant formula period. Acta Pediatr. 90, 93 95. Sherry, N., Hagopian, W., Ludvigsson, J., Jain, S.M., Wahlen, J., Ferry Jr., R.J., et al., 2011. Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet 378, 487 497. Silverstein, J., Maclaren, N., Riley, W., Spillar, R., Radjenovic, D., Johnson, S., 1988. Immunosuppression with azathioprine and prednisone in recent-onset insulin-dependent diabetes mellitus. N. Engl. J. Med. 319, 599 604. Skyler, J.S., Rabinovitch, A., 1992. Cyclosporine in recent onset type I diabetes mellitus. Effects on islet beta cell function. Miami Cyclosporine Diabetes Study Group. J. Diabetes Complications 6, 77 88. Skyler, J.S., Lorenz, T.J., Schwartz, S., Eisenbarth, G.S., Einhorn, D., Palmer, J.P., et al., 1993. Effects of an anti-CD5 immunoconjugate (CD5-plus) in recent onset type I diabetes mellitus: a preliminary investigation. The CD5 Diabetes Project Team. J. Diabetes Complications 7, 224 232. Skyler, J.S., Krischer, J.P., Wolfsdorf, J., Cowie, C., Palmer, J.P., Greenbaum, C., et al., 2005. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial—Type 1. Diabetes Care 28, 1068 1076. Slavin, A.J., Maron, R., Weiner, H.L., 2001. Mucosal administration of IL-10 enhances oral tolerance in autoimmune encephalomyelitis and diabetes. Int. Immunol. 13, 825 833. Stene, L.C., Ulriksen, J., Magnus, P., Joner, G., 2000. Use of cod liver oil during pregnancy associated with lower risk of type I diabetes in the offspring. Diabetologia 43, 1093 1098. Sutherland, D.E., Goetz, F.C., Sibley, R.K., 1989. Recurrence of disease in pancreas transplants. Diabetes 38 (suppl 1), 85 87. Suzuki, T., 1987. Diabetogenic effects of lymphocyte transfusion on the NOD or NOD nude mouse. In: Rygaard, J., Brunner, N., Graem, N., Spang-Thomson, M. (Eds.), Immune Deficient Animals in Biomedical Research. Karger, Basel, pp. 112 116. Tait, B.D., Harrison, L.C., Drummond, B.P., Stewart, V., Varney, M.D., Honeyman, M.C., 1995. HLA antigens and age at diagnosis of insulindependent diabetes mellitus. Human Immunol. 42, 116 122. Thorburn, A.N., Macia, L., Mackay, C.R., 2014. Diet, metabolites, and “western lifestyle” inflammatory diseases. Immunity 40, 833 842. Tian, J., Atkinson, M.A., Clare-Salzler, M., Herschenfeld, A., Forsthuber, T., Lehmann, P.V., et al., 1996. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med. 183, 1561 1567. Tisch, R., Wang, B., Weaver, D.J., Liu, B., Bui, T., Arthos, J., et al., 2001. Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination. J. Immunol. 166, 2122 2132. Trentham, D.A., Dynesius-Trentham, R.A., Orav, E.J., 1993. Effects of oral administration of type II collagen on rheumatoid arthritis. Science 261, 1727 1730. Tuomi, T., Groop, L.C., Zimmet, P.Z., Rowley, M.J., Knowles, W., Mackay, I.R., 1993. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42, 359 362. Turner, R., Stratton, I., Horton, V., Manley, S., Zimmet, P., Mackay, I.R., et al., 1997. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 350, 1288 1293. Vaarala, O., Ilonen, J., Ruohtula, T., Pesola, J., Virtanen, S.M., Harkonen, T., et al., 2012. Removal of bovine insulin from cow’s milk formula and early initiation of beta-cell autoimmunity in the FINDIA pilot study. Arch. Pediatr. Adolesc. Med. 166, 608 614. Vague, P., Picq, R., Bernal, M., Lassmann-Vague, V., Vialettes, B., 1989. Effect of nicotinamide treatment on the residual insulin secretion in type 1 (insulin-dependent) diabetic patients. Diabetologia 32, 316 321. Vatanen, T., Kostic, A.D., d’Hennezel, E., Siljander, H., Franzosa, E.A., Yassour, M., et al., 2016. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell. 165, 842 853. Ventura, A., Magazzu, G., Greco, L., 1999. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease (SIGEP study group for autoimmune disorders in celiac disease). Gastroenterology 117, 297 303.

VIII. MANAGEMENT

FURTHER READING

1413

Verge, C.F., Gianani, R., Kawasaki, E., Yu, L., Pietropaolo, M., Jackson, R.A., et al., 1996. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes 45, 926 933. Vidal, J., Fernandez-Balsells, M., Sesmilo, G., Aguilera, E., Casamitjana, R., Gomis, R., et al., 2000. Effects of nicotinamide and intravenous insulin therapy in newly diagnosed type 1 diabetes. Diabetes Care 23, 360 364. Waldo, F.B., van den Wall Bake, A.W., Mestecky, J., Husby, S., 1994. Suppression of the immune response by nasal immunization. Clin. Immunol. Immunopathol. 72, 30 34. Walter, M., Philotheou, A., Bonnici, F., Ziegler, A.G., Jimenez, R., Group, N.B.I.S., 2009. No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes. Diabetes Care 32, 2036 2040. Walter, M., Kaupper, T., Adler, K., Foersch, J., Bonifacio, E., Ziegler, A.G., 2010. No effect of the 1alpha,25-dihydroxyvitamin D3 on beta-cell residual function and insulin requirement in adults with new-onset type 1 diabetes. Diabetes Care 33, 1443 1448. Weiner, H.L., Mackin, G.A., Matsui, M., 1993. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science 259, 1321 1324. Wentworth, J.M., Fourlanos, S., Harrison, L.C., 2009. Deconstructing the stereotypes of diabetes within the modern diabetogenic environment. Nat. Rev. Endocrinol. 5, 483 489. Wherrett, D.K., Bundy, B., Becker, D.J., DiMeglio, L.A., Gitelman, S.E., Goland, R., et al., 2011. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 378, 319 327. Winkler, C., Schober, E., Ziegler, A.G., Holl, R.W., 2012. Markedly reduced rate of diabetic ketoacidosis at onset of type 1 diabetes in relatives screened for islet autoantibodies. Pediatr. Diabetes 13, 308 313. Yu, L.C., Wang, J.T., Wei, S.C., Ni, Y.H., 2012. Host-microbial interactions and regulation of intestinal epithelial barrier function: from physiology to pathology. World J. Gastrointest. Pathophysiol. 3, 27 43. Zhang, Z.H., Davidson, L., Eisenbarth, G., Weiner, H.L., 1991. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc. Natl. Acad. Sci. U.S.A. 88, 10252 10256. Ziegler, A.G., Rewers, M., Simell, O., Lempainen, J., Steck, A., Winkler, C., et al., 2013. Seroconversion to multiple islet antibodies and risk of progression to diabetes in children. JAMA 309, 2473 2479. Ziegler, A.G., Danne, T., Dunger, D.B., Berner, R., Puff, R., Kiess, W., et al., 2016. Primary prevention of beta-cell autoimmunity and type 1 diabetes—The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) perspectives. Mol. Metab. 5, 255 262.

Further Reading Atkinson, M.A., Leiter, E.H., 1999. The NOD mouse model of type 1 diabetes: as good as it gets? Nat. Med. 5, 601 604. Bennett, S.T., Lucassen, A.M., Gough, S.C., Powell, E.E., Undlien, D.E., Pritchard, L.E., et al., 1995. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat. Genet. 9, 284 292. Brown, C.T., Davis-Richardson, A.G., Giongo, A., Gano, K.A., Crabb, D.B., Mukherjee, N., et al., 2011. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One 6, e25792. Coulson, B.S., Witterick, P.D., Tan, Y., Hewish, M.J., Mountford, J.N., Harrison, L.C., et al., 2002. Growth of rotaviruses in primary pancreatic cells. J. Virol. 76, 9537 9544. DeStefano, F., Mullooly, J.P., Okoro, C.A., Chen, R.T., Marcy, S.M., Ward, J.I., et al., 2001. Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus. Pediatrics 108, E112. Durinovic-Bello, I., Wu, R.P., Gersuk, V.H., Sanda, S., Shilling, H.G., Nepom, G.T., 2010. Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin. Genes Immun. 11, 188 193. Harrison, L.C., 2001. Risk assessment, prediction and prevention of type 1 diabetes. Pediatr. Diabetes 2, 71 82. Honeyman, M.C., Stone, N.L., Falk, B.A., Nepom, G., Harrison, L.C., 2010. Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens. J. Immunol. 184, 2204 2210. Honeyman, M.C., Stone, N.L., Harrison, L.C., 1998. T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-2: potential for mimicry with rotavirus and other environmental agents. Mol. Med. 4, 231 239. Leonard, M.T., Davis-Richardson, A.G., Ardissone, A.N., Kemppainen, K.M., Drew, J.C., Ilonen, J., et al., 2014. The methylome of the gut microbiome: disparate Dam methylation patterns in intestinal Bacteroides dorei. Front. Microbiol. 5, 361. Available from: https://doi.org/ 10.3389/fmicb.2014.00361. Leslie, D., Lipsky, P., Notkins, A.B., 2001. Autoantibodies as predictors of disease. J. Clin. Invest. 108, 1417 1422. Lindberg, B., Ahlfors, K., Carlsson, A., Ericsson, U.B., Landin-Olsson, M., Lernmark, A., et al., 1999. Previous exposure to measles, mumps, and rubella—but not vaccination during adolescence—correlates to the prevalence of pancreatic and thyroid autoantibodies. Pediatrics 104, e12. Ou, D., Mitchell, L.A., Metzger, D.L., Gillam, S., Tingle, A.J., 2000. Cross-reactive rubella virus and glutamic acid decarboxylase (65 and 67) protein determinants recognised by T cells of patients with type I diabetes mellitus. Diabetologia 43, 750 762. Pugliese, A., Zeller, M., Fernandez Jr, A., Zalcberg, L.J., Bartlett, R.J., Ricordi, C., et al., 1997. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat. Genet. 15, 293 297. Rose, N.R., 2008. Predictors of autoimmune disease: autoantibodies and beyond. Autoimmunity 41, 419 428. Sarugeri, E., Dozio, N., Belloni, C., Meschi, F., Pastore, M.R., Bonifacio, E., 1998. Autoimmune responses to the beta cell autoantigen, insulin, and the INS VNTR-IDDM2 locus. Clin. Exp. Immunol. 114, 370 376. Yu, L.C., Wang, J.T., Wei, S.C., Ni, Y.H., 2012. Host-microbial interactions and regulation of intestinal epithelial barrier function: from physiology to pathology. World J. Gastrointest. Pathophysiol. 3, 27 43.

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