DISTINCT MECHANISMS FOR THE INDUCTION AND MAINTENANCE OF ALLOGRAFT TOLERANCE WITH CTLA4-FC TREATMENT

A murine CTLA4/Fc gamma 2a heavy chain (mCTLA4-Fc) chimeric fusion mol ecule was used in B6AF(1) recipients of BALB/c pancreatic islet allogr afts to study the induction and maintenance of tolerance following inh ibition of the CD28-B7 pathway for T cell activation, Donor-specific t olerance was achieved by administering 100 mu g of mCTLA4-Fc on altern ate days for 14 days (8 total doses) or a single 500 mu g dose of mCTL A4-Fc on day 2 after transplant, Tolerance was mediated by long-lived peripheral lymphocytes and showed features of organ and alloantigen sp ecificity, Whereas tolerance could not be established in allograft rec ipients receiving simultaneous mCTLA4-Fc and rIL-2, previously toleran t animals did not reject their grafts when given IL-2, suggesting that the induction and maintenance phases of tolerance were distinct and s eparate, The maintenance of donor-specific tolerance was an active imm unologic process that was CD4(+) T cell dependent and could be adoptiv ely transferred to naive lymphocytes, but could not be explained by ap optosis or deletion of alloreactive T cells, Although an IL-2-sensitiv e mechanism such as anergy may contribute toward the induction of tole rance, its maintenance involves active suppression.