Cytotoxically Impaired Transplant Recipients Can Efficiently Resist Major Histocompatibility Complex-Matched Bone Marrow Allografts

High rates of allograft rejecrion using T cell-depleted marrow or after transplantations into multiply transfused recipients have been reported. Together with current approaches to diminish host preparative immunosuppression before stem cell transplant, issues regarding the cells and effector pathways involved in resistance to progenitor cell presence in recipients are of increasing interest. The present investigation addressed questions concerning the contribution of cytotoxic effector mechanisms used by host cells involved in resistance to progenitor cell engraftment. A murine model was developed in which short-term resistance against major histocompatibility complex (MHC)-matched allogeneic T cell-depleted marrow was examined using a sensitive in vitro assay to detect progenitor cell presence by colony formation in vitro. Resistance was found to be dependent on previous priming to donor non-MHC antigens and could be transferred by a CD3⁺NK1.1^- population. The resistance mechanism explicitly discriminated between donor and syngeneic progenitors after mixed marrow transplantation. Interestingly, the resistance was not impaired in animals unable to mediate cell-mediated cytotoxicity involving perforin-dependent or CD95L-dependent pathways. These results indicate that either cytotoxic effector pathway alone is sufficient to effect marrow allograft resistance or that non-perforin and CD95L effector mechanisms are responsible for barrier activity. The findings are discussed with respect to previous studies concerning T-cell involvement in resistance to MHC-and hematopoietic histoincompatible-mismatched marrow grafts.