INSULIN-DEPENDENT DIABETES IN THE NOD MOUSE MODEL .2. BETA-CELL DESTRUCTION IN AUTOIMMUNE DIABETES IS A TH2 AND NOT A TH1 MEDIATED EVENT

Type I, insulin-dependent diabetes (IDD) in both man and animals resul ts from a specific autoimmune destruction of the pancreatic beta cells involving both humoral and cellular immune mechanisms. The pathognomo nic histologic lesion, termed insulitis, is an inflammatory and immune cell infiltrate of the pancreatic islet cells. While recent histologi cal and flow cytometric analyses have identified the cell composition of the infiltrate, the presence of a cell population may not reflect t he functional reactivities important for beta cell destruction. In the present study, we have investigated the possible functional reactivit ies of islet-infiltrating mononuclear cell populations by measuring in creased cytokine mRNA usage. Results indicate that 1) cytokine mRNA pr ofiles exhibited by islet-infiltrating cells of female and male NOD mi ce were quite similar with the exception of IL-6 expression and the ma rked differences in the levels of IL-2 receptor and IL-1alpha mRNA, 2) CD4+ T lymphocytes expressed IL-4, presumably IL-5, and occasionally IL-10 mRNA but no detectable IL-2 mRNA, 3) CD8+ T lymphocytes exhibite d TNF-beta, perforin and high levels of IFN-gamma, and 4) IL-7 was exp ressed in the islet at very high levels. These findings, together with our earlier flow cytometric analyses of the islet-infiltrating cells, have permitted construction of a detailed model for the natural histo ry of autoimmune diabetes. Interestingly, this model, based on a T(H2) - and not a T(H1)-mediated scheme, questions the more popular concepts currently thought to form the bases of the autoimmune reactions under lying IDD.