title: H-2D end confers dominant protection from IL-10-mediated acceleration of autoimmune diabetes in the nonobese diabetic mouse.
abstract: BALB/c mice that express IL-10 as a transgene in their pancreatic beta cells (Ins-IL-10 mice) do not develop diabetes, even after crossing to nonobese diabetic (NOD) mice ((Ins-IL-10 x NOD)F(1) mice). However, backcross of F(1) mice to NOD mice (NOD.Ins-IL-10 mice) results in N2 and N3 generations that develop accelerated diabetes. In this study, we found that NOD.Ins-IL-10 mice that expressed BALB/c-derived MHC molecules (NOD.Ins-IL-10(H-2(g7/d)) mice) were protected from diabetes. This protection associated with peri-islet infiltration and preserved beta cell function. Moreover, expression of I-A(d) and I-E(d) MHC class II molecules of BALB/c origin was not responsible for protection, but NOD.Ins-IL-10 mice that expressed BALB/c MHC class I D(d) molecules (NOD.Ins-IL-10(H-2(g7/d)) mice) did not develop diabetes. To directly test the possibility of a protective role of H-2D(d) in the development of accelerated diabetes, we generated transgenic mice expressing D(d) under the control of the MHC class I promoter. We found that double transgenic NOD.Ins-IL-10-D(d) mice developed accelerated diabetes in a fashion similar to NOD.Ins-IL-10 mice that were D(d) negative. Microsatellite analysis of H-2D(d)-linked loci confirmed association between BALB/c-derived alleles and protection of NOD.Ins-IL-10(H-2(g7/d)) mice. These results suggest a control of H-2D(d)-linked gene(s) on IL-10-mediated acceleration of autoimmune diabetes and dominant protection of the D(d) region in NOD.Ins-IL-10 mice.
authors: Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: A
authors: A
authors: La Cava
authors: B
authors: B
authors: Balasa
authors: A
authors: A
authors: Good
authors: K
authors: K
authors: van Gunst
authors: N
authors: N
authors: Jung
authors: N
authors: N
authors: Sarvetnick
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D008040:Genetic Linkage / Q000276:immunology; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics*; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000502:physiology*; D007515:Islets of Langerhans / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD / Q000235:genetics* / Q000276:immunology*; D016513:Mice, SCID; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D010179:Pancreas / Q000473:pathology; D011110:Polymorphism, Genetic / Q000276:immunology; D013045:Species Specificity
chemical_list: D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II; D016753:Interleukin-10