title: Inhibition of autoimmune diabetes in nonobese diabetic mice by transgenic restoration of H2-E MHC class II expression: additive, but unequal, involvement of multiple APC subtypes.
abstract: Transgenic restoration of normally absent H2-E MHC class II molecules on APC dominantly inhibits T cell-mediated autoimmune diabetes (IDDM) in nonobese diabetic (NOD) mice. We analyzed the minimal requirements for transgenic H2-E expression on APC subtypes (B lymphocytes vs macrophages/dendritic cells (DC)) to inhibit IDDM. This issue was addressed through the use of NOD stocks transgenically expressing high levels of H2-E and/or made genetically deficient in B lymphocytes in a series of genetic intercross and bone marrow/lymphocyte chimera experiments. Standard (H2-E(null)) NOD B lymphocytes exert a pathogenic function(s) necessary for IDDM. However, IDDM was inhibited in mixed chimeras where H2-E was solely expressed on all B lymphocytes. Interestingly, this resistance was abrogated when even a minority of standard NOD H2-E(null) B lymphocytes were also present. In contrast, in NOD chimeras where H2-E expression was solely limited to approximately half the macrophages/DC, an active immunoregulatory process was induced that inhibited IDDM. Introduction of a disrupted IL-4 gene into the NOD-H2-E transgenic stock demonstrated that induction of this Th2 cytokine does not represent the IDDM protective immunoregulatory process mediated by H2-E expression. In conclusion, high numbers of multiple subtypes of APC must express H2-E MHC class II molecules to additively inhibit IDDM in NOD mice. This raises a high threshold for success in future intervention protocols designed to inhibit IDDM by introduction of putatively protective MHC molecules into hemopoietic precursors of APC.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Johnson
authors.forename: P
authors.initials: P
authors.lastname: Silveira
authors.forename: H D
authors.initials: HD
authors.lastname: Chapman
authors.forename: E H
authors.initials: EH
authors.lastname: Leiter
authors.forename: D V
authors.initials: DV
authors.lastname: Serreze
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D017386:Sequence Homology, Amino Acid; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000276:immunology*
chemical_list: D006183:H-2 Antigens; D006684:HLA-DR Antigens; D015847:Interleukin-4