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.
Document Type
Article
Publication Date
2001
First Page
2404
Last Page
2410
JAX Source
J Immunol 2001 Aug; 167(4):2404-10.
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.
Recommended Citation
Johnson EA,
Silveira P,
Chapman HD,
Leiter EH,
Serreze DV.
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. J Immunol 2001 Aug; 167(4):2404-10.