The NOD (non-obese diabetic) mouse spontaneously develops insulin-dependent diabetes mellitus (IDDM) characterized by autoimmune insulitis, involving lymphocytic infiltration around and into the islets followed by pancreatic beta (beta) cell destruction, similar to human IDDM. Genetic analysis in breeding studies between NOD and C57BL/6 mice has demonstrated that two recessive genes on independent chromosomes contribute to the development of insulitis. One of the two recessive diabetogenic genes was found to be linked to the major histocompatibility complex (MHC). This is of interest, because the NOD strain has a unique class II MHC: it does not express I-E molecules as no messenger RNA for the alpha-chain of I-E is visible in Northern blot analysis; I-A molecules are not detected with any available monoclonal antibodies or by allo-reactive or autoreactive T-cell clones, although their expression is demonstrated with a conventional antiserum to Ia antigens. To examine whether the unusual expression of class II MHC molecules may be responsible for the development of autoimmune insulitis, we attempted to express I-E molecules in NOD mice selectively, without introducing other genes on chromosome 17 by using I-E-expressing C57BL/6 (B6(E alpha d)) transgenic mice. We report here that the expression of I-E molecules in NOD mice can prevent the development of autoimmune insulitis.

We have demonstrated that intestinal epithelial cells produce interleukin 7 (IL-7), and IL-7 serves as a potent regulatory factor for proliferation of intestinal mucosal lymphocytes expressing functional IL-7 receptor. To clarify the mechanism by which locally produced IL-7 regulates the mucosal lymphocytes, we investigated IL-7 transgenic mice. Here we report that transgenic mice expressing murine IL-7 cDNA driver by the SRα promoter developed chronic colitis in concert with the expression of SRα/IL-7 transgene in the colonic mucosa. IL-7 transgenic but not littermate mice developed chronic colitis at 4–12 wk of age, with histopathological similarity to ulcerative colitis in humans. Southern blot hybridization and competitive PCR demonstrated that the expression of IL-7 messenger RNA was increased in the colonic mucosal lymphocytes but not in the colonic epithelial cells. IL-7 protein accumulation was decreased in the goblet cell–depleted colonic epithelium in the transgenic mice. Immunohistochemical and cytokine production analysis showed that lymphoid infiltrates in the lamina propria were dominated by T helper cell type 1 CD4+ T cells. Flow cytometric analysis demonstrated that CD4+ intraepithelial T cells were increased, but T cell receptor γ/δ T cells and CD8α/α cells were not increased in the area of chronic inflammation. Increased IL-7 receptor expression in mucosal lymphocytes was demonstrated in the transgenic mice. These findings suggest that chronic inflammation in the colonic mucosa may be mediated by dysregulation of colonic epithelial cell–derived IL-7, and this murine model of chronic colitis may contribute to the understanding of the pathogenesis of human inflammatory bowel disease.

Brain natriuretic peptide (BNP) is a cardiac hormone that occurs predominantly in the ventricle. To study the roles of BNP in chronic cardiovascular regulation, we isolated mouse BNP cDNA and genomic clones, and generated transgenic mice with elevated plasma BNP concentration. The mouse BNP gene was organized into three exons and two introns. Two BNP mRNA species were identified, which were generated by the alternative mRNA splicing. The ventricle was a major site of BNP production in mice. Mouse preproBNP was a 121-(or 120-) residue peptide, and its COOH-terminal 45-residue peptide was the major storage form in the heart. Transgenic mice carrying the human serum amyloid P component/mouse BNP fusion gene were generated so that the hormone expression is targeted to the liver. In the liver of these mice, considerable levels of BNP mRNA and peptide were detected, reaching up to 10-fold greater than in the ventricle. These animals showed 10-to 100-fold increase in plasma BNP concentration accompanied by elevated plasma cyclic GMP concentration, and had significantly lower blood pressure than their nontransgenic littermates. The present study demonstrates that these mice provide a useful model system with which to assess the roles of BNP in cardiovascular regulation and suggests the potential usefulness of BNP as a long-term therapeutic agent. (J. Clin. In west. 1994.