title: Modulation of insulitis and type 1 diabetes by transgenic HLA-DR3 and DQ8 in NOD mice lacking endogenous MHC class II.
abstract: To evaluate the contributions of DR3 and DQ8 to the etiopathogenesis of type 1 diabetes in a diabetes-predisposing milieu, we developed human leukocyte antigen (HLA) transgenic mice on the nonobese diabetic (NOD) background in the absence of the endogenous class II molecule, I-A(g7) and studied the incidence of both spontaneous and experimental (induced) autoimmune diabetes. Transgenic expression of HLA-DR3 and -DQ8 (either alone or in combination) did not confer susceptibility to spontaneous or cyclophosphamide-induced type 1 diabetes. Expression of I-A(g7) was mandatory for development of spontaneous or cyclophosphamide-induced diabetes. However, multiple low doses of streptozotocin could induce diabetes in all groups of mice independent of the class II molecules expressed. In unmanipulated mice, only islets from I-A(g7+/+) mice revealed significant intra-islet infiltration. Although a characteristic peri-insulitis/peri-ductulitis was present in Abeta(0)/NOD mice, islets from DR3, DQ8 and DR3 x DQ8 double transgenic mice demonstrated significantly less infiltration. In conclusion, transgenic expression of HLA-DR3 and -DQ8 associated with predisposition to type 1 diabetes alone is not sufficient to induce spontaneous diabetes in NOD mice lacking endogenous class II molecules.
authors.affiliation: Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA.
authors.forename: Yogish C
authors.initials: YC
authors.lastname: Kudva
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
authors.forename: Raghavan
authors.initials: R
authors.lastname: Raju
authors.forename: Roshini S
authors.initials: RS
authors.lastname: Abraham
authors.forename: Michelle
authors.initials: M
authors.lastname: Smart
authors.forename: Julie
authors.initials: J
authors.lastname: Hanson
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000502:physiology; D003520:Cyclophosphamide / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D005260:Female; D005951:Glucose Tolerance Test; D006683:HLA-DQ Antigens / Q000502:physiology*; D015803:HLA-DR3 Antigen / Q000502:physiology*; D007249:Inflammation / Q000209:etiology; D007515:Islets of Langerhans / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D012469:Salivary Glands / Q000473:pathology; D013311:Streptozocin; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D015704:CD4 Antigens; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D015803:HLA-DR3 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta; D013311:Streptozocin; D003520:Cyclophosphamide