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 transplantation (BMT) is crucial to avoid the problems of graft-versus-host disease (GVHD) and graft rejection. GVHD can be eliminated by depleting mature donor T cells from the BM inoculum, thereby facilitating the development of graft-host tolerance. However, T-cell depletion often results in an increased incidence of graft rejection and an increased frequency of leukemia relapse. Thus, although graft-host tolerance is a desirable outcome, it can pose a significant threat t o leukemia-bearing hosts. Using a major histocompatability complex (MHC)-matched allogeneic model of BMT (B1O.BR into AKR), we found that irradiated recipients given donor BM alone displayed mixed T-cell chimerism and did not develop GVHD. Graft-host tolerance developed by 8 weeks after BMT in these chimeras, and they were susceptible to low-dose leukemia challenge. When sufficient numbers of donor spleen cells, as a source of T cells, were 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 administration 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 optimal time for infusion of cells without development of GVHD. Grafthost tolerance was broken by the delayed infusion of