CYTOTOXIC T LYMPHOCYTE-ASSOCIATED ANTIGEN-4 (CTLA-4) REGULATES THE UNFOLDING OF AUTOIMMUNE DIABETES

Evidence has been accumulating that shows that insulin-dependent diabe tes is subject to immunoregulation. To determine whether cytotoxic T l ymphocyte-associated antigen 4 (CTLA-4) is involved, we injected anti- CTLA-4 mAb into a TCR transgenic model of diabetes at different stages of disease. When injected into young mice, months before they would n ormally become diabetic, anti-CTLA-4 induced diabetes rapidly and esse ntially universally; this was not the result of a global activation of T lymphocytes, but did reflect a much more aggressive T cell infiltra te in the pancreatic islets. These effects were only observed if anti- CTLA-4 was injected during a narrow time window, before the initiation of insulitis. Thus, engagement of CTLA-4 at the time when potentially diabetogenic T cells are first activated is a pivotal event; if engag ement is permitted, invasion of the islets occurs, but remains quite i nnocuous for months, ii not, insulitis is much more aggressive, and di abetes quickly ensues.