Effects of two pediatric vaccines on autoimmune diabetes in NOD female mice

Toxicology Letters 146 (2003) 93–100

Effects of two pediatric vaccines on autoimmune diabetes in NOD female mice Guillaume Ravel a,b,∗ , Marielle Christ a , Pierre Liberge a , Roger Burnett a , Jacques Descotes b b

a MDS Pharma Services, les Oncins, 69210 St. Germain sur l’Arbresle, France Poison Center and INSERM U503, E. Herriot Hospital, 69437 Lyon Cedex 03, France

Received 11 July 2003; received in revised form 28 August 2003; accepted 1 September 2003

Abstract The induction or exacerbation of autoimmune diseases is a potential adverse effect of immunostimulating drugs. Vaccines have been suspected of such actions. Epidemiological studies, however, have so far failed to demonstrate any causal relationship between vaccination and autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). In this study, autoimmune diabetes-prone non-obese diabetic (NOD) mice were treated with two multivalent diphtheria, tetanus, pertussis, poliomyelitis and haemophilus vaccines (diphtheria, tetanus, acellular pertussis, inactivated polio (DTaP-IVP) or DTaP-IVP/Haemophilus influenza type b (Hib)) intraperitoneally at each of 10, 12 and 14 weeks of age. Although non-statistically significant, the incidence of autoimmune diabetes was slightly reduced by the DTaP-IVP vaccine. Blood glucose levels were actually significantly reduced in the mice treated with the DTaP-IVP vaccine relative to the untreated control mice. A slight decrease in blood glucose levels amongst the mice given the DTaP-IVP/Hib vaccine was also noted. Therefore this study does not support previous claims that children’s vaccination might be associated with acceleration or exacerbation of IDDM. © 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Vaccine; Autoimmunity; Immunotoxicity; Diabetes; NOD mice

1. Introduction The induction or exacerbation of autoimmune diseases is a potential adverse effect of immune-activating drugs, as shown by the clinical experience gained with therapeutic cytokines (Vial et al., 2002). It is well recognized that a variety of influences, including genetic, environmental and immunotoxic factors

∗

Corresponding author. E-mail address: [email protected] (G. Ravel).

are involved in the development of autoimmunity (Davidson and Diamond, 2001). Although vaccines are generally considered safe based on the large clinical experience, case reports of autoimmune diseases following vaccination fuelled concern for a possible causal relationship (Ada, 2001; Chen et al., 2001). For example, induction of insulin-dependent diabetes mellitus (IDDM) by immunization or infection in combination with genetic factors has been suggested (Robles and Eisenbarth, 2001). Interestingly, most of the reported autoimmune diseases following vaccination were organ-specific.

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In 1976, influenza vaccines were reported to induce an eight-fold increase in the risk of Guillain–Barre syndrome compared with the non-vaccinated population (Ropper and Victor, 1998). More recently, there has been a hot debate on a possible link between hepatitis B vaccine and multiple sclerosis or other demyelinating neural diseases (Confavreux et al., 2001; Jefferson and Heijbel, 2001). Measles, mumps and rubella (MMR) vaccines have been suspected to induce arthritis: 6 weeks after immunisation, MMR vaccinated children showed a higher risk of joint symptoms than non-immunized children (Benjamin et al., 1992). Arthritis was also reported in association with hepatitis B or tetanus vaccination (Shoenfeld and Aron-Maor, 2000). IDDM is another organ-specific autoimmune disease (Elliman, 1999). The most cited vaccine in connection with IDDM is the Haemophilus influenza type b (Hib) vaccine. Children who received a conjugate vaccine containing this valence have indeed been reported to be at a higher risk of developing IDDM (Classen, 1996). In contrast, only a few cases of systemic autoimmune diseases (e.g. lupus erythematosus) have been described following hepatitis B vaccine (Aron-Maor and Shoenfeld, 2001). Other cases of connective tissue diseases have been observed following Calmette Guerin Bacillus (BCG) vaccination (Sasmaz et al., 2001). A temporal relation between multivalent vaccines and systemic lupus erythematosus has also been suggested (Older et al., 1999). Epidemiological studies have, however, so far failed to demonstrate any increased risk of autoimmune diseases after vaccination (Gellin and Schaffner, 2001; Graves et al., 1999). Very few experimental studies focused on showing a causality link, if any. In fact, despite the long use of animal models of autoimmune diseases in fundamental immunology and immunopharmacological evaluation, these models have rarely been used to assess the risk of autoimmune disease associated with vaccines (Descotes et al., 2002). The non-obese diabetic (NOD) mouse is a widely used model of type 1 diabetes mellitus (IDDM) (Adorini et al., 2002). Autoimmune diabetes is closely linked to the MHC class II genes in both humans and NOD mice (McDevitt, 2001). Ineffective negative selection of autoreactive T cells in the thymus leads to autoreactive T cells infiltrating the islets of Langerhans causing pancreatic lesions and insulitis (Atkinson and

Leiter, 1999). Although the role of Th2 cells is still unclear, Th1 cells have been shown to play a pivotal role. In this study, female NOD mice were used to test the influence of two multivalent pediatric vaccines on autoimmune diabetes, namely a diphtheria, tetanus, acellular pertussis, inactivated polio (DTaP-IVP) vaccine, and a diphtheria, tetanus, acellular pertussis, inactivated polio, Haemophilus influenzae b (DTaP-IVP/Hib) vaccine. The immunostimulating agent tilorone hydrochloride was used as a positive control (Diamantstein, 1973; Kaibara et al., 1987; Levine et al., 1997).

2. Materials and methods 2.1. Animals Sixty female NOD/Bom mice were purchased from M&B (Gannat, France) at the age of 8 weeks. They were housed in groups of five in polycarbonate cages. The animal room was maintained at 19–25 ◦ C with a 12 h artificial lighting cycle and a minimum of eight air changes per hour. The animals had free access to diet and water. No contaminants were known to be present in the diet or water at levels that might have interfered with the objectives of the study. 2.2. Treatment NOD mice were randomly assigned to the treated and control groups (n = 15). Infanrix Polio ENF® (DTaP-IVP) and Infanrix Polio Hib NOUR® (DTaP-IVP/Hib) vaccines were purchased from GlaxoSmithKline (Nanterre, France). Tilorone hydrochloride was purchased from Sigma–Aldrich (Lyon, France). Vaccines were formulated under sterile conditions in 0.9% NaCl at 1:100. Treated mice were given 0.5 ml of the diluted vaccine. Tilorone hydrochloride was prepared as a 4 mg/ml solution under sterile conditions in 0.9% NaCl. The tilorone hydrochloride solution was filtered through a 0.22 ␮m filter. Treatment was administrated by intraperitoneal injection on days 0, 14 and 28 of the study (corresponding to 10, 12 and 14 weeks of age).

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2.3. Clinical examination

2.7. Statistical analysis

The animals were observed daily. Whenever severe clinical signs or suffering were evident, the animals were humanely sacrificed and submitted to necropsy. Animals were weighed once weekly and food consumption was recorded weekly for each cage during the study. Individual urine samples were collected every 2 weeks in metabolism cages from all animals deprived of food and water after receiving 20 ml/kg of tap water by gavage.

Levene’s test was used to test the equality of variance across groups and Shapiro–Wilkoxon’s test to assess the normality of the data distribution in each group. Data showing homogeneity across groups and normal distribution in the four groups were analyzed using Student’s t-test. Data showing non-homogeneous variances across groups or a non-normal distribution in at least one group was analyzed by the Kruskal–Wallis test, followed by a Wilcoxon rank sum test, if Kruskal–Wallis test was significant. Survival curves and percentage of treated mice with positive blood or urinary glucose levels were compared to those of non-treated mice using the log-rank test. The statistical analyses were performed using a SAS software package.

2.4. Assay of urinary proteins and glucose Urine samples from treated and control mice were analysed every 2 weeks for the presence of glucose and proteins using a standard dipstick (Bayer Co., Tarrytown, USA). Proteinuria was considered significant when the reading for urinary proteins was more than ++, corresponding to approximately 1.0 g/l.

3. Results 3.1. Incidence of autoimmune diabetes

2.5. Blood glucose determination Blood glucose analysis was performed every 2 weeks using a Lifescan One Touch Profile Meter (Issy les Moulineaux, France) with one drop of blood sampled from the tail. A 1.0 g/l calibration standard solution was assayed at least every 15 samples. In this study, attention was focused on any sign of glycemic disturbance. The threshold for positivity was set at the mean of the pretest values plus two standard errors. 2.6. Histopathological examination A full necropsy was performed on all surviving and decedent animals. Histopathological examinations were performed following fixation of the tissues in formalin (Chimie Plus, Denice, France) and embedding in paraffin wax (Lambert Riviere, Pierre-Benite, France). Four micrometer sections were cut and stained with hematoxylin–eosin prior to examination. Sections of the right kidneys were also stained with Periodic Acid Shiff’s reagent. The fixed tissues from the left kidneys were embedded in resin (Labonord, Templemars, France), 1 ␮m sections were cut and then stained in toluidine blue (Merck, Lyon, France).

The incidence of diabetes was determined by the percentage of mice with positive urinary glucose levels subsequent to increased blood glucose levels. The diabetes incidence in mice from the control and DTaP-IVP/Hib groups increased after 20 weeks of age (Fig. 1). At 34 weeks of age, namely at the end of the study, the incidence of diabetes was 19.8% in tilorone-treated mice and 40.6% in DTaP-IVP/Hib vaccine-treated mice. The diabetes incidence in DTaP-IVP treated mice did not exceed 13.3% during the whole study. Although the percentage of mice with diabetes at the end of the study was 46.7% in the control group, statistical significance was not attained. 3.2. Blood glucose levels Fasted animals with blood glucose levels exceeding 0.85 g/l on three successive occasions were considered positive. The percentage of control mice with positive blood glucose levels was statistically significantly increased from 16 weeks of age (Fig. 2). At 26 weeks of age, 93.3% of control mice were positive. In the vaccine-treated groups, an increase in the percentage of positive mice was seen between 16 and 20 weeks of age. The peak incidence occurred slightly

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100 incidence of diabetes (%)

90 80 70 60 50 40 30 20 10 0 10 12 14 16 18 20 22 24 26 28 30 32 34 Age (weeks) Fig. 1. Effect of tilorone hydrochloride (䊏), DTaP-IVP vaccine (䊉), DTaP-IVP/Hib vaccine (䉱) on the incidence of autoimmune diabetes of NOD mice, compared to control mice (䊐).

% of mice with positive blood glucose level

100 90 80 70 60 50 40 30 20 10 0 10 12 14 16 18 20 22 24 26 28 30 32 34 Age (weeks) Fig. 2. Effect of tilorone hydrochloride (䊏), DTaP-IVP vaccine (䊉), DTaP-IVP/Hib vaccine (䉱) on the incidence of hyperglycemia of NOD mice, compared to control mice (䊐). Blood glucose levels were significantly reduced in DTaP-IVP treated mice (P < 0.003) and tilorone treated mice (P < 0.03) when compared to control mice.

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Table 1 Microscopic findings on NOD mice after treatment Mice with microscopic lesions Control Lymphoid infiltrates around islets Kidneys Liver Eosinophilia Scattered necrosis Centrilobular necrosis Subcapsular area necrosis Spleen (extramedullary hemopoiesis) Lungs (thromboemboli) Heart (myocardial mineralisation)

Tilorone

DTaP-IVP

DTaP-IVP/Hib

6 –

5 –

6 –

6 –

10 8 – 2 –

3 2 – 1 –

4 2 1 1 –

7 5 – 1 1

3 2 1

5 – –

8 2 2

2 – –

later in the DTaP-IVP group than the DTaP-IVP/Hib group. Blood glucose levels were also significantly lower in the DTaP-IVP (P < 0.003) and tilorone (P < 0.03) groups than the untreated control mice. The peak incidence was nevertheless similar in the vaccine and tilorone groups. Although the percentage of mice with positive blood glucose levels was also lower in the DTaP-IVP/Hib group than the untreated control mice, statistical significance was not attained. 3.3. Urinary proteins Animals with urinary protein excretion exceeding 1 g/l on three successive occasions were considered positive. Urine protein concentrations were not significantly increased between 10 and 34 weeks of age in any of the groups of mice. 3.4. Histological examination The observed macroscopic changes, such as changes in the papillary process of the liver or enlargement of the uterus, were evenly distributed in the various groups and were not indicative of treatmentrelated pathology. The incidence of microscopic lesions is given in Table 1. Lymphoid infiltrates around pancreatic islets were observed in five or six mice in each of the four groups. The severity of this finding, graded from minimal to moderate, did not noticeably vary between the groups. No treatment-related changes were observed in the kidneys, even following special prepa-

ration and staining. Liver changes including intrahepatocyte eosinophilia and centrilobular scattered subcapsular necrosis was seen in ten controls and seven DTaP-IVP/Hib-treated mice. Only three mice given tilorone and four given DTaP-IVP had similar liver findings. Extramedullary hemopoiesis of the spleen was seen in three controls, five tilorone-treated mice, eight given DTaP-IVP and two given DTaP-IVP/Hib. There were no particular changes in the lymph nodes. Lung and myocardial abnormalities were seen in isolated control and DTaP-IVP treated animals. 3.5. Mortality, mean body weight, food consumption Mortality was similar in the vaccinated and untreated control mice. At 34 weeks of age, mortality was 26.7% in the DTaP-IVP group and 33.3% in the DTaP-IVP/Hib group. Tilorone induced early mortality with six mice between 10 and 18 weeks of age during or immediately after treatment. 53.3% of tilorone-treated mice survived to 34 weeks of age. None of these differences attained statistical significance. No differences in mean body weight and food consumption were observed between the four groups from 10 to 34 weeks of age.

4. Discussion This study shows that three administrations of the DTaP-IVP vaccine at 10, 12 and 14 weeks of age induced a slight reduction the incidence of autoimmune

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diabetes in NOD mice and a significant reduction in the percentage of mice with positive blood glucose levels. During the course of the study, the DTaP-IVP vaccine had a similar influence as that of tilorone hydrochloride, a known stimulant of humoral immunity (Megel et al., 1974). Importantly, the progress of diabetes appeared to be permanently inhibited, since the trend was still evident at 20 weeks after the last administration. The DTaP-IVP/Hib vaccine had less marked effects on the incidence of autoimmune diabetes and the percentage of mice with positive blood glucose levels. The reduction in both the incidence of autoimmune diabetes and blood glucose levels was observed without any noticeable effect on survival. In this study, only effects on the possible exacerbation or acceleration of the autoimmune diabetes were evaluated as vaccination started at 10 weeks of age whereas autoimmune process starts at about 4 weeks of age in NOD mice (Makino et al., 1981). Our experimental results are in disagreement with those of Classen who found an increased risk of autoimmune diabetes in NOD mice and BB rats after administration of pediatric vaccines (Classen, 1996). Although mice vaccinated at birth had a decreased incidence in diabetes, mice vaccinated after 2 months of age had an increased incidence in diabetes. However, no further studies using reference compounds known to induce or exacerbate IDDM in humans have been initiated to confirm these results (Descotes et al., 2002). In support of his experimental results, Classen and Classen (2000) found an increased risk of IDDM after childhood vaccination: vaccines given at birth, or in the first month of life, had a decreased incidence of IDDM, whereas administration after 2 months of age increased the risk (Classen and Classen, 2000). Several epidemiological studies including control groups did not provide evidence of an increased risk of IDDM after vaccination with Calmette Guerin Bacillus, Haemophilus influenzae b, poliomyelitis, diphteria, pertussis, tetanus, smallpox, rubella and mumps vaccines (DeStefano et al., 2001; Graves et al., 1999; Heijbel et al., 1997). In a cohort study on the relative risk of IDDM in Haemophilus influenzae b vaccinated children, no statistically significant difference was found between children not vaccinated, those vaccinated at 3 months of age and later with a recall administration and those vaccinated at 24 months of age (Karvonen et al., 1999).

The mechanisms by which vaccines might lead to autoimmune diseases are not known. Induction of autoimmunity by infectious agents has been observed in animal models (Wucherpfennig, 2001). The most frequently proposed mechanism is molecular mimicry that has also been proposed to explain the association between bacterial or viral infections and autoimmune diseases (Classen and Classen, 2001). Antigenic fractions of vaccines or residues of cell culture may have a similar molecular structure as self-antigens resulting in cross-reactivity between the infectious antigen and a self-antigen which could induce autoimmune reactivity or trigger autoimmune disease (Albert and Inman, 1999; Olson et al., 2001). Contrary to this, molecular mimicry could result in inhibition of autoimmunity as Haemophilus influenzae peptides have been reported to down regulate Th1 and Th2 responses in experimental autoimmune myasthenia gravis via mimicry with the nicotinic acetylcholine receptor (Im et al., 2002). Non-specific immune stimulation and a bystander effect on autoreactive T cells are other proposed mechanisms (Fournie et al., 2001). In a similar way, via a bystander effect involving microbial antigens or other constituents of the formulation (e.g. aluminium hydroxide), vaccines could influence autoreactive T cells. In the same way, vaccines could alter T-cell control of the immune response and induce polyclonal activation of autoreactive anti-class II T cells via an adjuvant effect (Classen and Classen, 2001). In NOD mice, the release of alpha interferon by macrophages following immunization has been proposed to explain why immunization could induce diabetes (Classen and Classen, 2001). Interestingly, alpha interferons have been reported to cause IDDM and other autoimmune diseases in humans (Okanoue et al., 1996). However, tilorone hydrochloride which exerted effects similar to those of either vaccine in this study is a potent interferon inducer (Walker, 1977). The inhibition of Experimental Allergic Encephalomyelitis (EAE) by tilorone hydrochloride is in keeping with our results (Levine et al., 1983). The Th1 /Th2 lymphocyte balance may also be influenced by vaccines. The adjuvant aluminium hydroxide is used as an adjuvant to stimulate the immune response induced by DTaP-IVP and DTaP-IVP/Hib vaccines, was shown to induce Th2 responses via IL-4 release (Del Giudice et al., 2001). As IL-4 inhibits Th1 responses, aluminium hydroxide can be assumed

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to exert the same effect than tilorone hydrochloride (Diamantstein, 1973; Megel et al., 1974). In keeping with this conclusion, BCG which induces a Th1 response can precipitate IDDM in NOD mice (Silveira and Baxter, 2001). In conclusion, when considering the available clinical data, vaccines are safe and protect healthy people from vital infectious diseases, even though additional studies are still needed to evaluate conflicting results (Elliman, 1999). Among these, epidemiological studies are likely to be essential, but more experimental work will also be helpful to investigate the influence of vaccines on autoimmunity (Shoenfeld and Aron-Maor, 2000). This study in NOD mice using two widely used multivalent pediatric vaccines does not support the assumption that vaccinated children might be at a higher risk of developing IDDM.

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