PANCREAS IN RECENT-ONSET INSULIN-DEPENDENT DIABETES-MELLITUS - CHANGES IN HLA, ADHESION MOLECULES AND AUTOANTIGENS, RESTRICTED T-CELL RECEPTOR V-BETA USAGE, AND CYTOKINE PROFILE

Insulin-dependent diabetes mellitus (IDDM), in which only the pancreat ic beta cells are destroyed by the autoimmune response, is the paradig m of organ-specific autoimmunity. As a result of a combination of fact ors, the number of immunohistologic/cellular/molecular studies of panc reas in IDDM is very limited. We report here studies conducted in the pancreata of two IDDM patients: one newly diagnosed (case 1) and one l ong standing (case 2). In case 1, we demonstrated the presence of morp hologically normal viable beta cells without evidence of viral infecti on. In both cases the expression of the autoantigens defined by islet cell Abs and by glutamic acid decarboxylase was markedly reduced in th e islet cells whereas expression of hsp60, another putative autoantige n, was normal. Over-expression of HLA class I was detected in 58% of t he islets in pancreatic sections and in cultured beta cells in case 1 and also in 30% of islets in case 2 but it was not restricted to any i nsular cell type. In case I, there was ''inappropriate'' HLA class II expression in islets cells but it was a rare finding and not beta cell specific. The analysis of the correlation between class I overexpress ion, residual insulin, and insulitis suggests that the first event is the increase of HLA class I expression. Of adhesion molecules, ICAM-1, VLA, VCAM, and LFA-3 were normal and only ICAM-1 was moderately overe xpressed in and around the islets of case 1 insulitis, as was detected by immunofluorescence which showed that 18% of the islets of case 1 h ad CD8(+) lymphocytes as the predominant population. Reverse transcrip tion-PCR demonstrated moderate V beta skewing and the profile of cytok ines expected in CTLs: IL-2, IL-4, IL-10, and IFN-gamma negative, perf orin positive. In addition, IFN-alpha, IFN-beta, and IL-6 transcripts were detected in the case 1 pancreas, consistent with the existence of a silent viral infection. Overall, the results indicated that, differ ently from spontaneous animal models of diabetes, in the pancreas of I DDM patients there are no elements of the inductive phase of the autoi mmune response.