PREVENTION OF DIABETES IN NOD MICE BY A MUTATED I-AB TRANSGENE

Susceptibility to the human autoimmune disease IDDM is strongly associ ated with those haplotypes of the major histocompatibility complex (MH C) carrying DQB1 alleles that do not encode aspartic acid at codon 57. Similarly in a spontaneous animal model of this disease, the NOD mous e, the genes of the MHC play an important role in the development of d iabetes. The DQB1 homolog in NOD mice, I-Ab(g7), encodes a histidine a t codon 56 and a serine at codon 57, while all other known I-Ab allele s encode proline and aspartic acid, respectively, at these positions. We therefore mutated the NOD I-Ab allele to encode proline at position 56 and aspartic acid at position 57 and introduced this allele onto t he NOD genetic background to study the effect; of these substitutions on susceptibility to diabetes. No transgenic mice developed diabetes b y 8 months of age, and transgenic mice had markedly reduced lymphocyti c infiltration in the pancreas compared with nontransgenic Littermates . Furthermore, splenocytes from transgenic mice failed to proliferate or secrete gamma-interferon in response to a panel of P-cen autoantige ns, although the mice did produce P-cen specific antibodies. Interesti ngly, the proportion of IgG1 and IgE relative to IgG2a comprising thes e autoantibodies was much greater in transgenic mice compared with non transgenic control mice. Finally T-cells fi om transgenic mice inhibit ed the adoptive transfer of diabetes to irradiated recipients. This in hibition was partially reversed by treatment of the recipients with a combination of anti-interleukin (IL)4 and anti-IL-10 monoclonal antibo dies. Thus, a transgenic class II MHC allele encoding aspartic acid at B57 prevents diabetes, in part, by promoting the production of IL-4 a nd IL-10, which interfere with the effector phase of the diabetic proc ess.