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Novel Leptin Receptor Mutation in NOD/LtJ Mice Suppresses Type 1 Diabetes Progression

II. Immunologic Analysis

¹ Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
² The Jackson Laboratory, Bar Harbor, Maine
³ Department of Pathology, The University of Florida, Gainesville, Florida

Address correspondence and reprint requests to Edward H. Leiter, PhD, The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609. E-mail: ehl{at}jax.org

Abbreviations: APC, antigen-presenting cell; ConA, concanavalin A; EAE, experimental autoimmune encephalomyelitis; IGRP, islet-specific glucose-6-phosphatase catalytic subunit–related protein; IL, interleukin; LEPR, leptin receptor; mAb, monoclonal antibody; PEC, peritoneal exudate cell; SMLR, syngeneic mixed lymphocyte response; TGF, transforming growth factor; Th1, T helper-1; T-reg, regulatory T-cell

Recently, we identified in normally type 1 diabetes–prone NOD/LtJ mice a spontaneous new leptin receptor (LEPR) mutation (designated Lepr^db-5J) producing juvenile obesity, hyperglycemia, hyperinsulinemia, and hyperleptinemia. This early type 2 diabetes syndrome suppressed intra-islet insulitis and permitted spontaneous diabetes remission. No significant differences in plasma corticosterone, splenic CD4⁺ or CD8⁺ T-cell percentages, or functions of CD3⁺ T-cells in vitro distinguished NOD wild-type from mutant mice. Yet splenocytes from hyperglycemic mutant donors failed to transfer type 1 diabetes into NOD.Rag1^–/– recipients over a 13-week period, whereas wild-type donor cells did so. This correlated with significantly reduced (P < 0.01) frequencies of insulin and islet-specific glucose-6-phosphatase catalytic subunit–related protein–reactive CD8⁺ T-effector clonotypes in mutant mice. Intra-islet insulitis was also significantly suppressed in lethally irradiated NOD-Lepr^db-5J/Lt recipients reconstituted with wild-type bone marrow (P < 0.001). In contrast, type 1 diabetes eventually developed when mutant marrow was transplanted into irradiated wild-type recipients. Mitogen-induced T-cell blastogenesis was significantly suppressed when splenic T-cells from both NOD/Lt and NOD-Lepr^db-5J/Lt donors were incubated with irradiated mutant peritoneal exudate cells (P < 0.005). In conclusion, metabolic disturbances elicited by a type 2 diabetes syndrome (insulin and/or leptin resistance, but not hypercorticism) appear to suppress type 1 diabetes development in NOD-Lepr^db-5J/Lt by inhibiting activation of T-effector cells.

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