Tolerance to Proinsulin-1 Reduces Autoimmune Diabetes in NOD Mice
Autor: | Gaurang Jhala, Claudia Selck, Jonathan Chee, Chun-Ting J. Kwong, Evan G. Pappas, Helen E. Thomas, Thomas W.H. Kay, Balasubramanian Krishnamurthy |
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Rok vydání: | 2021 |
Předmět: |
lcsh:Immunologic diseases. Allergy
0301 basic medicine immune tolerance endocrine system endocrine system diseases type 1 diabetes Immunology Nod Biology digestive system proinsulin-1 Immune tolerance Mice 03 medical and health sciences 0302 clinical medicine Antigen Mice Inbred NOD medicine Animals Insulin Immunology and Allergy Antigen-presenting cell Original Research Autoantibodies Proinsulin NOD mice Type 1 diabetes nutritional and metabolic diseases medicine.disease CD4+ T cells Diabetes Mellitus Type 1 030104 developmental biology Glucose-6-Phosphatase lcsh:RC581-607 Insulitis hormones hormone substitutes and hormone antagonists 030215 immunology |
Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 12 (2021) |
ISSN: | 1664-3224 |
Popis: | T-cell responses to insulin and its precursor proinsulin are central to islet autoimmunity in humans and non-obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes. Mice have two proinsulin genes proinsulin -1 and 2 that are differentially expressed, with predominant proinsulin-2 expression in the thymus and proinsulin-1 in islet beta-cells. In contrast to proinsulin-2, proinsulin-1 knockout NOD mice are protected from autoimmune diabetes. This indicates that proinsulin-1 epitopes in beta-cells maybe preferentially targeted by autoreactive T cells. To study the contribution of proinsulin-1 reactive T cells in autoimmune diabetes, we generated transgenic NOD mice with tetracycline-regulated expression of proinsulin-1 in antigen presenting cells (TIP-1 mice) with an aim to induce immune tolerance. TIP-1 mice displayed a significantly reduced incidence of spontaneous diabetes, which was associated with reduced severity of insulitis and insulin autoantibody development. Antigen experienced proinsulin specific T cells were significantly reduced in in TIP-1 mice indicating immune tolerance. Moreover, T cells from TIP-1 mice expressing proinsulin-1 transferred diabetes at a significantly reduced frequency. However, proinsulin-1 expression in APCs had minimal impact on the immune responses to the downstream antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and did not prevent diabetes in NOD 8.3 mice with a pre-existing repertoire of IGRP reactive T cells. Thus, boosting immune tolerance to proinsulin-1 partially prevents islet-autoimmunity. This study further extends the previously established role of proinsulin-1 epitopes in autoimmune diabetes in NOD mice. |
Databáze: | OpenAIRE |
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