The long range goal of this proposal is to determine the precise role of the so called "passenger leukocytes" that are present within islets of Langerhans transplanted across a major histocompatibility barrier (MHC). Data accumulated over the past several years have provided circumstantial and indirect evidence that "passenger" cells are in fact present on tissue to be transplanted and furthermore, these "passenger cells express class II (Ia) antigens encoded for by the MHC. Recent studies have reported the detection of discrete Ia bearing cells within islets. These Ia bearing cells were neither lymphocytes nor endothelial cells as judged by morphological criteria. The specific aims of the proposed study are to: 1) Determine in functional assays whether Ia bearing cells from intact or singly dispersed islets can stimulate allogeneic lymphocyte proliferation and/or activation of allospecific cytotoxic T lymphocytes (CTL); 2)\Determine the optimal conditions to deplete islets of those Ia bearing cells. This will be approached by either: a) culturing islets at 24C or 37C; b) treating islets with monoclonal or polyclonal antibodies directed against Ia antigens or; c) a combination of a and b; 3) correlate the removal of Ia bearing cells from islets with functional activity in vivo (reversal of chemically induced diabetes in allogeneic recipients) and in vitro (ability to stimulate allogeneic lymphocyte proliferation and or CTL generation). The results of these studies will be of fundamental importance with regard to islet transplantation in man.