Mg. Vonherrath et al., COEXPRESSION OF B7-1 AND VIRAL (SELF) TRANSGENES IN PANCREATIC BETA-CELLS CAN BREAK PERIPHERAL IGNORANCE AND LEAD TO SPONTANEOUS AUTOIMMUNEDIABETES, Immunity, 3(6), 1995, pp. 727-738
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.