title: Cellular expression requirements for inhibition of type 1 diabetes by a dominantly protective major histocompatibility complex haplotype.
abstract: The H2(g7) (K(d), A(g7), E(null), and D(b)) major histocompatibility complex (MHC) is the primary genetic contributor to type 1 diabetes in NOD mice. NOD stocks congenically expressing other MHC haplotypes such as H2(nb1) (K(b), A(nb1), E(k), and D(b)) in a heterozygous state are type 1 diabetes resistant. Hematopoietically derived antigen-presenting cells (APCs) expressing H2(nb1) MHC molecules delete or inactivate autoreactive diabetogenic T-cells. Thus, provided a relatively benign preconditioning protocol is ultimately developed, hematopoietic chimerization by APCs expressing dominantly protective MHC molecules could conceivably provide a means for type 1 diabetes prevention in humans. Before hematopoietic chimerization can be considered for type 1 diabetes prevention, it must be determined what subtype(s) of APCs (B-cells, macrophages, and/or dendritic cells) expressing protective MHC molecules most efficiently inhibit disease, as well as the engraftment level they must achieve to accomplish this. These issues were addressed through analyses of NOD background bone marrow chimeras in which H2(nb1) molecules were selectively expressed on variable proportions of different APC subtypes. While a modest B-cell effect was observed, the strongest type 1 diabetes protection resulted from at least 50% of dendritic cells and macrophages expressing H2(nb1) molecules. At this engraftment level, H2(nb1)-expressing dendritic cells and macrophages mediated virtually complete deletion of a highly pathogenic CD8 T-cell population.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Yi-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Pablo A
authors.initials: PA
authors.lastname: Silveira
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Osborne
authors.forename: Harold D
authors.initials: HD
authors.lastname: Chapman
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000145:classification / Q000276:immunology*; D001402:B-Lymphocytes / Q000378:metabolism; D001853:Bone Marrow / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics; D002678:Chimera; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D006239:Haplotypes; D007113:Immunity, Innate; D050417:Insulin-Secreting Cells / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D016827:CD8 Antigens