Protection against Diabetes by MHC Heterozygosity and Reversal by Cyclophosphamide

• Published in: Cellular immunology Vol. 184; no. 2; pp. 112 - 120
• Main Authors: Wu, Adrian Y., Schulman, Stacey J., Marconi, Lori Anne, Reilly, Christina R., Scott, Bernadette, Lo, David
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15-03-1998
• Subjects: Animals; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - prevention & control; autoimmunity; Base Sequence; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cyclophosphamide - pharmacology; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; DNA Primers - genetics; Genes, MHC Class II; genetics; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Heterozygote; Humans; Interferon-gamma - genetics; interferon-γ; interleukin-4; Interleukin-4 - genetics; major histocompatibility complex (MHC); Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Transgenic; Polymerase Chain Reaction; Receptors, Antigen, T-Cell - genetics; interleukin-4; interferon-γ; genetics; autoimmunity; major histocompatibility complex (MHC)
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1006/cimm.1998.1269

In type I diabetes in both rodents and humans, genetic susceptibility to disease is strongly linked to MHC class II alleles. In some cases, however, certain class II alleles provide resistance to disease. To examine this effect in a well-defined system, we studied double transgenic mice expressing influenza hemagglutinin (HA) on pancreatic islet β cells and an HA-specific TCR on CD4 T cells. On a susceptible B10.D2 background, 70% of double transgenic mice develop an early-onset spontaneous autoimmune diabetes. MHC heterozygosity induced variable protection from diabetes, depending on the specific nonpermissive allele, but insulitis was invariably present. Autoreactive T cells retained the ability to induce diabetes because cyclophosphamide treatment induced diabetes in 81% of young MHC(d/b) transgenic mice, although the effect was diminished in older mice. Most importantly, treatment induced higher IFN-γ/IL-4 ratios among CD4 T cells, suggesting a strong shift toward Th1 development, perhaps through direct effects on patterns of gene expression in CD4 T cells.