RESUMO
By administering physiological doses of interleukin-1 (IL-1) concurrently with multiple low doses of the beta cell toxin streptozotocin (MSZ), we observed an augmentation of diabetes by IL-1 in four different strains of mice. Augmentation of hyperglycemia by IL-1 was most prominent in the two MSZ-resistant mouse strains Balb/cJ and A/J. Furthermore, concurrent treatment with IL-1 and MSZ rendered these MSZ-resistant mice susceptible to the development of significant insulitis when compared to mice treated with MSZ alone. Development of insulitis was dependent upon the dose of IL-1; it was only observed at an IL-1 dose of 250 ng/kg body weight. Analysis of the leukocytic infiltrate in the islets of mice after treatment with 250 ng/kg IL-1 plus MSZ revealed the presence of L3T4+ and Lyt-2+ T lymphocytes. Administration of MSZ alone or IL-1 alone did not produce diabetes in the MSZ-resistant mice, indicating that neither of these agents was toxic to the beta cells by itself. We conclude that IL-1 synergizes with MSZ to augment diabetes in mice that are normally resistant to the diabetogenic effects of MSZ.
Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Hiperglicemia/etiologia , Interleucina-1/administração & dosagem , Pancreatite/etiologia , Animais , Diabetes Mellitus Experimental/imunologia , Suscetibilidade a Doenças , Sinergismo Farmacológico , Imunidade Inata , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Pancreatite/patologia , Especificidade da Espécie , EstreptozocinaRESUMO
Insulin-dependent diabetes mellitus results from the autoimmune destruction of the insulin-producing beta cells of the pancreatic islets. The target antigen(s) involved in this immunopathological process has not been identified. Our strategy was to determine whether expression of a novel surface antigen by murine pancreatic beta cells would result in insulin-dependent diabetes mellitus. We have generated lines of transgenic mice (RIP-HA) that express the hemagglutinin of the A/Japan/305/57 strain of influenza virus on their insulin-producing beta cells. Hyperglycemia developed in mice derived from all three founders at a frequency varying from 13% to 27%, and was associated with lymphocytic infiltration of the islets and a humoral response against beta cell antigens, including hemagglutinin. These results suggest that the RIP-HA mice should provide a useful system in which to study the cellular interactions involved in the induction of self-tolerance and autoimmunity.