title: Novel leptin receptor mutation in NOD/LtJ mice suppresses type 1 diabetes progression: II. Immunologic analysis.
abstract: 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.
authors.affiliation: The Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609, USA. ehl@jax.org
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Yi-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Peter C
authors.initials: PC
authors.lastname: Reifsnyder
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Michael
authors.initials: M
authors.lastname: Clare-Salzler
authors.forename: Michelle
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
authors.forename: Edward H
authors.initials: EH
authors.lastname: Leiter
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose; D003208:Concanavalin A; D003345:Corticosterone / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D007515:Islets of Langerhans / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010641:Phenotype; D017354:Point Mutation; D011828:Radiation Chimera; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism*; D054411:Receptors, Leptin; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D003208:Concanavalin A; D003345:Corticosterone