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Perinatal tolerance to proinsulin is sufficient to prevent autoimmune diabetes
Gaurang Jhala, … , Thomas W.H. Kay, Balasubramanian Krishnamurthy
Gaurang Jhala, … , Thomas W.H. Kay, Balasubramanian Krishnamurthy
Published July 7, 2016
Citation Information: JCI Insight. 2016;1(10):e86065. https://doi.org/10.1172/jci.insight.86065.
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Research Article

Perinatal tolerance to proinsulin is sufficient to prevent autoimmune diabetes

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Abstract

High-affinity self-reactive thymocytes are purged in the thymus, and residual self-reactive T cells, which are detectable in healthy subjects, are controlled by peripheral tolerance mechanisms. Breakdown in these mechanisms results in autoimmune disease, but antigen-specific therapy to augment natural mechanisms can prevent this. We aimed to determine when antigen-specific therapy is most effective. Islet autoantigens, proinsulin (PI), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) were expressed in the antigen-presenting cells (APCs) of autoimmune diabetes-prone nonobese diabetic (NOD) mice in a temporally controlled manner. PI expression from gestation until weaning was sufficient to completely protect NOD mice from diabetes, insulitis, and development of insulin autoantibodies. Insulin-specific T cells were significantly diminished, were naive, and did not express IFN-γ when challenged. This long-lasting effect from a brief period of treatment suggests that autoreactive T cells are not produced subsequently. We tracked IGRP206–214-specific CD8+ T cells in NOD mice expressing IGRP in APCs. When IGRP was expressed only until weaning, IGRP206–214-specific CD8+ T cells were not detected later in life. Thus, anti-islet autoimmunity is determined during early life, and autoreactive T cells are not generated in later life. Bolstering tolerance to islet antigens in the perinatal period is sufficient to impart lasting protection from diabetes.

Authors

Gaurang Jhala, Jonathan Chee, Prerak M. Trivedi, Claudia Selck, Esteban N. Gurzov, Kate L. Graham, Helen E. Thomas, Thomas W.H. Kay, Balasubramanian Krishnamurthy

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Figure 1

Temporal proinsulin expression and spontaneous diabetes development in TIP mice.

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Temporal proinsulin expression and spontaneous diabetes development in T...
(A) Scheme for generation of tetracycline-regulated NOD-IEα-tTA (TA-NOD) and TetO-Ins2 dual-transgenic mice, referred to herein as TIP mice. (B) ELISA assay showing Dox-regulated proinsulin expression (mean ± SEM) in thymic and splenic homogenates of WT-NOD mice, untreated TIP mice, and TIP mice with the indicated duration of Dox treatment. (C) Western blot analysis of proinsulin expression in thymic lysates of WT-NOD mice and TIP mice with indicated treatments (2–3 independent experiments with n ≥ 2 per group). (D) Study design depicting different cohorts of TIP mice with the duration of induced PI expression indicated in gray. (E) Incidence of diabetes in cohorts 1–3 of TIP and WT-NOD mice. P = 0.0006 NOD vs. cohort 2; P = 0.0009 cohort 1 vs. cohort 2; P = 0.0015 cohort 3 vs. cohort 1. (F) Individual insulitis scores (mean ± SEM) for indicated cohorts of TIP mice (n ≥ 3/group, >90 islets scored per mouse). (G) Incidence of diabetes following transfer of splenocytes from 14- to 16-week-old donor TIP mice (cohorts 1–3) into 10- to 12-week-old irradiated NOD recipients (n > 5 each, P = 0.03 cohort 1 vs. cohort 2; P = 0.0012 cohort 1 vs. cohort 3). (H) IAA in sera of 12- to 15-week-old TIP mice, represented as absorbance at 450 nm (mean ± SEM). Each symbol in scatter plots (F and H) represents data from an individual mouse. *P < 0.05, **P < 0.01, ****P < 0.0001. Values compared using One-way ANOVA with Tukey’s multiple comparisons test (B, F and H)”. Survival curves (E and G) compared using log-rank test.

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