Clinical transplantation tolerance twelve years after prospective withdrawal of immunosuppressive drugs: Studies of chimerism and anti-donor reactivity

Background Previous studies showed the feasibility of inducing transplantat ion tolerance to cadaveric renal allografts in patients given pretransplant total lymphoid irradiation (TLI). Microchimerism has been theorized to be an important or necessary factor in long-term graft acceptance and toleranc e in humans. Methods. A cadaveric renal transplant recipient given pretransplant total l ymphoid irradiation and withdrawn from immunosuppressive drugs more than 12 years ago was tested for microchimerism using a sensitive nested polymeras e chain reaction technique, and for anti-donor reactivity using the mixed l eukocyte reaction and an ELISA screen for anti-HLA antibodies, Donor and re cipient were mismatched for all HLA-A, B, and DR antigens. Results, The "tolerant" recipient had good graft function, no detectable do nor-type cells in the blood by polymerase chain reaction analysis, vigorous reactivity to donor stimulator cells in the mixed leukocyte reaction, and no detectable serum anti-HLA antibodies. Conclusions. Operational tolerance to HLA-A,B, and DR mismatched organ allo grafts can be induced prospectively in humans for at least 12 years after w ithdrawal of immunosuppressive drugs. The allograft can be maintained in th e absence of detectable donor microchimerism and in the presence of anti-do nor reactivity in the mixed leukocyte reaction, suggesting that neither chi merism nor clonal deletion or anergy of recipient T cells to alloantigens p resented by donor Class II HLA molecules is required for persistence of the tolerant state using this total lymphoid irradiation protocol.