Genetic-induced variations in the GAD65 T-cell repertoire governs efficacy of anti-CD3/GAD65 combination therapy in new-onset type 1 diabetes.
To enhance efficacy of forthcoming type 1 diabetes (T1D) clinical trials, combination therapies (CTs) are envisaged. In this study, we showed that efficacy of a CT, using anti-CD3 antibody and glutamic acid decarboxylase of 65 kd (GAD65)-expressing plasmid, to reverse new-onset T1D was dependent upon the genetic background. Synergism between both treatments was only observed in the RIP-LCMV-GP but not in the nonobese diabetic (NOD) or RIP-LCMV-NOD models. Efficacy was associated with an expansion of bystander suppressor regulatory T cells (Tregs) recognizing the C-terminal region of GAD65 and secreting interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and interferon-gamma (IFN-gamma). In addition, we found that frequency and epitope specificity of GAD65-reactive CD4(+) T cells during antigen priming at diabetes onset and Tregs detected after CT correlated. Consequently, NOD mice harbored significantly lower levels of GAD65-reactive CD4(+) T cells than RIP-LCMV-GP before and after treatment. Our results demonstrate that antigen-specific T cells available at treatment may differ between various major histocompatibility complex (MHC) and genetic backgrounds. These cells play a major role in shaping T-cell responses following antigen-specific immune intervention and determine whether a beneficial Tregs response is generated. Our findings hold important implications to understand and predict the success of antigen-based clinical trials, where responsiveness to immunotherapy might vary from patient to patient.
Bresson
Damien
D
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA. damien@liai.org
Fradkin
Matthew
M
Manenkova
Yulia
Y
Rottembourg
Diane
D
von Herrath
Matthias
M
D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D017252:CD3 Complex / Q000276:immunology*; D016466:CHO Cells; D049109:Cell Proliferation; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D004797:Enzyme-Linked Immunosorbent Assay; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D017252:CD3 Complex; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2
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