The goal of this application is a) to investigate anti-idiotypic antibodies (anti-Id) directed to the four major autoantibodies in human Type 1 Diabetes (T1D), and b) to develop anti-Id to selectively deplete autoantigen-reactive B lymphocytes as a novel therapy to prevent T1D. Anti-Id to a major autoantibody in T1D (GAD65Ab) are found in the majority of healthy individuals. These anti-Id specifically target the antigen-binding site of GAD65Ab and thus block antigen recognition. Anti- Id to another major autoantibody (IAA) have been described previously in both T1D patients and the BB rat - an animal model for T1D- indicating that these idiotypic networks may be of relevance for T1D pathogenesis. At clinical diagnosis patients with T1D have significantly lower GAD65Ab-specific anti-Id titers as compared to healthy individuals. Moreover, anti-Id activity correlates with beta cell function, as observed in a longitudinal analysis of children with new onset T1D, who experienced a transitional increase in c-peptide levels. These data strongly suggest that GAD65Ab-specific anti-Id are part of the regulatory immune response to GAD65 and may therefore protect against T1D. Recent findings that injections of NOD mice with a monoclonal anti-Id prevented T1D support this hypothesis of protective anti-Id. This application will determine when anti-Id activiy is lost during development of T1D. Longitudinal samples from progressors and non-progressors will be analyzed for anti-Id to establish whether loss of anti-Id activity in progressors precedes T1D development. Another aim is to determine whether known high-risk and protective HLA genotypes are associated with low and high anti-Id activity, respectively. Such an association would support the hypothesis that HLA risk/protection is mediated in part by anti-Id activity. Anti Id are described to have regulatory immune functions. They neutralize autoantibodies, downregulate autoantibody secretion, and induce depletion of antigen-specific B lymphocytes. These characteristics are already employed in the treatment of other autoimmune diseases. A role of B lymphocytes in T1D has been suggested in animal studies, and the recent Rituximab trial demonstrated that global B lymphocyte depletion has a beneficial effect on the preservation of beta cell function. However global B lymphocyte depletion also eliminates beneficial B lymphocytes and is not a realistic option for the prevention of T1D. To avoid the global depletion of B lymphocytes, autoantigen-Fc fusion proteins will be used as mimetics of anti-Id. These fusion proteins will deplete B lymphocytes that are reactive to all epitopes of the autoantigen, while anti-Id will only target B lymphocytes of a single antibody epitope specificity. Autoantigen-Fc fusion proteins of all four major autoantigens (insulin, GAD65, IA-2, and ZnT8) will be used in this approach. The results from this project will be crucial for the further development of a novel preventative therapy.
To date no cure for Type 1 diabetes is available and new directions are necessary to identify pathogenic pathways to design prevention and intervention therapies. We identified a novel immune factor in the pathogenesis of Type 1 diabetes. While a protective role for similar factors has been described in other autoimmune diseases, this is a novel concept in Type 1 diabetes research.
|Zhao, Lue Ping; Alshiekh, Shehab; Zhao, Michael et al. (2016) Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes. Diabetes 65:710-8|
|Ganelin-Cohen, Esther; Modan-Moses, Dalit; Hemi, Rina et al. (2016) Epilepsy and behavioral changes, type 1 diabetes mellitus and a high titer of glutamic acid decarboxylase antibodies. Pediatr Diabetes 17:617-622|
|Zhao, Lue Ping; Bolouri, Hamid; Zhao, Michael et al. (2016) An Object-Oriented Regression for Building Disease Predictive Models with Multiallelic HLA Genes. Genet Epidemiol 40:315-32|
|Mitoma, Hiroshi; Adhikari, Keya; Aeschlimann, Daniel et al. (2016) Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias. Cerebellum 15:213-32|
|Chefdeville, Aude; Honnorat, JÃ©rÃ´me; Hampe, Christiane S et al. (2016) Neuronal central nervous system syndromes probably mediated by autoantibodies. Eur J Neurosci 43:1535-52|
|Bansal, N; Hampe, C S; Rodriguez, L et al. (2016) DPD epitope-specific glutamic acid decarboxylase (GAD)65 autoantibodies in children with Type 1 diabetes. Diabet Med :|
|Maziarz, M; Hagopian, W; Palmer, J P et al. (2015) Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies. Genes Immun 16:541-51|
|Rolandsson, Olov; Hampe, Christiane S; Wennberg, Patrik et al. (2015) Prevalence and Regional Distribution of Autoantibodies Against GAD65Ab in a European Population Without Diabetes: The EPIC-InterAct Study. Diabetes Care 38:e114-5|
|Gaba, Ruchi; Gambhire, Dhiraj; Uy, Natalie et al. (2015) Factors associated with early relapse to insulin dependence in unprovoked A-Î²+ ketosis-prone diabetes. J Diabetes Complications 29:918-22|
|Costa, Olivier R; StangÃ©, Geert; Verhaeghen, Katrijn et al. (2015) Development of an Enhanced Sensitivity Bead-Based Immunoassay for Real-Time In Vivo Detection of Pancreatic Î²-Cell Death. Endocrinology 156:4755-60|
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