POSSIBLE ROLE OF MACROPHAGE-DERIVED SOLUBLE MEDIATORS IN THE PATHOGENESIS OF ENCEPHALOMYOCARDITIS VIRUS-INDUCED DIABETES IN MICE

Pancreatic islets from DBA/2 mice infected with the D variant of encep halomyocarditis (EMC-D) virus revealed lymphocytic infiltration with m oderate to severe destruction of pancreatic beta cells. Our previous s tudies showed that the major population of infiltrating cells at the e arly stages of infection is macrophages. The inactivation of macrophag es prior to viral infection resulted in the prevention of diabetes, wh ereas activation of macrophages prior to viral infection resulted in t he enhancement of beta-cell destruction. This investigation was initia ted to determine whether macrophage-produced soluble mediators play a role in the destruction of pancreatic beta cells in mice infected with a low dose of EMC-D virus, When we examined the expression of the sol uble mediators interleukin-l beta (IL-1 beta), tumor necrosis factor a lpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) in the pa ncreatic islets, we found that these mediators were clearly expressed at an early stage of insulitis and that this expression was evident un til the development of diabetes. We confirmed the expression of these mediators by in situ hybridization with digoxigenin-labelled RNA probe s or immunohistochemistry in the pancreatic islets. Mice treated with antibody against IL-1 beta or TNF-alpha or with the iNOS inhibitor ami noguanidine exhibited a significant decrease in the incidence of diabe tes. Mice treated with a combination of anti-IL-1 beta antibody, anti- TNF-alpha antibody, and aminoguanidine exhibited a greater decrease in the incidence of disease than did mice treated with one of the antibo dies or aminoguanidine. On the basis of these observations, we conclud e that macrophage-produced soluble mediators play an important role in the destruction of pancreatic beta cells, resulting in the developmen t of diabetes in mice infected with a low dose of EMC-D virus.