COEXPRESSION OF B7-1 AND VIRAL (SELF) TRANSGENES IN PANCREATIC BETA-CELLS CAN BREAK PERIPHERAL IGNORANCE AND LEAD TO SPONTANEOUS AUTOIMMUNEDIABETES

We evaluated the role of the costimulatory molecule B7-1 in overcoming peripheral ignorance in transgenic mice, which expressed the glycopro tein (GP) or nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) as the self-antigen in pancreatic beta cells. The viral transge nes or B7-1 alone did not induce autoimmune diabetes (IDDM). However, in bigenic mice expressing B7-1 and LCMV-GP, anti-self (viral) cytotox ic T lymphocytes (CTL) were activated without viral infection and spon taneous IDDM occurred. In contrast, bigenic RIP-B7-1 x RIP-NP mice wit h thymic expression of the self (viral-NP) antigen deleted the majorit y of their autoreactive CTL and did not develop spontaneous IDDM. Howe ver, these mice developed fast-onset IDDM 14 days after LCMV infection , whereas single-transgenic RIP-NP littermates developed IDDM only wit hin 4-5 months. Rapid IDDM was associated with increased numbers of an ti-self CTL and a predominance of IFN gamma produced by islet-infiltra ting lymphocytes, whereas single transgenic RIP-NP littermates with sl ow-onset IDDM displayed less anti-self CTL and more IL-4- and IL-10-pr oducing T lymphocytes in pancreatic infiltrates.