IMMUNOLOGICAL-TOLERANCE TO A DEFINED MYELIN BASIC-PROTEIN ANTIGEN ADMINISTERED INTRATHYMICALLY

To explore the mechanisms responsible for the development of tolerance to allografts after intrathymic (IT) injection of alloantigen, the we ll-defined model of experimental autoimmune encephalomyelitis (EAE), w hich mimics the human autoimmune disease multiple sclerosis, was used. This inflammatory neurologic syndrome is initiated by myelin basic pr otein (MBP)-reactive CD4(+) T lymphocytes restricted to self-MHC class II molecules. Naive adult, EAE-susceptible Lewis (RT1(1)) rats were t reated IT, i.v., or i.p. with a single dose (100 mu g) of guinea pigmy elin basic protein (GP-MBP 1-176) in PBS plus 1 mt rabbit anti-rat lym phocyte serum i.p. Twenty-one days later, all rats were challenged by intradermal hind footpad injections of 50 mu g GP-MBP in PBS emulsifie d in CFA. Only IT, but not i.p. or i.v., administration of GP-MBP plus anti-lymphocyte serum conferred marked resistance to a subsequent sys temic challenge of GP-MBP, as demonstrated by the prevention of weight loss and paralysis characteristic of EAE. The IT administration drama tically decreased the size and number of histologic perivascular infil trates observed per visual field in spinal cords of the tolerant anima ls and decreased CP-MBP-specific T lymphocyte in vitro proliferation ( p < 0.01), whereas proliferation to a nonspecific mitogen (Con A) was not altered. With the addition of rIL-2, the decreased Ag-specific pro liferative responses of IT-treated animals increased to control levels . Adoptive transfer of 100 x 10(6) splenocytes from tolerant hosts i.v . to naive syngeneic Lewis rats challenged with 100 mu g GP-MBP in CFA had no effect on clinical or histologic EAE. Exposure of MBP to matur ing thymocytes results in functionally immunounresponsive lymphocytes and prevention of autoimmune EAE.