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Autoimmunity to Both Proinsulin and IGRP Is Required for Diabetes in Nonobese Diabetic 8.3 TCR Transgenic Mice¹

Balasubramanian Krishnamurthy^*, Lina Mariana^*, Shane A. Gellert, Peter G. Colman, Leonard C. Harrison, Andrew M. Lew, Pere Santamaria, Helen E. Thomas^* and Thomas W. H. Kay^2,*,¶

^* St. Vincent’s Institute, Fitzroy, Victoria, Australia; Department of Diabetes and Endocrinology and Pathology, The Royal Melbourne Hospital, Parkville, Victoria, Australia; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Julia McFarlane Diabetes Research Centre and Department of Microbiology and Infectious Disease, University of Calgary Faculty of Medicine, Calgary, Alberta, Canada; and ^¶ The University of Melbourne Department of Medicine, St. Vincent’s Hospital, Fitzroy, Victoria, Australia

T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) induce diabetes in nonobese diabetic (NOD) mice. TCR transgenic mice with CD8⁺ T cells specific for IGRP_206–214 (NOD8.3 mice) develop accelerated diabetes that requires CD4⁺ T cell help. We previously showed that immune responses against proinsulin are necessary for IGRP_206–214-specific CD8⁺ T cells to expand. In this study, we show that diabetes development is dramatically reduced in NOD8.3 mice crossed to NOD mice tolerant to proinsulin (NOD-PI mice). This indicates that immunity to proinsulin is even required in the great majority of NOD8.3 mice that have a pre-existing repertoire of IGRP_206–214-specific cells. However, protection from diabetes could be overcome by inducing islet inflammation either by a single dose of streptozotocin or anti-CD40 agonist Ab treatment. This suggests that islet inflammation can substitute for proinsulin-specific CD4⁺ T cell help to activate IGRP_206–214-specific T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ P.S. is a scientist of the Alberta Heritage Foundation for Medical Research and is supported by the Canadian Institutes of Health Research, the Canadian Diabetes Association, and the Juvenile Diabetes Research Foundation. The Julia McFarlane Diabetes Research Centre is supported by the Diabetes Association (Foothills). The work was supported by a Program Grant; Career Development Award (to H.T.) and Clinical Centre for Research Excellence from the National Health and Medical Research Council of Australia; a Program-Project Grant and a post-doctoral fellowship (to B.K.) from the Juvenile Diabetes Research Foundation; and a Millennium Research Grant from Diabetes Australia (to T.K.).

² Address correspondence and reprint requests to Dr. Thomas W. H. Kay, St. Vincent’s Institute, 41 Victoria Parade, Fitzroy, VIC 3065, Australia. E-mail address: tkay{at}svi.edu.au

³ Abbreviations used in this paper: T1D, type 1 diabetes; NOD, nonobese diabetic; IGRP, islet-specific glucose-6-phosphatase catalytic subunit related protein; DC, dendritic cell; NOD-PI, NOD mice tolerant to proinsulin; STZ, streptozotocin; IAA, insulin autoantibody assay; Treg, regulatory T cell.

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The JI 2008 180: 4349-4350. [Full Text]