title: RIP-beta 2-microglobulin transgene expression restores insulitis, but not diabetes, in beta 2-microglobulin null nonobese diabetic mice.
abstract: Beta2m-deficient nonobese diabetic (NODbeta2mnull) do not develop insulitis or diabetes. Expression of a beta2m transgene controlled by the rat insulin promoter (RIP-beta2m) in NODbeta2mnull mice resulted in reconstitution of IFN-gamma-inducible cell surface MHC class I protein on pancreatic beta-cells. These mice developed insulitis, but did not develop diabetes. Transfer of T cells from diabetic NOD mice to NODbeta2mnull recipients resulted in insulitis, which took several months to progress to diabetes. In contrast, transgenic RIP-beta2m/NODbeta2mnull mice with islet MHC class I reconstitution developed diabetes rapidly after transfer of diabetic NOD spleen cells. Administration of cyclophosphamide, which accelerates diabetes in NOD mice, resulted in 43% of RIPbeta2m/NODbeta2mnull mice becoming diabetic compared with 75% of wild-type mice and 0% of NODbeta2mnull mice. Acceleration of diabetes by cyclophosphamide was prevented by anti-CD8 mAb treatment. FACS analysis of peripheral blood and lymphoid organs from transgene-bearing animals did not show an increase in the number of CD8+ T cells compared with that in NODbeta2mnull mice. In summary, beta-cell expression of beta2m in NODbeta2mnull mice resulted in a return of insulitis, but not spontaneous diabetes. These studies demonstrate that beta2m and cell surface MHC class I expression on beta-cells are essential for the initiation of diabetes in the NOD mouse and further confirm that efficient progression to diabetes requires both CD4+ and CD8+ T cells.
authors.affiliation: Burnet Clinical Research Unit, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Victoria, Australia.
authors.forename: T W
authors.initials: TW
authors.lastname: Kay
authors.forename: J L
authors.initials: JL
authors.lastname: Parker
authors.forename: L A
authors.initials: LA
authors.lastname: Stephens
authors.forename: H E
authors.initials: HE
authors.lastname: Thomas
authors.forename: J
authors.initials: J
authors.lastname: Allison
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics*; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D051381:Rats; D001613:beta 2-Microglobulin / Q000172:deficiency* / Q000235:genetics*
chemical_list: D015395:Histocompatibility Antigens Class I; D007328:Insulin; D001613:beta 2-Microglobulin