TOLERANCE INDUCTION BY MEGADOSE HEMATOPOIETIC TRANSPLANTS - DONOR-TYPE HUMAN CD34 STEM-CELLS INDUCE POTENT SPECIFIC REDUCTION OF HOST ANTIDONOR CYTOTOXIC T-LYMPHOCYTE PRECURSORS IN MIXED LYMPHOCYTE CULTURE

Background Recently, the use of megadoses of CD34(+) hematopoietic pro genitors has been reported to abrogate resistance to engraftment, thus overcoming major histocompatibility barriers in bone marrow transplan tation in leukemia patients. Methods. The ability of human CD34(+) cel ls to possess potent tolerizing activity was studied by limiting dilut ion analysis of cytotoxic T lymphocyte (CTL) precursors (CTL-p) in hum an peripheral blood lymphocytes after addition of purified CD34(+) cel ls, Results, The addition of purified human CD34(+) cells to primary m ixed lymphocyte culture led to a marked reduction of antiallogeneic CT L-p frequency against stimulator cells of the same origin, compared wi th the response against cells of third-party origin. The CD34(+) cells caused a marked inhibition of the CTL activity, when added at an equa l number with the responder T cells, and they were still present after the mixed lymphocyte culture, which suggests that no significant kill ing of CD34(+) cells had occurred. The tolerizing activity is abrogate d by irradiation and requires cell contact. This pattern of tolerizati on most closely resembles what has been ascribed to veto cells in othe r systems. Phenotypic analysis of the purified CD34(+) cells showed th at they express MHC class I and class II antigens, but do not express costimulatory molecules of the B7 family, Conclusions. It is possible, that CD34(+) cells in the megadose transplants-perhaps by their inabi lity to provide costimulatory molecules-are actively reducing the freq uency of CTL-p directed against their antigens, and thereby help to ov ercome allogeneic rejection, and enhance their own engraftment.