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Immune cells, pancreas development, regeneration and type 1 diabetes
Opinion
TRENDS in Immunology
Vol.25 No.5 May 2004
Immune cells, pancreas development, regeneration and type 1 diabetes Franc¸oise Homo-Delarche1 and Hemmo A. Drexhage2 1 2
CNRS UMR 7059, Universite´ Paris 7/Denis Diderot, 2 place Jussieu, 75251, Paris Cedex 05, France Department of Immunology, Erasmus MC, Dr Molewaterplein 50, 3000 DR Rotterdam, The Netherlands
Macrophages (MFs), dendritic cells (DCs) and lymphocytes are involved in the pathogenesis of type 1 diabetes (T1D). However, the presence of these cells is not specific for a diabetes-prone background. MFs are also constituents of the normal fetal, neonatal and adult pancreas. We hypothesize that MFs, DCs and lymphocytes have a role in pancreas and islet development because immune cells (particularly MFs) are known to participate in the morphogenesis of various organs. In addition, we hypothesize that a defective function of immune cells generates an aberrant islet morphogenesis in T1D-prone individuals or animals. In the postweaning period (a period of islet remodelling), the same defective function of immune cells might precipitate the pro-inflammatory peri-islet microenvironment that favours islet autoimmune reactivity. In type 1 diabetes (T1D), and particularly in spontaneous animal models of the disease such as the nonobese diabetic (NOD) mouse and the Bio-Breeding (BB) rat, macrophages (MFs) and dendritic cells (DCs) are the first cells that appear at the periphery of pancreatic ducts and islets of Langerhans around weaning (3 weeks of age) [1]. These cells are then joined by lymphocytes, which induce periinsulitis before they enter the islet (insulitis), where they contribute to the death of insulin-producing b cells. MFs have a pivotal role in T1D because diabetes can be prevented by their selective depletion or the prevention of their extravasation into the pancreas [2]. However, as reviewed here, immune cell infiltration and accumulation is not an exclusive characteristic of T1D-prone animal models. Indeed, numerous MFs have been detected in human fetal pancreases in association with DCs and/or lymphocytes, as well as in control mouse pancreases, during the peri-natal period. Because immune cells and particularly MFs are involved in the morphogenesis of various other organs, we postulate that immune cell infiltration is a normal feature of pancreas development and that defects of such cells disturb pancreas organogenesis, potentially triggering T1D. Immune cells are normally present in fetal and neonatal pancreases In rodents, MFs are well recognized as being normal components of the adult pancreas, but the reason for their Corresponding author: Franc¸oise Homo-Delarche ([email protected]).
presence in fetal and neonatal pancreases is less obvious. In late fetal, neonatal and adult mice from control, NOD and NODscid (severe combined immunodeficiency) groups, high numbers of various types of MFs, especially mature BM8þ scavenger MFs, are localized at the periphery of vessels, nerves, ducts and islets, and are found scattered in the exocrine tissue and septa [1,3,4]. At birth, some types of MF (and DC) are more numerous in NOD and NODscid pancreases than in controls, which is suggestive of an already ongoing abnormal event in the islet environment [3]. During the first month of life, the number of MFs declines progressively in all strains until weaning, and the number then rebounds only in mice with the NOD genetic background (i.e. in NOD and NODscid mice) [3]. An early study on the human pancreas described lymphocyte infiltration concomitant with the two successive waves of islet degeneration that take place during development (see Ref. [3] and references therein). A more recent study showed that fetal and neonatal human pancreases harbour large focal leukocyte infiltrates, consisting mainly of T cells, which are present in the connective tissue of septa and in the capsule [5]. These areas sometimes contain high endothelial venule-like structures, DCs and MFs. DCs are also present at the periphery of the fetal islets. Diabetic human neonates present similar but enlarged structures. Others have confirmed the presence of MHC class II antigens and lymphocytes in human fetal pancreases [6]. Also intriguing are several reports describing the presence in humans of pancreatic lymphoid cysts, whose origin remains unknown [7]. Until now, the presence of considerable numbers of lymphocytes has not been described in the peri-natal pancreas of the normal rodent. Of note, inflammatory infiltrates and peri-insulitis have been described in situations other than spontaneous or induced models of T1D (listed in Table 1). Intriguingly, lymphocyte infiltration exists in two models of type 2 diabetes (T2D): the Otsuka Long Evans Tokushima fatty (OLETF) rat and the NZO/HI mouse. In young OLETF rats, a moderate lymphocyte infiltration takes place in and around the islets of Langerhans and this is replaced by islet fibrosis and pancreatic duct hyperplasia after 12 weeks [8]. In NZO/HI mice, focal peri-vascular and periductular leukocyte infiltrates are first observed in the pancreas of both sexes and, later, in chronically diabetic males, infiltrates are predominantly located along the
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Opinion
TRENDS in Immunology
Table 1. Immune cell infiltration is not an exclusive characteristic of type 1 diabetes (T1D)-prone animal models Animal model Aging, autoimmune-prone, nondiabetic strains and induced autoimmune disorders Aging C57BL/6 mice NZB, MRL, NZB/NZW and BXSB mice Drugs and graft-versus-host (GVH) reaction Diabetes-resistant (or relatively resistant) strains related to the nonobese diabetic (NOD) mouse ICR, CTS, NOR Class I b-cell-deprived NOD mice In vivo model of hyperglycaemia Prolonged hyperglycaemia 90% Pancreatectomy Animal models of type 2 diabetes (T2D) NZO/HI mouse Otsuka Long Evans Tokushima fatty (OLETF) rat Transgenic (Tg) mice for pro-inflammatory cytokinesa Rat insulin promoter –interferon g (RIP – IFN-g) Tg mice with a NOD background NOD mice Tg for pro-inflammatory cytokines, such as interleukin (IL)-6 and tumour necrosis factor (TNF)-a or -b RIP –TNF-a Tg NMRI mice Duct-ligation-induced pancreatitis a
Ref.
[60] [61] [62]
[63] [64] [65] [66] [9] [8] [11] [10] [12] [67]
Diabetes delayed or absent.
main pancreatic ducts and form follicle-like aggregates adjacent to islets [9]. Moreover, mice transgenic (Tg) for particular cytokines [e.g. interferon (IFN)-g] develop inflammatory infiltrates associated with morphological anomalies of pancreatic ducts and islets [10,11]. Generally, if these mice also have a diabetic background, diabetes onset is paradoxically delayed as a result of the continuous regeneration of new islets from duct cells, reminiscent of islet ontogeny, as shown by ductal hyperplasia, accumulation of inflammatory cells around islets and enlargement of the ductules near the inflamed islets. Pertinently, diabetes never develops in Tg NMRI mice expressing rat insulin promoter (RIP) –tumour necrosis factor (TNF)-a; these mice show islet fibrosis and development of intraislet ductules, with b cells sporadically seen in their walls, suggesting a regenerative capacity [12]. Importantly, islet disorganization and fibrosis do not result from lymphocyte infiltration, because they are also observed in scid mice bearing the transgene. Taken together, these observations suggest that the presence of mononuclear leukocytes within the pancreas is a common phenomenon potentially involved in pancreas differentiation, regeneration, aging, and immune and autoimmune reactions. Immune cells might have a role in normal pancreas development/regeneration Pancreas development starts with endodermal budding of the embryonic foregut into the surrounding mesenchyme (Figure 1) [13]. As for gastrointestinal, urogenital and respiratory organs, pancreas development, particularly ductal branching and differentiation, morphogenesis and growth of pancreatic islets and acini, results from intricate mesenchyme– epithelium interactions [14 – 17]. Vessels are also a crucial source of signals for inducing organ development [e.g. vascular endothelial growth factor (VEGF)], especially in the liver and pancreas [18]. www.sciencedirect.com
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Vasculogenesis and neurogenesis also appear to be tightly linked during organogenesis, by the production of factors such as bone morphogenic protein (BMP) and brainderived growth factor (BDNF) [18,19]. In addition, pancreas development is strongly dependent on that of innervation [14]. A variety of cytokines and growth factors appear to be implicated in pancreas organogenesis, such as IL-6, TNF-a, IFN-g, epidermal growth factor (EGF) ligands, transforming growth factor (TGF)-b ligands, hepatocyte growth factor (HGF), nerve growth factor (NGF), VEGF, and insulin growth factor I and II (IGF-I and -II) [20,21] (Box 1). Cell adhesion molecules (e.g. cadherins, neuralCAM) and extracellular matrix (ECM) proteins (e.g. laminin, fibronectin, collagens) are also involved in pancreas development [22]. ECM proteins bind cytokines and growth factors, and thereby modify their actions and modulate immune cell migration and function [23]. Also during the early postnatal period, tissue-remodelling phenomena (e.g. apoptosis, islet neogenesis, exocrine tissue growth) normally take place in the rodent pancreas [24– 26]. At all steps of these pancreatic developmental events, it still remains unclear which cells are transmitting and which cells are receiving signals, as underlined elsewhere [15]. In this context, immune cells, especially MFs and DCs, merit attention because their presence has been described during development of the limb, nervous system (brain, optic and sciatic nerves), retina, kidney, gut and thymus in birds and/or rodents (see Ref. [4] and references therein). Generally, immune cells, particularly MFs, are observed concomitantly with apoptotic phenomena [27,28]. Several findings suggest that MFs might be involved: (i) they have a well-recognized role in tissue remodelling Box 1. Growth and differentiation-inducing factors potentially involved in islet neogenesis Mesenchyme and extracellular matrix Activin A b-Cellulin Fibronectin Follistatin Laminin Matrix metalloproteinases (MMPs)
Cytokines and growth factors Epidermal growth factor (EGF) Fibroblast growth factor (FGF) Hepatocyte growth factor (HGF) Insulin growth factor (IGF)-I and -II Interferon (IFN)-g Interleukin (IL)-6 Keratinocyte growth factor (KGF) Nerve growth factor (NGF) Transforming growth factor (TGF)-a or -b Tumour necrosis factor (TNF)-a or -b Vascular endothelial growth factor (VEGF)
Miscellaneous Gastrin Glucagon-like protein (GLP)-1 Islet neogenesis-associated protein (INGAP) Parathormone-related protein (PTHrP) Reg protein
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Signals from mesoderm specify pancreatic fields
Endoderm foregut Ventral
Hlxb9 Initiation Dorsal and ventral buds
E9–9.5
Onset of branching
Ipf1 p48
Invaginated epithelium
E10.5
Growth and early morphogenesis
Ipf1 Pbx1 p48
Tubules bearing precursor cells E12.5 Stomach
Duodenum
Ipf1 Pbx1 Differentiation >E13.5
Hlxb9 p48 Ipf1
Islets
Islet
Acini
Acinus
Figure 1. Sequence of events that take place during pancreatic organogenesis. Development of the dorsal rudiment has been described only after E8.5. Proliferation of the pancreatic epithelium and fusion of the dorsal and ventral buds by E12.5 produces an epithelial tubular complex that contains the precursor cells for islets, acini and ducts. The extent of expression of the gene encoding insulin-promoter factor 1 [ipf1; also called pancreatic duodenum homeobox 1 (Pdx1)] is shown in yellow and the early endocrine cell clusters are in grey. The wave of exocrine and endocrine cell differentiation begins about E13.5 in mice, and is marked by the appearance of acinar cell digestive enzymes and marked increases in the number of insulin- and glucagon-expressing cells. The key pancreatic transcription factors required throughout development are placed at all steps that require them. Black ovals signify those with new roles. Figure reproduced with permission from Ref. [13].
and phagocytosis during embryogenesis; (ii) they secrete numerous substances, such as cytokines, growth factors, metalloproteinases and ECM proteins (Figure 2); and (iii) they are able to participate in various steps of organogenesis, such as angiogenesis/vasculogenesis, www.sciencedirect.com
neurogenesis/peri-natal nerve degeneration and epithelial branching [29 –32]. Regarding angiogenesis, a process that is crucial for pancreas development, MFs might, by producing growth factor(s) and cytokine(s), modify the composition of the
Opinion
TRENDS in Immunology
FGFb
IL-1α, β IL-6
+
HGF
IL-8
–
+
IGFs
IL-12 Mφ
–
IFN-γ
+
TNF-α
PDGFα, β TGF-α
LIF
TGF-β
+
+
+
VEGF
NGF
Activin A TIMPs
Collagenases
ECM proteins MMP-2
+
Fibronectin
MMP-9
Thrombospondin
–
Proteoglycans TRENDS in Immunology
Figure 2. Products that have been described as being secreted by MFs and that are capable of having a role in pancreas development. Green indicates factors involved in islet neogenesis and regeneration, pink is for those implicated in angiogenesis and vasculogenesis, and yellow for those with a role in neurogenesis. (þ) and (2) correspond to stimulatory and inhibitory effects, respectively. Abbreviations: ECM, extracellular matrix; EGF, epidermal growth factor; FGFb, fibroblast growth factor b; HGF, hepatocyte growth factor; IFN-g, interferon g; IGFs, insulin growth factors; IL, interleukin; LIF, leukocyte inhibitory factor; MF, macrophages; MMP, matrix metalloproteinase; NGF, nerve growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TIMPs, tissue inhibitors of metalloproteinases; TNF-a, tumor necrosis factor a; VEGF, vascular endothelial growth factor.
ECM, which in turn affects capillary growth [18,33 –35]. It is also pertinent to keep in mind that DCs derived from monocytes might even become endothelial cells [36]. Concerning innervation, neurodegeneration phenomena, which are prominent during development and the early postnatal period, are controlled by MFs (see Refs [4,37] and references therein). In the peri-natal pancreas of control, NOD and NODscid mice, Fasþ nerves are present in peri-islet, peri-ductular and peri-vascular areas [4]. Concomitantly, nerves expressing IFN-g-inducible protein (IP)-10 are surrounded by MFs, suggesting that this chemokine might attract leukocytes. MFs also influence ductal branching during postnatal mouse mammary gland development and a similar phenomenon might exist in the pancreas [38]. Finally, the mechanisms that control the detachment of the islet from the duct once differentiation and proliferation of endocrine cells have been achieved are unknown. Such detachment occurs during the peri-natal period and, in some adaptative situations (e.g. pregnancy), in adults. MFs might be involved in this phenomenon, because the cells are well situated for such a purpose www.sciencedirect.com
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by their peri-ductular and peri-insular localization during these periods (Fig. 3) [25].
EGF
–
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Immune cell defects might perturb organ development and/or early glucose homeostasis in NOD mice There is some evidence that defects in immune cells might interfere with normal pancreas development and glucose homeostasis. The absence of thymocytes or thymic products is able to affect glucose homeostasis. Indeed, the latter is altered in athymic BALB/c nude mice, which exhibit several precocious postnatal endocrine and metabolic defects, including spontaneous hyperglycaemia, impaired glucose tolerance and peripheral insensitivity to insulin [39]. Adult rat thymectomy modifies the properties of the pancreatic islets [40]. In human T1D and rodent models of the disease, lymphocytes have many, often innate, anomalies [41]. Of note, diabetes-prone (DP)-BB rats are severely lymphopenic owing to a mutation in the Ian-5 gene, whereas Tcells of NOD mice show innate disturbances in apoptosis [42]. Also MFs and DCs show numerous (innate) abnormalities in the NOD mouse, the BB rat and T1D patients, such as a defective differentiation from bone-marrow precursors, an enhanced arachidonic acid and NF-kB metabolism, an altered cytokine secretion and an abnormal Fc receptor gene (FcgRII) expression (see Refs [3,4] and references therein). FcgRII is involved in phagocytosis and, in this context, the reduced phagocytic ability of the MFs of the NOD mouse, and also of the BB rat, should be underlined [43]. Other autoimmune-prone nondiabetic strains (e.g. NZB, BXSB, SB/Le and MRL) also have the same FcgRII defect and some of them develop periinsulitis, as mentioned in Table 1 [44]. Interestingly, the innate immune cell aberrations in the NOD mouse model of T1D are accompanied by early, perinatal islet abnormalities: NOD fetal b cells produce more insulin in vitro; there is b-cell stimulation at birth, accompanied by a higher rate of b-cell apoptosis; and there are higher numbers of antigen-presenting cells (APCs) and FasLþ structures in NOD mice than in controls [3,4,45,46]. Moreover, at the salivary gland level, which is another target of the autoimmune reaction in NOD mice, a delayed morphological differentiation in 1-day-old salivary glands is associated throughout the preweaning period with higher matrix metalloproteinases (MMP)-2 and -9 activities (see Ref. [4] and references therein). Fas and FasL are also strongly expressed at birth and are localized around ducts and acini. Intriguingly, most of these structures resemble nerves, which are present in these same locations, as are the first infiltrating APCs. A scenario for the progression of disease in the NOD mouse model of T1D Owing to the various anomalies, NOD MFs and DCs might have a deleterious role in the successive waves of neuroendocrine events occurring at the islet level from the peri-natal to the post-weaning stage. This might ultimately lead to an excessive inflammatory response and islet autoimmunity (Figure 4). As argued above, MFs and DCs at the vascular– ductular pole and the periphery of the islet probably have a
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Fas or BCL-2+nerve
Fibroblast
Mesenchyme
Lumen Capillary
Mφ Ductal epithelial cells
Basal lamina Islet cells
Figure 3. Diagram showing that infiltrated macrophages (MFs) line the basal lamina that encircles the duct and the islet, once endocrine cells have differentiated and proliferated. Such a pattern of MF infiltration exists from peri-natal life in all strains of mice, including controls, and is observed around very small but also larger islets [3]. MFs are also in close contact with vessels and nerves at the ductular– insular pole. During postnatal pancreas development, nerves can be Fasþ or BCL-2þ [4]. The basal lamina is composed of extracellular matrix proteins, particularly fibronectin and collagens, and in spontaneous autoimmune diabetes must be broken to allow lymphocyte penetration at the ductular– vascular pole of the islet and into the islet [37]. Adapted with permission from Ref. [25].
role in the normal morphogenesis and early functional adaptation of the islets during the fetal and peri-natal period. After these early peri-natal morphogenic events, the islets enter a stage of ‘quiescence’. The ‘quiescent’ period, between birth and weaning, probably results from the lack of b-cell stimulation owing to the rich-lipid/lowcarbohydrate diet of maternal milk (Figure 4). At the end of this ‘quiescent period’ a wave of b-cell apoptosis takes place in rodents [24]. At weaning, a lack of sympathetic innervation might have an additional role: b-cell hyperactivity is downregulated by sympathetic innervation and primarily sympathetic nerves regress during the early peri-natal period (see Refs [4,37] and references therein). Pertinently, the peri-islet nerves are an early focus for MF and DC accumulation and appear to be a more likely precocious target than b cells [37,47]. Also, in NOD mice, islet neogenesis and ductal cell proliferation are enhanced in the early post-weaning phase [48,49]. In fact, the early post-weaning phase represents a new stage of islet remodelling and recalls the events taking place during the peri-natal period, including MF and DC infiltration [37,50]. Because MFs and DCs are again located at the same sites as during the peri-natal period, it is likely that the islet and its peripheral components (ducts, vessels, nerves) in principle again attract the immune cells for housekeeping (e.g. for growth regulation by cytokines, degradation/production of ECM and phagocytosis of debris). Under normal conditions, this entire process should not induce a destructive inflammatory reaction. It is reasonable to think that, in T1D-prone NOD mice, the same innate MF and DC functional defects that induce the perinatal islet morphogenic and functional aberrations now also allow for a break in tolerance (further supported by the anomalies of lymphocytes), and finally for the www.sciencedirect.com
development of an excessive islet inflammatory reaction and a pathological islet autoimmune response, leading to a ‘specific’ b-cell loss. Pertinently, we observed that the site where lymphocyte infiltration begins is the same as that used by MFs and DC (i.e. at the ductular– insular junction), as also mentioned by Yui and Fujita, who described the phenomenon as ‘lymphocytes infiltrating into islets on the side of peri-ductal connective tissue’ [51]. In the early post-weaning period, NOD hyperactive b cells might additionally contribute to the induction of the autoimmune response by elevating the expression of adhesion and MHC class II molecules and potential b-cell-specific autoantigens [50]. In this view, in which the whole islet and its duct, vascular and nerve structures, rather than b cells alone, are of importance in the early attraction of immune cells, the co-occurrence is not surprising of islet cell antibodies (ICAs) reacting with various islet endocrine cell types, and of duct antibodies in control and BB rats [52,53]. It would also explain the non-b-cell-specificity of ICAs, as discussed elsewhere [37]. ICAs and glutamic acid decarboxylase (GAD)67 mRNA have been described during the early postnatal period in control and NOD pancreases, and autoantibodies and cellular reactivities against nerves and the adjacent Schwann cells, such as anti-GAD, antiperipherin and anti-glial fibrillary acidic protein (GFAP), are detected just after weaning in NOD mice [37,47,54]. Moreover, autoantibodies to endothelial cells have been detected in DP-BB rats and RT6þ lymphocyte-depleted diabetes-resistant (DR)-rats before the onset of diabetes, and are able to induce vascular leakage, a process in which MFs appear to participate [55]. Finally, phagocytic MHC class IIþ mononuclear cells with vacuoles immunoreactive for insulin and glucagon in control rat islets might be interpreted as MFs that have phagocytosed apoptotic
Opinion
TRENDS in Immunology
- Abnormal maternal glucose homeostasis - Maternal insulin resistance? - Maternal–fetal HPA axis alteration?
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Abnormalities in islet development and nerve degeneration
?
- APC abnormalities - Defective phagocytosis
Glucose-priming effect?
Fetus
? - Hyperactive β cells - Increased islet neogenesis
Low glucosecontaining maternal milk
?
High number of APC
Birth
Abnormalities progressively normalize after birth
shift in diet High glucosecontaining laboratory chow
Weaning
Glucose-priming effect
Puberty Hyperglucagonemia
Cytokines? Hyperinsulinemia
GAD autoreactivity
Accumulation of infiltrating cells around and into the islets
Cytokines?
Damage of GABAergic innervation
Adult Diabetes TRENDS in Immunology
Figure 4. Hypothetical scenario for the progression of the diabetogenic process in NOD mice that takes into account fetal and peri-natal morphological disturbances (at the islet and nerve level), immune disturbances (e.g. those of APCs, particularly of MFs), and also potential maternal and fetal alterations in glucose homeostasis, sensitivity to insulin and the HPA axis. At birth, NOD (and NODscid) islets are characterized by hyperactive b cells, increased neogenesis and mild APC infiltration [3,45]. Also at birth, in NOD (and NODscid), but not in control, pancreases, numerous FasLþ structures are present in close contact to ducts, vessels, Fasþ nerves and islets (data not shown) [4,37]. NOD islet parameters normalize to control strain levels until weaning, probably owing to the low glucose-containing maternal milk. Thereafter, hyper-insulinaemia rapidly appears because diet shifts to high-glucose-containing laboratory chow [50]. Concomitantly, the well-recognized APC infiltration takes place at the periphery of ducts and islets, where it is rapidly joined by lymphocytes [1]. Then, antibodies and T-cell reactivities against GAD, peripherin, GFAP (a marker of Schwann cells that accompany neurons) appear, whereas the peri-islet Schwann cell sheet and GABAergic (GAD-containing) innervation progressively disappears (see Ref. [37] and references therein). The mild hyper-glucagonaemia that is observed after weaning in NOD (and NODscid) mice might result from the damage of GABAergic innervation and also, like hyper-insulinaemia, from the stimulatory effects of low doses of cytokines produced by infiltrating cells in the islet vicinity [50]. Finally, accumulating infiltrating immune cells break the peri-islet basal membrane, and b cells are destroyed by the combined deleterious effects of cytokines, immune cells and hyperglycaemia. Abbreviations: APC, antigen-presenting cell; FasL, Fas ligand; GABA, g-aminobutyric acid; GAD, glutamic acid decarboxylase; GFAP, glial fibrillary acidic protein; HPA, hypothalamus– pituitary–adrenal; MF, macrophages; NOD, nonobese diabetic; scid, severe combined immunodeficiency.
b and a cells [56]. Therefore, it cannot be excluded that these MFs have, at the same time, ingested other molecules such as GAD, peripherin, ductal and endothelial components. Taken together, these data highlight the complex orchestration of factors that are potentially at work from fetal life onwards into the post-weaning period to induce the autoimmune reaction on a T1D-prone background. As in other organs, pancreatic immune cells might have a role both in organ development and tolerance induction [5,57]. It is now beginning to be appreciated that the steady state turnover and trafficking of DCs and MFs from tissues to the draining lymph nodes serves the induction of peripheral tolerance and that the switching over of such steady state cells to an inflammatory phenotype induces www.sciencedirect.com
the process of (auto-)sensitization. Therefore, a disturbed pancreas development and an altered islet neogenesis might create a microenvironment favouring the development of an autoimmune reaction. Such a scenario might also explain the difficulty encountered in characterizing the multiple genes involved and the intricate dependence on numerous environmental factors. Suggestions for forthcoming research in the diabetes field The peri-natal period, which is a crucial moment for islet development, warrants extensive further investigation in terms of the cytokines and growth factors that are potentially produced by MFs and DCs and are susceptible to act on pancreas development. The causes of immune cell
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attraction during this period should also be examined by studying, for example, the expression of chemokines and chemokine receptors. Factors able to retain MFs, like macrophage inhibitory factor (MIF), which is present during pancreas organogenesis, also deserve further attention [58]. Such studies should be carried out on control strains, spontaneous models of T1D, related strains known to be resistant to diabetes and strains depleted, in one way or another, of MFs or lymphocytes. Spontaneous rat models of T1D should also be evaluated. Moreover, based on our experience with NOD and NODscid, we think that, when peri-natal pancreatic anomalies exist, studies should be completed by careful long-term analysis of glucose homeostasis. Finally, it is intriguing to see that T2D, a disease that is well recognized to be influenced by events taking place during fetal life, and therefore pancreas development, appears to have inflammatory components, including MF accumulation [59]. Acknowledgements We wish to thank M. Dardenne (CNRS FRE 2444, Hoˆpital Necker, Paris, France) and W. Savino (Dept of Immunology, Oswaldo Cruz Foundation of Rio de Janeiro, Brazil) for their continued support and long-term collaboration; V. Alves, J. Coulaud and S. Durant for their daily assistance; A. Amrani, S. Charre´, S. Geutkens, C. Pelegri, J. Rosmalen and F. Saravia who worked with enthusiasm as doctoral and postdoctoral fellows; H. Feillet and the staff of the Jean Hamburger– Pierre Royer library of Necker Hospital for bibliographical help; J. Jacobson for editorial assistance; and M. Netter for artwork. Our research was supported by grants from CNRS, Universite´ Paris V, Fondation de France, Alfediam (associated with Lilly Laboratories), INSERM-NWO, INSERM-CONICET, INSERM-CNPq, BIOMED ‘Betimmune’, 5th PCRD ‘Monodiab’ and Dutch Diabetes Foundation.
References 1 Jansen, A. et al. (1994) Immunohistochemical characterization of monocytes-macrophages and dendritic cells involved in the initiation of the insulitis and beta-cell destruction in NOD mice. Diabetes 43, 667 – 675 2 Jun, H.S. et al. (1999) The role of macrophages in T cell-mediated autoimmune diabetes in nonobese diabetic mice. J. Exp. Med. 189, 347 – 358 3 Charre, S. et al. (2002) Abnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period. Histol. Histopathol. 17, 393 – 401 4 Durant, S. et al. (2003) Proapoptosis and antiapoptosis-related molecules during postnatal pancreas development in control and nonobese diabetic mice: relationship with innervation. Lab. Invest. 83, 227 – 239 5 Jansen, A. et al. (1993) An immunohistochemical study on organized lymphoid cell infiltrates in fetal and neonatal pancreases. A comparison with similar infiltrates found in the pancreas of a diabetic infant. Autoimmunity 15, 31 – 38 6 Koo Seen Lin, L. et al. (1991) The immunology of the human foetal pancreas aged 8 – 13 gestational weeks. Transpl. Int. 4, 195 – 199. 7 Adsay, N.V. et al. (2002) Lymphoepithelial cysts of the pancreas: a report of 12 cases and a review of the literature. Mod. Pathol. 15, 492 – 501 8 Kawano, K. et al. (1994) OLETF (Otsuka Long-Evans Tokushima Fatty) rat: a new NIDDM rat strain. Diabetes Res. Clin. Pract. 24, S317 – S320 9 Junger, E. et al. (2002) The diabetes-prone NZO/Hl strain. II. Pancreatic immunopathology. Lab. Invest. 82, 843 – 853 10 Grewal, I.S. and Flavell, R.A. (1997) New insights into insulin dependent diabetes mellitus from studies with transgenic mouse models. Lab. Invest. 76, 3 – 10 11 Gu, D. and Sarvetnick, N. (1993) Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development 118, 33 – 46 www.sciencedirect.com
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12 Higuchi, Y. et al. (1992) Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes. J. Exp. Med. 176, 1719– 1731 13 Kim, S.K. and MacDonald, R.J. (2002) Signaling and transcriptional control of pancreatic organogenesis. Curr. Opin. Genet. Dev. 12, 540– 547 14 Edlund, H. (2002) Pancreatic organogenesis – developmental mechanisms and implications for therapy. Nat. Rev. Genet. 3, 524 – 532 15 Kim, S.K. and Hebrok, M. (2001) Intercellular signals regulating pancreas development and function. Genes Dev. 15, 111 – 127 16 Muller, U. and Brandli, A.W. (1999) Cell adhesion molecules and extracellular-matrix constituents in kidney development and disease. J. Cell Sci. 112, 3855– 3867 17 Rolland, G. et al. (1998) Ontogeny of extracellular matrix gene expression by rat lung cells at late fetal gestation. Biol. Neonate 73, 112 – 120 18 Lammert, E. et al. (2003) Role of endothelial cells in early pancreas and liver development. Mech. Dev. 120, 59 – 64 19 Jin, K. et al. (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 99, 11946 – 11950 20 Bonner-Weir, S. (2000) Islet growth and development in the adult. J. Mol. Endocrinol. 24, 297 – 302 21 Nielsen, J.H. et al. (2001) Regulation of beta-cell mass by hormones and growth factors. Diabetes 50, S25– S29 22 Jiang, F.X. and Harrison, L.C. (2002) Extracellular signals and pancreatic beta-cell development: a brief review. Mol. Med. 8, 763 – 770 23 Schor, H. et al. (2000) Modulation of leukocyte behavior by an inflamed extracellular matrix. Dev. Immunol. 7, 227 – 238 24 Finegood, D.T. et al. (1995) Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44, 249 – 256 25 Pictet, R. and Rutter, W. (1972) Development of the embryonic endocrine pancreas. In Handbook of Physiology, Section 7 Endocrinology (Vol. 1, Endocrine pancreas), pp. 25 – 66, American Physiological Society 26 Scaglia, L. et al. (1997) Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 138, 1736– 1741 27 Fadok, V.A. et al. (2001) Phagocyte receptors for apoptotic cells: recognition, uptake, and consequences. J. Clin. Invest. 108, 957– 962 28 Saikumar, P. et al. (1999) Apoptosis: definition, mechanisms, and relevance to disease. Am. J. Med. 107, 489 – 506 29 Duffield, J.S. (2003) The inflammatory macrophage: a story of Jekyll and Hyde. Clin. Sci. 104, 27– 38 30 Garcia-Garcia, E. and Rosales, C. (2002) Signal transduction during Fc receptor-mediated phagocytosis. J. Leukocyte Biol. 72, 1092 – 1108 31 Hume, D.A. et al. (2002) The mononuclear phagocyte system revisited. J. Leukocyte Biol. 72, 621 – 627 32 Stoy, N.S. (2002) Monocyte/macrophage initiation of organ-specific autoimmunity: the ultimate ‘bystander’ hypothesis? Med. Hypotheses 58, 312 – 326 33 Lingen, M.W. (2001) Role of leukocytes and endothelial cells in the development of angiogenesis in inflammation and wound healing. Arch. Pathol. Lab. Med. 125, 67 – 71 34 Polverini, P.J. (1995) The pathophysiology of angiogenesis. Crit. Rev. Oral Biol. Med. 6, 230– 247 35 Raines, E.W. (2000) The extracellular matrix can regulate vascular cell migration, proliferation, and survival: relationships to vascular disease. Int. J. Exp. Pathol. 81, 173 – 182 36 Fernandez Pujol, B. et al. (2001) Dendritic cells derived from peripheral monocytes express endothelial markers and in the presence of angiogenic growth factors differentiate into endothelial-like cells. Eur. J. Cell Biol. 80, 99 – 110. 37 Saravia, F. and Homo-Delarche, F. (2003) Is innervation an early target in autoimmune diabetes? Trends Immunol. 24, 574– 579 38 Gouon-Evans, V. et al. (2000) Postnatal mammary gland development requires macrophages and eosinophils. Development 127, 2269– 2282 39 Zeidler, A. et al. (1991) Peripheral insulin insensitivity in the hyperglycemic athymic nude mouse: similarity to noninsulin-dependent diabetes mellitus. Proc. Soc. Exp. Biol. Med. 196, 457 – 460 40 Zafirova, M. et al. (1992) Immunohistochemical and electron
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microscope studies of rat islets of Langerhans one month after adult thymectomy. Eur. J. Histochem. 36, 423 – 433 Delovitch, T.L. and Singh, B. (1997) The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7, 727 – 738 Lam-Tse, W.K. et al. (2002) Animal models of endocrine/organ-specific autoimmune diseases: do they really help us to understand human autoimmunity? Springer Semin. Immunopathol. 24, 297– 321 O’Brien, B.A. et al. (2002) Phagocytosis of apoptotic cells by macrophages from NOD mice is reduced. Diabetes 51, 2481 – 2488. Pritchard, N.R. et al. (2000) Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII. Curr. Biol. 10, 227– 230 Homo-Delarche, F. et al. (2003) Neonatal beta-cell hyperactivity in nonobese diabetic (NOD) and lymphocyte-deficient NODscid mice. Diabetologia 46, A168 Wilson, S.S. and DeLuca, D. (1997) NOD fetal thymus organ culture: an in vitro model for the development of T cells involved in IDDM. J. Autoimmun. 10, 461– 472 Winer, S. et al. (2003) Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. Nat. Med. 9, 198 – 205 Fernandes, A. et al. (1997) Differentiation of new insulin-producing cells is induced by injury in adult pancreatic islets. Endocrinology 138, 1750 – 1762 O’Reilly, L.A. et al. (1997) a-Cell neogenesis in an animal model of IDDM. Diabetes 46, 599– 606. Rosmalen, J.G. et al. (2002) Islet abnormalities in the pathogenesis of autoimmune diabetes. Trends Endocrinol. Metab. 13, 209 – 214 Yui, R. and Fujita, T. (1988) Islet pathology in NOD mice. In Frontiers in Diabetes Research. Lessons From Animal Diabetes II (Shafrir, E. and Renold, A., eds), pp. 112 – 116, John Libbey and Company Contreas, G. et al. (1990) Novel islet, duct, and acinar cell markers defined by monoclonal autoantibodies from prediabetic BB rats. Pancreas 5, 540– 547 de Krijger, R.R. et al. (1994) Islet cell cytoplasmic antibody reactivity in midgestational human fetal pancreas. Acta Diabetol. 31, 232 – 235
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54 Martignat, L. et al. (1995) Pancreatic expression of antigens for islet cell antibodies in non-obese diabetic mice. J. Autoimmun. 8, 465 – 482 55 Doukas, J. et al. (1996) Anti-endothelial cell autoantibodies in BB rats with spontaneous and induced IDDM. Diabetes 45, 1209 – 1216 56 Pipeleers, D.G. et al. (1987) Presence of pancreatic hormones in islet cells with MHC-class II antigen expression. Diabetes 36, 872 – 876 57 Alferink, J. et al. (1999) Peripheral T-cell tolerance: the contribution of permissive T-cell migration into parenchymal tissues of the neonate. Immunol. Rev. 169, 255– 261 58 Kobayashi, S. et al. (1999) Expression pattern of macrophage migration inhibitory factor during embryogenesis. Mech. Dev. 84, 153– 156 59 Dandona, P. et al. (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 25, 4 – 7 60 Hayashi, Y. et al. (1989) Spontaneous development of organ-specific autoimmune lesions in aged C57BL/6 mice. Clin. Exp. Immunol. 78, 120– 126 61 Kolb, H. et al. (1980) Spontaneous autoimmune reactions against pancreatic islets in mouse strains with generalized autoimmune disease. Diabetologia 19, 216 – 221 62 Saitoh, T. et al. (1990) Ductal lesions of exocrine glands and insulitis induced by L3T4þ T cells following graft-versus-host reaction due to major histocompatibility complex class II disparity. Clin. Immunol. Immunopathol. 57, 339 – 350 63 Kikutani, H. and Makino, S. (1992) The murine autoimmune diabetes model: NOD and related strains. Adv. Immunol. 51, 285– 322 64 Hamilton-Williams, E.E. et al. (2003) Beta cell MHC class I is a late requirement for diabetes. Proc. Natl. Acad. Sci. U. S. A. 100, 6688– 6693 65 Lipsett, M. and Finegood, D.T. (2002) b-cell neogenesis during prolonged hyperglycemia in rats. Diabetes 51, 1834 – 1841 66 Lampeter, E.F. et al. (1995) Regeneration of beta-cells in response to islet inflammation. Exp. Clin. Endocrinol. Diabetes 103, 74 – 78 67 Yamaguchi, Y. et al. (1993) In situ kinetics of acinar, duct, and inflammatory cells in duct ligation-induced pancreatitis in rats. Gastroenterology 104, 1498 – 1506
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Immune cells, pancreas development, regeneration and type 1 diabetes Franc¸oise Homo-Delarche1 and Hemmo A. Drexhage2 1 2
CNRS UMR 7059, Universite´ Paris 7/Denis Diderot, 2 place Jussieu, 75251, Paris Cedex 05, France Department of Immunology, Erasmus MC, Dr Molewaterplein 50, 3000 DR Rotterdam, The Netherlands
Macrophages (MFs), dendritic cells (DCs) and lymphocytes are involved in the pathogenesis of type 1 diabetes (T1D). However, the presence of these cells is not specific for a diabetes-prone background. MFs are also constituents of the normal fetal, neonatal and adult pancreas. We hypothesize that MFs, DCs and lymphocytes have a role in pancreas and islet development because immune cells (particularly MFs) are known to participate in the morphogenesis of various organs. In addition, we hypothesize that a defective function of immune cells generates an aberrant islet morphogenesis in T1D-prone individuals or animals. In the postweaning period (a period of islet remodelling), the same defective function of immune cells might precipitate the pro-inflammatory peri-islet microenvironment that favours islet autoimmune reactivity. In type 1 diabetes (T1D), and particularly in spontaneous animal models of the disease such as the nonobese diabetic (NOD) mouse and the Bio-Breeding (BB) rat, macrophages (MFs) and dendritic cells (DCs) are the first cells that appear at the periphery of pancreatic ducts and islets of Langerhans around weaning (3 weeks of age) [1]. These cells are then joined by lymphocytes, which induce periinsulitis before they enter the islet (insulitis), where they contribute to the death of insulin-producing b cells. MFs have a pivotal role in T1D because diabetes can be prevented by their selective depletion or the prevention of their extravasation into the pancreas [2]. However, as reviewed here, immune cell infiltration and accumulation is not an exclusive characteristic of T1D-prone animal models. Indeed, numerous MFs have been detected in human fetal pancreases in association with DCs and/or lymphocytes, as well as in control mouse pancreases, during the peri-natal period. Because immune cells and particularly MFs are involved in the morphogenesis of various other organs, we postulate that immune cell infiltration is a normal feature of pancreas development and that defects of such cells disturb pancreas organogenesis, potentially triggering T1D. Immune cells are normally present in fetal and neonatal pancreases In rodents, MFs are well recognized as being normal components of the adult pancreas, but the reason for their Corresponding author: Franc¸oise Homo-Delarche ([email protected]).
presence in fetal and neonatal pancreases is less obvious. In late fetal, neonatal and adult mice from control, NOD and NODscid (severe combined immunodeficiency) groups, high numbers of various types of MFs, especially mature BM8þ scavenger MFs, are localized at the periphery of vessels, nerves, ducts and islets, and are found scattered in the exocrine tissue and septa [1,3,4]. At birth, some types of MF (and DC) are more numerous in NOD and NODscid pancreases than in controls, which is suggestive of an already ongoing abnormal event in the islet environment [3]. During the first month of life, the number of MFs declines progressively in all strains until weaning, and the number then rebounds only in mice with the NOD genetic background (i.e. in NOD and NODscid mice) [3]. An early study on the human pancreas described lymphocyte infiltration concomitant with the two successive waves of islet degeneration that take place during development (see Ref. [3] and references therein). A more recent study showed that fetal and neonatal human pancreases harbour large focal leukocyte infiltrates, consisting mainly of T cells, which are present in the connective tissue of septa and in the capsule [5]. These areas sometimes contain high endothelial venule-like structures, DCs and MFs. DCs are also present at the periphery of the fetal islets. Diabetic human neonates present similar but enlarged structures. Others have confirmed the presence of MHC class II antigens and lymphocytes in human fetal pancreases [6]. Also intriguing are several reports describing the presence in humans of pancreatic lymphoid cysts, whose origin remains unknown [7]. Until now, the presence of considerable numbers of lymphocytes has not been described in the peri-natal pancreas of the normal rodent. Of note, inflammatory infiltrates and peri-insulitis have been described in situations other than spontaneous or induced models of T1D (listed in Table 1). Intriguingly, lymphocyte infiltration exists in two models of type 2 diabetes (T2D): the Otsuka Long Evans Tokushima fatty (OLETF) rat and the NZO/HI mouse. In young OLETF rats, a moderate lymphocyte infiltration takes place in and around the islets of Langerhans and this is replaced by islet fibrosis and pancreatic duct hyperplasia after 12 weeks [8]. In NZO/HI mice, focal peri-vascular and periductular leukocyte infiltrates are first observed in the pancreas of both sexes and, later, in chronically diabetic males, infiltrates are predominantly located along the
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Table 1. Immune cell infiltration is not an exclusive characteristic of type 1 diabetes (T1D)-prone animal models Animal model Aging, autoimmune-prone, nondiabetic strains and induced autoimmune disorders Aging C57BL/6 mice NZB, MRL, NZB/NZW and BXSB mice Drugs and graft-versus-host (GVH) reaction Diabetes-resistant (or relatively resistant) strains related to the nonobese diabetic (NOD) mouse ICR, CTS, NOR Class I b-cell-deprived NOD mice In vivo model of hyperglycaemia Prolonged hyperglycaemia 90% Pancreatectomy Animal models of type 2 diabetes (T2D) NZO/HI mouse Otsuka Long Evans Tokushima fatty (OLETF) rat Transgenic (Tg) mice for pro-inflammatory cytokinesa Rat insulin promoter –interferon g (RIP – IFN-g) Tg mice with a NOD background NOD mice Tg for pro-inflammatory cytokines, such as interleukin (IL)-6 and tumour necrosis factor (TNF)-a or -b RIP –TNF-a Tg NMRI mice Duct-ligation-induced pancreatitis a
Ref.
[60] [61] [62]
[63] [64] [65] [66] [9] [8] [11] [10] [12] [67]
Diabetes delayed or absent.
main pancreatic ducts and form follicle-like aggregates adjacent to islets [9]. Moreover, mice transgenic (Tg) for particular cytokines [e.g. interferon (IFN)-g] develop inflammatory infiltrates associated with morphological anomalies of pancreatic ducts and islets [10,11]. Generally, if these mice also have a diabetic background, diabetes onset is paradoxically delayed as a result of the continuous regeneration of new islets from duct cells, reminiscent of islet ontogeny, as shown by ductal hyperplasia, accumulation of inflammatory cells around islets and enlargement of the ductules near the inflamed islets. Pertinently, diabetes never develops in Tg NMRI mice expressing rat insulin promoter (RIP) –tumour necrosis factor (TNF)-a; these mice show islet fibrosis and development of intraislet ductules, with b cells sporadically seen in their walls, suggesting a regenerative capacity [12]. Importantly, islet disorganization and fibrosis do not result from lymphocyte infiltration, because they are also observed in scid mice bearing the transgene. Taken together, these observations suggest that the presence of mononuclear leukocytes within the pancreas is a common phenomenon potentially involved in pancreas differentiation, regeneration, aging, and immune and autoimmune reactions. Immune cells might have a role in normal pancreas development/regeneration Pancreas development starts with endodermal budding of the embryonic foregut into the surrounding mesenchyme (Figure 1) [13]. As for gastrointestinal, urogenital and respiratory organs, pancreas development, particularly ductal branching and differentiation, morphogenesis and growth of pancreatic islets and acini, results from intricate mesenchyme– epithelium interactions [14 – 17]. Vessels are also a crucial source of signals for inducing organ development [e.g. vascular endothelial growth factor (VEGF)], especially in the liver and pancreas [18]. www.sciencedirect.com
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Vasculogenesis and neurogenesis also appear to be tightly linked during organogenesis, by the production of factors such as bone morphogenic protein (BMP) and brainderived growth factor (BDNF) [18,19]. In addition, pancreas development is strongly dependent on that of innervation [14]. A variety of cytokines and growth factors appear to be implicated in pancreas organogenesis, such as IL-6, TNF-a, IFN-g, epidermal growth factor (EGF) ligands, transforming growth factor (TGF)-b ligands, hepatocyte growth factor (HGF), nerve growth factor (NGF), VEGF, and insulin growth factor I and II (IGF-I and -II) [20,21] (Box 1). Cell adhesion molecules (e.g. cadherins, neuralCAM) and extracellular matrix (ECM) proteins (e.g. laminin, fibronectin, collagens) are also involved in pancreas development [22]. ECM proteins bind cytokines and growth factors, and thereby modify their actions and modulate immune cell migration and function [23]. Also during the early postnatal period, tissue-remodelling phenomena (e.g. apoptosis, islet neogenesis, exocrine tissue growth) normally take place in the rodent pancreas [24– 26]. At all steps of these pancreatic developmental events, it still remains unclear which cells are transmitting and which cells are receiving signals, as underlined elsewhere [15]. In this context, immune cells, especially MFs and DCs, merit attention because their presence has been described during development of the limb, nervous system (brain, optic and sciatic nerves), retina, kidney, gut and thymus in birds and/or rodents (see Ref. [4] and references therein). Generally, immune cells, particularly MFs, are observed concomitantly with apoptotic phenomena [27,28]. Several findings suggest that MFs might be involved: (i) they have a well-recognized role in tissue remodelling Box 1. Growth and differentiation-inducing factors potentially involved in islet neogenesis Mesenchyme and extracellular matrix Activin A b-Cellulin Fibronectin Follistatin Laminin Matrix metalloproteinases (MMPs)
Cytokines and growth factors Epidermal growth factor (EGF) Fibroblast growth factor (FGF) Hepatocyte growth factor (HGF) Insulin growth factor (IGF)-I and -II Interferon (IFN)-g Interleukin (IL)-6 Keratinocyte growth factor (KGF) Nerve growth factor (NGF) Transforming growth factor (TGF)-a or -b Tumour necrosis factor (TNF)-a or -b Vascular endothelial growth factor (VEGF)
Miscellaneous Gastrin Glucagon-like protein (GLP)-1 Islet neogenesis-associated protein (INGAP) Parathormone-related protein (PTHrP) Reg protein
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Signals from mesoderm specify pancreatic fields
Endoderm foregut Ventral
Hlxb9 Initiation Dorsal and ventral buds
E9–9.5
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Ipf1 p48
Invaginated epithelium
E10.5
Growth and early morphogenesis
Ipf1 Pbx1 p48
Tubules bearing precursor cells E12.5 Stomach
Duodenum
Ipf1 Pbx1 Differentiation >E13.5
Hlxb9 p48 Ipf1
Islets
Islet
Acini
Acinus
Figure 1. Sequence of events that take place during pancreatic organogenesis. Development of the dorsal rudiment has been described only after E8.5. Proliferation of the pancreatic epithelium and fusion of the dorsal and ventral buds by E12.5 produces an epithelial tubular complex that contains the precursor cells for islets, acini and ducts. The extent of expression of the gene encoding insulin-promoter factor 1 [ipf1; also called pancreatic duodenum homeobox 1 (Pdx1)] is shown in yellow and the early endocrine cell clusters are in grey. The wave of exocrine and endocrine cell differentiation begins about E13.5 in mice, and is marked by the appearance of acinar cell digestive enzymes and marked increases in the number of insulin- and glucagon-expressing cells. The key pancreatic transcription factors required throughout development are placed at all steps that require them. Black ovals signify those with new roles. Figure reproduced with permission from Ref. [13].
and phagocytosis during embryogenesis; (ii) they secrete numerous substances, such as cytokines, growth factors, metalloproteinases and ECM proteins (Figure 2); and (iii) they are able to participate in various steps of organogenesis, such as angiogenesis/vasculogenesis, www.sciencedirect.com
neurogenesis/peri-natal nerve degeneration and epithelial branching [29 –32]. Regarding angiogenesis, a process that is crucial for pancreas development, MFs might, by producing growth factor(s) and cytokine(s), modify the composition of the
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FGFb
IL-1α, β IL-6
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HGF
IL-8
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IGFs
IL-12 Mφ
–
IFN-γ
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TNF-α
PDGFα, β TGF-α
LIF
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+
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NGF
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Collagenases
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Figure 2. Products that have been described as being secreted by MFs and that are capable of having a role in pancreas development. Green indicates factors involved in islet neogenesis and regeneration, pink is for those implicated in angiogenesis and vasculogenesis, and yellow for those with a role in neurogenesis. (þ) and (2) correspond to stimulatory and inhibitory effects, respectively. Abbreviations: ECM, extracellular matrix; EGF, epidermal growth factor; FGFb, fibroblast growth factor b; HGF, hepatocyte growth factor; IFN-g, interferon g; IGFs, insulin growth factors; IL, interleukin; LIF, leukocyte inhibitory factor; MF, macrophages; MMP, matrix metalloproteinase; NGF, nerve growth factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TIMPs, tissue inhibitors of metalloproteinases; TNF-a, tumor necrosis factor a; VEGF, vascular endothelial growth factor.
ECM, which in turn affects capillary growth [18,33 –35]. It is also pertinent to keep in mind that DCs derived from monocytes might even become endothelial cells [36]. Concerning innervation, neurodegeneration phenomena, which are prominent during development and the early postnatal period, are controlled by MFs (see Refs [4,37] and references therein). In the peri-natal pancreas of control, NOD and NODscid mice, Fasþ nerves are present in peri-islet, peri-ductular and peri-vascular areas [4]. Concomitantly, nerves expressing IFN-g-inducible protein (IP)-10 are surrounded by MFs, suggesting that this chemokine might attract leukocytes. MFs also influence ductal branching during postnatal mouse mammary gland development and a similar phenomenon might exist in the pancreas [38]. Finally, the mechanisms that control the detachment of the islet from the duct once differentiation and proliferation of endocrine cells have been achieved are unknown. Such detachment occurs during the peri-natal period and, in some adaptative situations (e.g. pregnancy), in adults. MFs might be involved in this phenomenon, because the cells are well situated for such a purpose www.sciencedirect.com
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by their peri-ductular and peri-insular localization during these periods (Fig. 3) [25].
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Immune cell defects might perturb organ development and/or early glucose homeostasis in NOD mice There is some evidence that defects in immune cells might interfere with normal pancreas development and glucose homeostasis. The absence of thymocytes or thymic products is able to affect glucose homeostasis. Indeed, the latter is altered in athymic BALB/c nude mice, which exhibit several precocious postnatal endocrine and metabolic defects, including spontaneous hyperglycaemia, impaired glucose tolerance and peripheral insensitivity to insulin [39]. Adult rat thymectomy modifies the properties of the pancreatic islets [40]. In human T1D and rodent models of the disease, lymphocytes have many, often innate, anomalies [41]. Of note, diabetes-prone (DP)-BB rats are severely lymphopenic owing to a mutation in the Ian-5 gene, whereas Tcells of NOD mice show innate disturbances in apoptosis [42]. Also MFs and DCs show numerous (innate) abnormalities in the NOD mouse, the BB rat and T1D patients, such as a defective differentiation from bone-marrow precursors, an enhanced arachidonic acid and NF-kB metabolism, an altered cytokine secretion and an abnormal Fc receptor gene (FcgRII) expression (see Refs [3,4] and references therein). FcgRII is involved in phagocytosis and, in this context, the reduced phagocytic ability of the MFs of the NOD mouse, and also of the BB rat, should be underlined [43]. Other autoimmune-prone nondiabetic strains (e.g. NZB, BXSB, SB/Le and MRL) also have the same FcgRII defect and some of them develop periinsulitis, as mentioned in Table 1 [44]. Interestingly, the innate immune cell aberrations in the NOD mouse model of T1D are accompanied by early, perinatal islet abnormalities: NOD fetal b cells produce more insulin in vitro; there is b-cell stimulation at birth, accompanied by a higher rate of b-cell apoptosis; and there are higher numbers of antigen-presenting cells (APCs) and FasLþ structures in NOD mice than in controls [3,4,45,46]. Moreover, at the salivary gland level, which is another target of the autoimmune reaction in NOD mice, a delayed morphological differentiation in 1-day-old salivary glands is associated throughout the preweaning period with higher matrix metalloproteinases (MMP)-2 and -9 activities (see Ref. [4] and references therein). Fas and FasL are also strongly expressed at birth and are localized around ducts and acini. Intriguingly, most of these structures resemble nerves, which are present in these same locations, as are the first infiltrating APCs. A scenario for the progression of disease in the NOD mouse model of T1D Owing to the various anomalies, NOD MFs and DCs might have a deleterious role in the successive waves of neuroendocrine events occurring at the islet level from the peri-natal to the post-weaning stage. This might ultimately lead to an excessive inflammatory response and islet autoimmunity (Figure 4). As argued above, MFs and DCs at the vascular– ductular pole and the periphery of the islet probably have a
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Fas or BCL-2+nerve
Fibroblast
Mesenchyme
Lumen Capillary
Mφ Ductal epithelial cells
Basal lamina Islet cells
Figure 3. Diagram showing that infiltrated macrophages (MFs) line the basal lamina that encircles the duct and the islet, once endocrine cells have differentiated and proliferated. Such a pattern of MF infiltration exists from peri-natal life in all strains of mice, including controls, and is observed around very small but also larger islets [3]. MFs are also in close contact with vessels and nerves at the ductular– insular pole. During postnatal pancreas development, nerves can be Fasþ or BCL-2þ [4]. The basal lamina is composed of extracellular matrix proteins, particularly fibronectin and collagens, and in spontaneous autoimmune diabetes must be broken to allow lymphocyte penetration at the ductular– vascular pole of the islet and into the islet [37]. Adapted with permission from Ref. [25].
role in the normal morphogenesis and early functional adaptation of the islets during the fetal and peri-natal period. After these early peri-natal morphogenic events, the islets enter a stage of ‘quiescence’. The ‘quiescent’ period, between birth and weaning, probably results from the lack of b-cell stimulation owing to the rich-lipid/lowcarbohydrate diet of maternal milk (Figure 4). At the end of this ‘quiescent period’ a wave of b-cell apoptosis takes place in rodents [24]. At weaning, a lack of sympathetic innervation might have an additional role: b-cell hyperactivity is downregulated by sympathetic innervation and primarily sympathetic nerves regress during the early peri-natal period (see Refs [4,37] and references therein). Pertinently, the peri-islet nerves are an early focus for MF and DC accumulation and appear to be a more likely precocious target than b cells [37,47]. Also, in NOD mice, islet neogenesis and ductal cell proliferation are enhanced in the early post-weaning phase [48,49]. In fact, the early post-weaning phase represents a new stage of islet remodelling and recalls the events taking place during the peri-natal period, including MF and DC infiltration [37,50]. Because MFs and DCs are again located at the same sites as during the peri-natal period, it is likely that the islet and its peripheral components (ducts, vessels, nerves) in principle again attract the immune cells for housekeeping (e.g. for growth regulation by cytokines, degradation/production of ECM and phagocytosis of debris). Under normal conditions, this entire process should not induce a destructive inflammatory reaction. It is reasonable to think that, in T1D-prone NOD mice, the same innate MF and DC functional defects that induce the perinatal islet morphogenic and functional aberrations now also allow for a break in tolerance (further supported by the anomalies of lymphocytes), and finally for the www.sciencedirect.com
development of an excessive islet inflammatory reaction and a pathological islet autoimmune response, leading to a ‘specific’ b-cell loss. Pertinently, we observed that the site where lymphocyte infiltration begins is the same as that used by MFs and DC (i.e. at the ductular– insular junction), as also mentioned by Yui and Fujita, who described the phenomenon as ‘lymphocytes infiltrating into islets on the side of peri-ductal connective tissue’ [51]. In the early post-weaning period, NOD hyperactive b cells might additionally contribute to the induction of the autoimmune response by elevating the expression of adhesion and MHC class II molecules and potential b-cell-specific autoantigens [50]. In this view, in which the whole islet and its duct, vascular and nerve structures, rather than b cells alone, are of importance in the early attraction of immune cells, the co-occurrence is not surprising of islet cell antibodies (ICAs) reacting with various islet endocrine cell types, and of duct antibodies in control and BB rats [52,53]. It would also explain the non-b-cell-specificity of ICAs, as discussed elsewhere [37]. ICAs and glutamic acid decarboxylase (GAD)67 mRNA have been described during the early postnatal period in control and NOD pancreases, and autoantibodies and cellular reactivities against nerves and the adjacent Schwann cells, such as anti-GAD, antiperipherin and anti-glial fibrillary acidic protein (GFAP), are detected just after weaning in NOD mice [37,47,54]. Moreover, autoantibodies to endothelial cells have been detected in DP-BB rats and RT6þ lymphocyte-depleted diabetes-resistant (DR)-rats before the onset of diabetes, and are able to induce vascular leakage, a process in which MFs appear to participate [55]. Finally, phagocytic MHC class IIþ mononuclear cells with vacuoles immunoreactive for insulin and glucagon in control rat islets might be interpreted as MFs that have phagocytosed apoptotic
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- Abnormal maternal glucose homeostasis - Maternal insulin resistance? - Maternal–fetal HPA axis alteration?
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Abnormalities in islet development and nerve degeneration
?
- APC abnormalities - Defective phagocytosis
Glucose-priming effect?
Fetus
? - Hyperactive β cells - Increased islet neogenesis
Low glucosecontaining maternal milk
?
High number of APC
Birth
Abnormalities progressively normalize after birth
shift in diet High glucosecontaining laboratory chow
Weaning
Glucose-priming effect
Puberty Hyperglucagonemia
Cytokines? Hyperinsulinemia
GAD autoreactivity
Accumulation of infiltrating cells around and into the islets
Cytokines?
Damage of GABAergic innervation
Adult Diabetes TRENDS in Immunology
Figure 4. Hypothetical scenario for the progression of the diabetogenic process in NOD mice that takes into account fetal and peri-natal morphological disturbances (at the islet and nerve level), immune disturbances (e.g. those of APCs, particularly of MFs), and also potential maternal and fetal alterations in glucose homeostasis, sensitivity to insulin and the HPA axis. At birth, NOD (and NODscid) islets are characterized by hyperactive b cells, increased neogenesis and mild APC infiltration [3,45]. Also at birth, in NOD (and NODscid), but not in control, pancreases, numerous FasLþ structures are present in close contact to ducts, vessels, Fasþ nerves and islets (data not shown) [4,37]. NOD islet parameters normalize to control strain levels until weaning, probably owing to the low glucose-containing maternal milk. Thereafter, hyper-insulinaemia rapidly appears because diet shifts to high-glucose-containing laboratory chow [50]. Concomitantly, the well-recognized APC infiltration takes place at the periphery of ducts and islets, where it is rapidly joined by lymphocytes [1]. Then, antibodies and T-cell reactivities against GAD, peripherin, GFAP (a marker of Schwann cells that accompany neurons) appear, whereas the peri-islet Schwann cell sheet and GABAergic (GAD-containing) innervation progressively disappears (see Ref. [37] and references therein). The mild hyper-glucagonaemia that is observed after weaning in NOD (and NODscid) mice might result from the damage of GABAergic innervation and also, like hyper-insulinaemia, from the stimulatory effects of low doses of cytokines produced by infiltrating cells in the islet vicinity [50]. Finally, accumulating infiltrating immune cells break the peri-islet basal membrane, and b cells are destroyed by the combined deleterious effects of cytokines, immune cells and hyperglycaemia. Abbreviations: APC, antigen-presenting cell; FasL, Fas ligand; GABA, g-aminobutyric acid; GAD, glutamic acid decarboxylase; GFAP, glial fibrillary acidic protein; HPA, hypothalamus– pituitary–adrenal; MF, macrophages; NOD, nonobese diabetic; scid, severe combined immunodeficiency.
b and a cells [56]. Therefore, it cannot be excluded that these MFs have, at the same time, ingested other molecules such as GAD, peripherin, ductal and endothelial components. Taken together, these data highlight the complex orchestration of factors that are potentially at work from fetal life onwards into the post-weaning period to induce the autoimmune reaction on a T1D-prone background. As in other organs, pancreatic immune cells might have a role both in organ development and tolerance induction [5,57]. It is now beginning to be appreciated that the steady state turnover and trafficking of DCs and MFs from tissues to the draining lymph nodes serves the induction of peripheral tolerance and that the switching over of such steady state cells to an inflammatory phenotype induces www.sciencedirect.com
the process of (auto-)sensitization. Therefore, a disturbed pancreas development and an altered islet neogenesis might create a microenvironment favouring the development of an autoimmune reaction. Such a scenario might also explain the difficulty encountered in characterizing the multiple genes involved and the intricate dependence on numerous environmental factors. Suggestions for forthcoming research in the diabetes field The peri-natal period, which is a crucial moment for islet development, warrants extensive further investigation in terms of the cytokines and growth factors that are potentially produced by MFs and DCs and are susceptible to act on pancreas development. The causes of immune cell
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attraction during this period should also be examined by studying, for example, the expression of chemokines and chemokine receptors. Factors able to retain MFs, like macrophage inhibitory factor (MIF), which is present during pancreas organogenesis, also deserve further attention [58]. Such studies should be carried out on control strains, spontaneous models of T1D, related strains known to be resistant to diabetes and strains depleted, in one way or another, of MFs or lymphocytes. Spontaneous rat models of T1D should also be evaluated. Moreover, based on our experience with NOD and NODscid, we think that, when peri-natal pancreatic anomalies exist, studies should be completed by careful long-term analysis of glucose homeostasis. Finally, it is intriguing to see that T2D, a disease that is well recognized to be influenced by events taking place during fetal life, and therefore pancreas development, appears to have inflammatory components, including MF accumulation [59]. Acknowledgements We wish to thank M. Dardenne (CNRS FRE 2444, Hoˆpital Necker, Paris, France) and W. Savino (Dept of Immunology, Oswaldo Cruz Foundation of Rio de Janeiro, Brazil) for their continued support and long-term collaboration; V. Alves, J. Coulaud and S. Durant for their daily assistance; A. Amrani, S. Charre´, S. Geutkens, C. Pelegri, J. Rosmalen and F. Saravia who worked with enthusiasm as doctoral and postdoctoral fellows; H. Feillet and the staff of the Jean Hamburger– Pierre Royer library of Necker Hospital for bibliographical help; J. Jacobson for editorial assistance; and M. Netter for artwork. Our research was supported by grants from CNRS, Universite´ Paris V, Fondation de France, Alfediam (associated with Lilly Laboratories), INSERM-NWO, INSERM-CONICET, INSERM-CNPq, BIOMED ‘Betimmune’, 5th PCRD ‘Monodiab’ and Dutch Diabetes Foundation.
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