Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A β-chain or normal I-E α-chain

Abstract

Insulin-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The inbred non-obese diabetic (NOD) mouse strain provides a good animal model of the human disease and genetic analysis suggests that, as in man, at least one of the several genes controlling the development of IDDM is linked to the major histocompatibility complex. The NOD mouse does not express I-E owing to a deletion in the promoter region of the I-E alpha-chain gene, and the sequence of NOD I-A beta-chain in the first external domain is unique with His 56 and Ser 57 replacing Pro and Asp, respectively, at these positions. There has been considerable interest in the role amino acid 57 might have in conferring susceptibility to autoimmune diseases, including IDDM. The presence of a charged residue (such as Asp) at this position might affect the conformation of the peptide binding groove. But it could be assumed that Pro 56 gives rise to a different conformation of I-A beta-chain than does His 56. We therefore constructed transgenic NOD mice in which the transgene encoded a modified A beta nod with Pro 56, and studied its effect on the development of IDDM in this mouse strain. Previous studies have suggested that NOD mice expressing I-E as a result of the introduction of an I-E alpha-chain (E alpha) transgene are protected from the development of insulitis and hence IDDM. To explore further the protective effect of this molecule we constructed a second class of transgenic NOD mouse carrying an E alpha d transgene. Both transgenes protected the mice from IDDM, but this was not associated with a complete deletion of any T cells expressing commonly used T-cell receptor V beta genes.

Restricted islet-cell reactive T cell repertoire of early pancreatic islet infiltrates in NOD mice

“…Concordantly, treatment of NOD mice with anti-CD4 antibody abrogates disease (12,13). Introduction of MHC-II other than I-A g7 , the endogenous NOD MHC-II, also prevents diabetes, possibly by altering the CD4 ϩ T cell repertoire (14)(15)(16). Finally, the strong genetic linkage of disease to MHC-II provides a rationale for focusing on CD4 ϩ T cells (5,17,18).…”

A 320-Kilobase Artificial Chromosome Encoding the Human HLA DR3-DQ2 MHC Haplotype Confers HLA Restriction in Transgenic Mice

“…This approach has several drawbacks. First, the DRB3 and DRB4 genes are omitted from consideration despite their importance in many immune responses (15,16) and the fact that even single chain MHC class II genes can profoundly influence expression of autoimmune disease such as IDDM (17)(18)(19). Second, expression of independent transgenes ignores the possibility that multiple genes in the class II region contribute to disease susceptibility through interactions during positive and negative selection of the T cell repertoire or through aspects of their peripheral coregulation (20,21).…”

Specificity of peptide selection by antigen-presenting cells homozygous or heterozygous for expression of class II MHC molecules: The lack of competition

“…In the NOD model of autoimmune diabetes, numerous past reports have indicated that MHC heterozygosity results in protection from disease (9)(10)(11)(12)(13)(14). In fact, the presence of any other ␤57 Asp-expressing class II MHC, in addition to I-A g7 , results in markedly decreased incidence of diabetes; for example is the result of F1 mice derived from mating of wild type NOD (I-A g7 ) to NOD.GD (I-A d ), which are protected from diabetes (15).…”