Étude de la cytolyse autologue et du mimétisme immunitaire dans l'hépatite autoimmune de type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Étude de la cytolyse autologue et du mimétisme immunitaire dans l'hépatite autoimmune de type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Développement d’immunothérapies spécifiques pour le traitement de l’hépatite autoimmune de type 2 chez un modèle murin

L’hépatite autoimmune (HAI) est une maladie grave affectant le foie et présentant un haut taux de mortalité lorsque non traitée. Les traitements disponibles sont efficaces, mais de graves effets secondaires leur sont associés. Ces effets secondaires sont généralement le résultat d'une forte immunosuppression et d’autres sont spécifiques à chaque médicament. Aucune immunothérapie spécifique n’est présentement disponible pour le traitement de l’HAI. Récemment, un modèle murin d’HAI a été développé dans notre laboratoire par xénoimmunisation des souris C57BL/6 avec les antigènes humains de l'HAI de type 2. Ce modèle présente la plupart des caractéristiques biochimiques et cliniques retrouvées chez les patients atteints d'HAI de type 2. Dans cette étude, nous avons évaluée l’efficacité de deux types de traitement pour l’HAI de type 2 à l’aide de notre modèle murin. Dans un premier temps, l’anticorps anti-CD3ε a été étudié en prophylaxie et en traitement. Nous avons montré qu’une posologie de 5µg d’anti-CD3 i.v. par jour pendant 5 jours consécutifs induit une rémission chez les souris avec HAI de type 2 établie (traitement). Cette rémission est caractérisée par une normalisation des niveaux d’alanine aminotransférase et une diminution significative de l’inflammation hépatique. Cette rémission semble être associée à une déplétion partielle et transitoire des lymphocytes T CD3+ dans la périphérie et une augmentation des lymphocytes T régulateurs CD4+, CD25+ et Foxp3+ dans le foie. La même posologie lorsqu’elle est appliquée en prophylaxie n’a pas réussi à prévenir l’apparition de l’HAI de type 2. La deuxième voie de traitement consiste en l’administration par voie intranasale d’un forte dose de formiminotransférase cyclodésaminase murin (mFTCD), un autoantigène reconnu dans l’HAI de type 2. Une administration en prophylaxie par voie intranasale de 100µg de mFTCD par jour durant 3 jours consécutifs arrive à prévenir l’HAI de type 2 en diminuant l’inflammation hépatique au bout de deux semaines post-traitement.

Copolymer 1 induces T cells of the T helper type 2 that crossreact with myelin basic protein and suppress experimental autoimmune encephalomyelitis

The synthetic amino acid copolymer copolymer 1 (Cop 1) suppresses experimental autoimmune encephalomyelitis (EAE) and is beneficial in multiple sclerosis. To further understand Cop 1 suppressive activity, we studied the cytokine secretion profile of various Cop 1-induced T cell lines and clones. Unlike T cell lines induced by myelin basic protein (MBP), which secreted either T cell helper type 1 (Th1) or both Th1 and Th2 cytokines, the T cell lines/clones induced by Cop 1 showed a progressively polarized development toward the Th2 pathway, until they completely lost the ability to secrete Th1 cytokines. Our findings indicate that the polarization of the Cop 1-induced lines did not result from the immunization vehicle or the in vitro growing conditions, but rather from the tendency of Cop 1 to preferentially induce a Th2 response. The response of all of the Cop 1 specific lines/clones, which were originated in the (SJL/J×BALB/c)F1 hybrids, was restricted to the BALB/c parental haplotype. Even though the Cop 1-induced T cells had not been exposed to the autoantigen MBP, they crossreacted with MBP by secretion of interleukin (IL)-4, IL-6, and IL-10. Administration of these T cells in vivo resulted in suppression of EAE induced by whole mouse spinal cord homogenate, in which several autoantigens may be involved. Secretion of anti-inflammatory cytokines by Cop 1-induced suppressor cells, in response to either Cop 1 or MBP, may explain the therapeutic effect of Cop 1 in EAE and in multiple sclerosis.

Étude du rôle pathogénique de la formiminotransférase-cyclodésaminase dans l'hépatite auto-immune de type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Étude du rôle pathogénique de la formiminotransférase-cyclodésaminase dans l'hépatite auto-immune de type 2

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Associations of interleukin-1 (IL-1) gene variation and IL-1 receptor antagonist phenotypes with immunological responses, metabolic dysregulation and type 2 diabetes

The upstream proinflammatory interleukin-1 (IL-1) cytokines, together with a naturally occurring IL-1 receptor antagonist (IL-1Ra), play a significant role in several diseases and physiologic conditions. The IL-1 proteins affect glucose homeostasis at multiple levels contributing to vascular injuries and metabolic dysregulations that precede diabetes. An association between IL-1 gene variations and IL-1Ra levels has been suggested, and genetic studies have reported associations with metabolic dysregulation and altered inflammatory responses. The principal aims of this study were to: 1) examine the associations of IL-1 gene variation and IL-1Ra expression in the development and persistence of thyroid antibodies in subacute thyroiditis; 2) investigate the associations of common variants in the IL-1 gene family with plasma glucose and insulin concentrations, glucose homeostasis measures and prevalent diabetes in a representative population sample; 3) investigate genetic and non-genetic determinants of IL-1Ra phenotypes in a cross-sectional setting in three independent study populations; 4) investigate in a prospective setting (a) whether variants of the IL-1 gene family are predictors for clinically incident diabetes in two population-based observational cohort studies; and (b) whether the IL-1Ra levels predict the progression of metabolic syndrome to overt diabetes during the median follow-up of 10.8 and 7.1 years. Results from on patients with subacte thyroiditis showed that the systemic IL-1Ra levels are elevated during a specific proinflammatory response and they correlated with C-reactive protein (CRP) levels. Genetic variation in the IL-1 family seemed to have an association with the appearance of thyroid peroxidase antibodies and persisting local autoimmune responses during the follow-up. Analysis of patients suffering from diabetes and metabolic traits suggested that genetic IL-1 variation and IL-1Ra play a role in glucose homeostasis and in the development of type 2 diabetes. The coding IL-1 beta SNP rs1143634 was associated with traits related to insulin resistance in cross-sectional analyses. Two haplotype variants of the IL-1 beta gene were associated with prevalent diabetes or incident diabetes in a prospective setting and both of these haplotypes were tagged by rs1143634. Three variants of the IL-1Ra gene and one of the IL-1 beta gene were consistently identified as significant, independent determinants of the IL-1Ra phenotype in two or three populations. The proportion of the phenotypic variation explained by the genetic factors was modest however, while obesity and other metabolic traits explained a larger part. Body mass index was the strongest predictor of systemic IL-1Ra concentration overall. Furthermore, the age-adjusted IL-1Ra concentrations were elevated in individuals with metabolic syndrome or diabetes when compared to those free of metabolic dysregulation. In prospective analyses the systemic IL-1Ra levels were found as independent predictors for the development of diabetes in people with metabolic syndrome even after adjustment for multiple other factors, including plasma glucose and CRP levels. The predictive power of IL-1Ra was better than that of CRP. The prospective results also provided some evidence for a role of common IL-1 alpha promoter SNP rs1800587 in the development of type 2 diabetes among men and suggested that the role may be gender specific. Likewise, common variations in the IL-1 beta coding region may have a gender specific association with diabetes development. Further research on the potential benefits of IL-1Ra measurements in identifying individuals at high risk for diabetes, who then could be targeted for specific treatment interventions, is warranted. It has been reported in the recent literature that IL-1Ra secreted from adipose tissue has beneficial effects on glucose homeostasis. Furthermore, treatment with recombinant human IL-1Ra has been shown to have a substantial therapeutic potential. The genetic results from the prospective analyses performed in this study remain inconclusive, but together with the cross-sectional analyses they suggest gender-specific effects of the IL-1 variants on the risk of diabetes. Larger studies with more extensive genotyping and resequencing may help to pinpoint the exact variants responsible and to further elucidate the biological mechanisms for the observed associations. This would improve our understanding of the pathways linking inflammation and obesity with glucose and insulin metabolism.

Pathogenèse de l’hépatite autoimmune : influence des gènes, du sexe, de l’âge et de l’environnement

L’hépatite autoimmune (HAI) résulte d’une perte de tolérance du système immunitaire envers des antigènes de l’hépatocyte. Elle peut se présenter sous forme d’hépatite aiguë, parfois fulminante, ou comme une maladie chronique menant progressivement à une cirrhose hépatique. En absence de traitement, cette maladie est fatale. La pathogenèse de l’HAI et les mécanismes responsables de sa progression restent inconnus à ce jour. L’objectif global de ce projet est d’examiner les facteurs prédisposants et les mécanismes immunologiques responsables de l’apparition et de la progression de l’HAI. Pour permettre l’étude de la pathogenèse de l’HAI, nous avons développé un modèle murin expérimental d’hépatite autoimmune de type 2. Celui-ci est basé sur la xénoimmunisation de souris C57BL/6 avec les deux antigènes ciblés dans l’HAI de type 2 chez l’homme (CYP2D6 et FTCD). Par mimétisme moléculaire, le système immunitaire de ces souris réagit contre les protéines murines homologues et une HAI s’ensuit. Ce modèle expérimental présente la plupart des caractéristiques histologiques, biochimiques et sérologiques d’une HAI de type 2. Les souris développent une inflammation autoimmune chronique avec présence d’hépatite d’interface et d’infiltrations intralobulaires, un infiltrat composé majoritairement de lymphocytes T CD4+ mais aussi de lymphocytes T CD8+ et B, d’une élévation des ALT sériques, des niveaux d’immunoglobulines G circulantes augmentés ainsi que d’autoanticorps anti-LKM1 et anti-LC1. L’étude de l’influence du bagage génétique a permis de définir l’importance relative des gènes du CMH et des gènes non-CMH sur le développement d’une HAI. Les gènes du locus CMH sont essentiels mais insuffisants pour mener au développement d’une HAI et donc, la susceptibilité génétique à l’HAI est comme chez l’homme, multigénique. Les patients atteints d’HAI de type 2 sont généralement des jeunes filles. L’étude des influences de l’âge et du sexe dans ce modèle a permis de montrer que les souris femelles avant et au début de leur maturité sexuelle sont plus susceptibles au développement d’une HAI de type 2. De plus, les femelles ont un nombre réduit de lymphocytes T régulateurs, ce qui leur confère une susceptibilité accrue comparé aux mâles. L’ensemble de ces travaux nous a conduits à proposer un mécanisme où le développement d’une HAI chez les femelles d’un âge particulier résulterait de l’activation de cellules T CD4+ autoréactives ayant échappé aux mécanismes de tolérance centrale, via un mécanisme de mimétisme moléculaire avec un antigène exogène. En présence d’une tolérance périphérique réduite due à un faible nombre de cellules T régulatrices, les cellules T autoréactives proliféreraient et activeraient des cellules B autoréactives entraînant la sécrétion d’autoanticorps. L’activation subséquente de cellules T CD8+ cytotoxiques spécifiques amènerait la lyse des hépatocytes et la relâche d’autoantigènes permettant la perpétuation de l’autoimmunité.

Switch from a type 2 to a type 1 T helper cell response and cure of established Leishmania major infection in mice is induced by combined therapy with interleukin 12 and Pentostam.

Successful treatment in allergic, autoimmune, and infectious diseases often requires altering the nature of a detrimental immune response mediated by a particular CD4+ T helper (Th) cell subset. While several factors contribute to the development of CD4+ Th1 and Th2 cells, the requirements for switching an established response are not understood. Here we use infection with Leishmania major as a model to investigate those requirements. We report that treatment with interleukin 12 (IL-12), in combination with the antimony-based leishmanicidal drug Pentostam, induces healing in L. major-infected mice and that healing is associated with a switch from a Th2 to a Th1 response. The data suggest that decreasing antigen levels may be required for IL-12 to inhibit a Th2 response and enhance a Th1 response. These observations are important for treatment of nonhealing forms of human leishmaniasis and also demonstrate that in a chronic infectious disease an inappropriate Th2 response can be switched to an effective Th1 response.

Modulation of immune cells and Th1/Th2 cytokines in insulin-treated type 2 diabetes mellitus.

Background: The role of the immune system in insulin resistance associated with type 2 diabetes has been suggested. Objectives: We assessed the profile of Th1/Th2 cytokines along with the frequencies of immune cells in insulin-treated type 2 diabetic patients (T2DP). Methods: 45 T2D patients and 43 age-matched healthy subjects were selected. Serum concentrations of T-helper type 1 (Th1) and Th2 cytokines and the frequencies of innate and adaptive immunity cells were assessed. Results: T2DP were hyperglycemic and showed high level of insulin, normal levels of triglycerides and total-cholesterol and without any change in HDL-cholesterol.Compared to healthy subjects, T2DP exhibited significant decreased frequencies of neutrophils, without any change in monocytes, eosinophils and natural killer cells. The percentages of total lymphocytes (CD3+) and CD8+-T-cells decreased whereas those of regulatory T-cells increased without any change in CD4+ T-cells in T2DP. Interestingly, the frequencies of effector CD4+-T and B-cells increased in T2DP. Serum concentrations of IL-2, IFN-γ and IL-4 decreased while IL-10 significantly enhanced in T2DP, suggesting a differentiation of CD4+T helper cells towards IL-10-producing- Teff-cells in these patients. Conclusion: Insulin-treated type 2 diabetes is associated with anti-inflammatory profile consistent with differentiation of CD4+-Th-cells towards IL-10-producing-Teff-cells, concomitant with increased frequencies of Treg and B-cells, and this may probably offer prevention against certain infections or autoimmune/inflammatory diseases.

Is liraglutide or exenatide better in type 2 diabetes?

Background: Subjects with type 2 diabetes have high circulating levels of glucose. Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that has a major role in glucose homeostasis. Exenatide and liraglutide are both agonists at the GLP-1 receptor, and are effective at reducing circulating glucose levels (measured as HbA1c levels), but they have not been compared. Objectives/methods: This evaluation is of a clinical trial comparing liraglutide once a day with exenatide twice a day in subjects with type 2 diabetes. Results: In the Liraglutide Effect and Action in Diabetes (LEAD)-6 trial, subcutaneous liraglutide 1.8 mg once a day was compared with exenatide 10 μg twice a day. The primary efficacy outcome was change in HbA1c levels, and this was significantly greater with liraglutide (1.12%) than with exenatide (0.79%). Liraglutide and exenatide had similar small abilities to reduce body weight, blood pressure and LDL-cholesterol. Conclusions: Liraglutide was more effective than exenatide for overall glycaemic control in subjects with type 2 diabetes. However, this is only true for the preparations and doses tested, that is liraglutide 1.8 mg once weekly and exenatide 10 μg b.i.d., and may not apply when the comparison is undertaken with the new longer-lasting preparation of exenatide once weekly.

Resistance training for obese, type 2 diabetic adults: A review of the evidence

In both developed and developing countries, increased prevalence of obesity has been strongly associated with increased incidence of type 2 diabetes mellitus (T2DM) in the adult population. Previous research has emphasized the importance of physical activity in the prevention and management of obesity and T2DM, and generic exercise guidelines originally developed for the wider population have been adapted for these specific populations. However, the guidelines traditionally focus on aerobic training without due consideration to other exercise modalities. Recent reviews on resistance training in the T2DM population have not compared this modality with others including aerobic training, or considered the implications of resistance training for individuals suffering from both obesity and T2DM. In short, the optimal mix of exercise modalities in the prescription of exercise has not been identified for it benefits to the metabolic, body composition and muscular health markers common in obesity and T2DM. Similarly, the underlying physical, social and psychological barriers to adopting and maintaining exercise, with the potential to undermine the efficacy of exercise interventions, have not been addressed in earlier reviews. Because it is well established that aerobic exercise has profound effects on obesity and T2DM risk, the purpose of this review was to address the importance of resistance training to obese adults with T2DM.

Self-efficacy, outcome expectations and self-care behaviour in people with type 2 diabetes in Taiwan

Aims. To explore differences in self-care behaviour according to demographic and illness characteristics; and relationships among self-care behaviour and demographic and illness characteristics, efficacy expectations and outcome expectations of people with type 2 diabetes in Taiwan. Background. Most people with diabetes do not control their disease appropriately in Taiwan. Enhanced self-efficacy towards managing diseases can be an effective way of improving disease control as proposed by the self-efficacy model which provides a useful framework for understanding adherence to self-care behaviours. Design and methods. The sample comprised 145 patients with type 2 diabetes aged 30 years or more from diabetes outpatient clinics in Taipei. Data were collected using a self-administered questionnaire for this study. One-way anova, t-tests, Pearson product moment correlation and hierarchical regression were analysed for the study. Results. Significant differences were found: between self-care behaviour and complications (t = −2·52, p < 0·01) and patient education (t = −1·96, p < 0·05). Self-care behaviour was significantly and positively correlated with duration of diabetes (r = 0·36, p < 0·01), efficacy expectations (r = 0·54, p < 0·01) and outcome expectations (r = 0·44, p < 0·01). A total of 39·1% of variance in self-care behaviour can be explained by duration of diabetes, efficacy expectations and outcome expectations. Conclusions. Findings support the use of the self-efficacy model as a framework for understanding adherence to self-care behaviour. Relevance to clinical practice. Using self-efficacy theory when designing patient education interventions for people with type 2 diabetes will enhance self-management routines and assist in reducing major complications in the future.

Factors that affect health outcomes in adults with type 2 diabetes : a cross-sectional study

Background: Factors that individually influence blood sugar control, health-related quality of life, and diabetes self-care behaviors have been widely investigated; however, most previous diabetes studies have not tested an integrated association between a series of factors and multiple health outcomes. ---------- Objectives: The purposes of this study are to identify risk factors and protective factors and to examine the impact of risk factors and protective factors on adaptive outcomes in people with type 2 diabetes.---------- Design: A descriptive correlational design was used to examine a theoretical model of risk factors, protective factors, and adaptive outcomes.---------- Settings: This study was conducted at the endocrine outpatient departments of three hospitals in Taiwan. Participants A convenience sample of 334 adults with type 2 diabetes aged 40 and over.---------- Methods: Data were collected by a self-reported questionnaire and physiological examination. Using the structural equation modeling technique, measurement and structural regression models were tested.---------- Results: Age and life events reflected the construct of risk factors. The construct of protective factors was explained by diabetes symptoms, coping strategy, and social support. The construct of adaptive outcomes comprised HbA1c, health-related quality of life, and self-care behaviors. Protective factors had a significant direct effect on adaptive outcomes (β = 0.68, p < 0.001); however, risk factors did not predict adaptive outcomes (β = − 0.48, p = 0.118).---------- Conclusions: Identifying and managing risk factors and protective factors are an integral part of diabetes care. This theoretical model provides a better understanding of how risk factors and protective factors work together to influence multiple adaptive outcomes in people living with type 2 diabetes.