DELAYED INFUSION OF IMMUNOCOMPETENT DONOR CELLS AFTER BONE-MARROW TRANSPLANTATION BREAKS GRAFT-HOST TOLERANCE AND ALLOWS FOR PERSISTENT ANTILEUKEMIC REACTIVITY WITHOUT SEVERE GRAFT-VERSUS-HOST DISEASE

The development of graft-host tolerance after bone marrow transplantat ion (BMT) is crucial to avoid the problems of graft-versus-host diseas e (GVHD) and graft rejection. GVHD can be eliminated by depleting matu re donor T cells from the BM inoculum, thereby facilitating the develo pment of graft-host tolerance, However, T-cell depletion often results in an increased incidence of graft rejection and an increased frequen cy of leukemia relapse, Thus, although graft-host tolerance is a desir able outcome, it can pose a significant threat to leukemia-bearing hos ts. Using a major histocompatability complex (MHC)-matched allogeneic model of BMT (B10.BR into AKR), we found that irradiated recipients gi ven donor BM alone displayed mixed T-cell chimerism and did not develo p GVHD. Graft-host tolerance developed by 8 weeks after BMT in these c himeras, and they were susceptible to low-dose leukemia challenge, Whe n sufficient numbers of donor spleen cells, as a source of T cells, we re added to the BM graft, AKR hosts developed severe and lethal GVHD. Antihost reactive donor T cells persisted in chimeras undergoing GVHD, indicating that graft-host tolerance did not develop. When administra tion of the spleen cells was delayed for 7 to 21 days after BMT, there was significantly less mortality because of GVHD. Day 21 was the opti mal time for infusion of cells without development of GVHD. Graft-host tolerance was broken by the delayed infusion of donor cells, as indic ated by the persistence of antihost-reactive donor T cells in these ch imeras in T-cell receptor crosslinking and mixed lymphocyte reaction a ssays, Importantly, the persistence of antihost-reactive donor T cells correlated with a long-term antileukemic effect that was still presen t at 100 days after transplant. Multiple infusions of immunocompetent donor cells could be administered without increasing the risk for GVHD if delayed until 21 days post-BMT, Delayed infusions of donor spleen cells also resulted in a long-term antileukemic effect in the absence of GVHD in an MHC-haplotype-mismatched model of BMT (SJL into [SJL x A KR]F1). Although delayed infusion of normal donor cells did not induce GVHD, spleen cells from donors previously sensitized to host alloanti gens induced GVHD when infused 21 days after BMT, Thus, the ability of previously activated cells to induce GVHD was not inhibited in the sa me manner as naive cells. Results from limiting dilution analysis assa ys indicated that alloactivated interleukin-2-secreting CD4(+) T cells were preferentially inhibited over cytolytic T cells, Because CD4(+) T cells are required for the induction of GVHD in these murine BMT mod els, selective inhibition of CD4(+) T-cell activation may explain why significant GVHD did not occur in chimeras infused with donor cells 21 days after BMT. (C) 1995 by The American Society of Hematology.