Donor bone marrow-derived chimeric cells present in renal, transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses

Background. Even though a number of transplant centers have adopted donor-s pecific bone marrow cell (DBMC) infusions to enhance donor cell chimerism, to date there has been no direct evidence linking chimerism with tolerance induction in human organ transplant recipients. Methods. Cells of donor phenotype were isolated 1 year postoperatively from the peripheral blood lymphocytes and iliac crest bone marrow of 11 living- related-donor (LRD) renal transplant recipients, who had received periopera tive donor bone marrow cell infusions. These recipient-derived donor (RdD) cells were characterized phenotypically by flow cytometric analysis and fun ctionally as modulators in mixed lymphocyte reaction (MLR) and cell-mediate d lympholysis (CML) assays. Results. The yield of RdD cells ranged from 0.1 to 0.9% of the starting mat erial with the majority being TcR alpha beta, CD3 positive T cells, a subst antial percentage of which coexpressed CD28, At 1 year posttransplant almos t 50% of the LRD-kidney/DBMC recipients tested so far exhibited donor-speci fic unresponsiveness in MLR (7/17) and CML (6/13) reactions and this trend was further enhanced at 2-3 years. In the recipients with residual positive antidonor immune responses, the RdD cells inhibited recipient antidonor ML R and CML responses significantly more strongly than freshly isolated and s imilarly treated iliac crest bone marrow cells from the donor. RdD cells al so inhibited the MLR of the recipient to third party allogeneic stimulator cells; however, this nonspecific effect was significantly weaker than speci fic inhibition. We also established long-term bone marrow cultures stimulat ed every 2 weeks with irradiated allogeneic feeder cells, that had similar functional properties thus possibly providing us with an in vitro correlate the RdD cells. Conclusions. These results clearly support the notion that the infused dono r cells play a positive role in the induction and/or maintenance of transpl ant tolerance.