INDUCTION OF PERI-INSULITIS BUT NOT DIABETES IN ISLET TRANSPLANTS EXPRESSING A SINGLE FOREIGN ANTIGEN - A MULTISTAGE MODEL OF DISEASE

We have created a new transgenic model in which the human Epstein-Barr virus receptor, CR2 (CD21), has been expressed in pancreatic beta-cel ls. Mice derived from three transgenic founders bred into H-2b (C57BL/ 6) or H-2k (CBA) genetic backgrounds did not become spontaneously diab etic. After transplantation of CR2-expressing islets under the kidney capsule of genetically matched recipients, a histologic picture of per i-insulitis was found. However, animals did not manifest cellular inva sion of the islets, destruction of the islets, or diabetes for at leas t 230 days. Significant numbers of both T and B lymphocytes were found in the cell population surrounding the islets. A pronounced serologic response to CR2 was also present and appeared to precede the onset of peri-insulitis. Thus, in this model, we have separated the process of diabetes induction into at least two phases. One is associated with p eri-islet infiltration and an antibody response. However, at least one second signal is likely necessary for the process of islet destructio n to follow.