title: Cellular mechanisms involved in experimental insulin-dependent diabetes mellitus.
abstract: Many tissue-specific autoimmune diseases are mediated by the induction of autoantigen-specific T cells. These cells are believed to cause tissue damage through the production of cytokines, through direct lysis of cells expressing self-antigens, or through the induction of inflammatory responses. The escape from self-tolerance or anergy is a prerequisite for initiation of an autoimmune process. INS-HA (insulin-hemagglutinin) transgenic mice express the HA of A PR8 34 influenza virus in the pancreatic beta-cells under the rat insulin promotor. TCR-HA (T cell receptor-hemagglutinin) transgenic mice express the TCR specific for the immunodominant epitope HA110-120 from the same virus. Double transgenic (dTg) mice expressing both genes represent an excellent model for understanding the mechanism leading to autoimmune diabetes independently of susceptibility genes. In order to gain information on the breaking down of neonatal self-tolerance we studied the occurrence of insulin dependent diabetes mellitus (IDDM) after birth. Our results showed that newborn mice develop fulminant IDDM characterized by occurrence of insulitis as early as 3 days after birth, followed by hyperglycemia by 7 days, and significant hypoinsulinemia by 28 days. Such "double transgenic" mice expressing wild-type or targeted IL-4R alpha genes were examined for the onset of IDDM. Eight of eleven mice homozygous for the wild-type IL-4R alpha were hyperglycemic by 8 weeks of age, whereas only 1 of 16 mice homozygous for the targeted allele were hyperglycemic at this time. Most IL-4R alpha -/- mice remained normoglycemic to 36 weeks of age. Although only 10% of double transgenic mice homozygous for wild-type IL-4R alpha allele survived to 30 weeks, 80% of mice homozygous for the targeted allele did so. Even as late as 270 days of age, mice homozygous for the targeted allele had no insulitis or only peri-insulitis. Heterozygous mice displayed an intermediate frequency of diabetes. The IL-4R alpha chain acts as the high affinity binding chain and the principal signaling chain for IL-4; it also acts as the signaling chain for IL-13, but in this case the IL-13R alpha 1 chain conveys the bulk of the cytokine specificity. Thus, IL-4R alpha knock-out mice are unresponsive to both IL-4 and IL-13. The finding that the lack of IL-4R alpha chain protects TCR-HA, INS-HA double transgenic mice against diabetes, and death implies that either IL-4 or IL-13 plays a role in the progression of this disease. These studies demonstrate that TCR-HA, INS-HA double transgenic mice may provide a useful model to evaluate new strategies for the prevention of diabetes.
authors.affiliation: Cantacuzino Institute, Department of Immunology Bucharest, Romania.
authors.forename: D L
authors.initials: DL
authors.lastname: Radu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010179:Pancreas / Q000473:pathology; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D019948:Receptors, Interleukin-4 / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011948:Receptors, Antigen, T-Cell; D019948:Receptors, Interleukin-4