Avoiding graft-vs .-host disease (GVHD)' while retaining the engraftment-promoting and antileukemic effects of T cells in allogeneic marrow remains a major challenge in the field of bone marrow transplantation (BMT). While T cell depletion reduces the incidence of GVHD, it is associated with an increased probability ofengraftment failure (1-6) and a greater risk ofleukemic relapse (4, 5, 7). Previous work from this laboratory has demonstrated that the GVHD-related mortality of lethally irradiated, bone marrow-reconstituted mice can be delayed by the coadministration of T cell-depleted (TCD) syngeneic marrow (8). Although this result was encouraging, we have found the magnitude ofthe protection from acute GVHD mortality to be limited, and no protection from chronic GVHD mortality has been apparent (8). We therefore sought a method of augmenting this protective effect of TCD syngeneic marrow. We have previously demonstrated that TCD syngeneic marrow is responsible for most of the natural suppressor (NS) activity arising in spleens of lethally irradiated mice reconstituted with a mixture of allogeneic plus syngeneic marrow, and have hypothesized that such cells might be responsible for the anti-GVHD effect of TCD syngeneic marrow (9). Since cell lines with in vitro NS activity and in vivo anti-GVHD effects have been successfully cultured in IL-2 (10, 11; Sykes M., K. A. Hoyles, M. L. Romick, and D. H. Sachs, manuscript in preparation), we wished to address the possibility that the administration of IL-2 in vivo to lethally irradiated, bone marrow-transplanted mice might increase the anti-GVHD effect of TCD syngeneic bone marrow. Our results indicate that IL-2 provides significant protection against GVHD mortality from allogeneic lymphocytes while permitting complete repopulation by allogeneic bone marrow cells (BMC). When suboptimal amounts of IL-2 were given, maximal protection was achieved when TCD syngeneic marrow was also administered . Survivors protected in this manner similarly demonstrated complete allogeneic reconstitution .
The opposing problems of graft-vs-host disease vs failure of alloengraftment severely limit the success of allogeneic bone marrow transplantation as a therapeutic modality. We have recently used a murine bone marrow transplantation model involving reconstitution of lethally irradiated mice with mixtures of allogeneic and syngeneic marrow to demonstrate that an allogeneic bone marrow subpopulation, removed by T cell depletion with rabbit anti-mouse brain serum and complement (RAMB/C), is capable of increasing levels of allogeneic chimerism. This effect was observed in an F1 into parent genetic combination lacking the potential for graft-vs-host disease, and radiation protection studies suggested that it was not due to depletion of stem cells by RAMB/C. We have now attempted to characterize the cell population responsible for increasing allogeneic chimerism in this model. The results indicate that neither mature T cells nor NK cells are responsible for this activity. However, an assay involving mixed marrow reconstitution in an Ly-5 congenic strain combination was found to be more sensitive to small degrees of stem cell depletion than radiation protection assays using three-fold titrations of bone marrow cells. Using this assay, we were able to detect some degree of stem cell depletion by treatment with RAMB/C, but not with anti-T cell mAb. Nevertheless, if the effects of alloresistance observed in this model are considered, the degree of stem cell depletion detected by such mixing studies in insufficient to account for the effects of RAMB/C depletion on levels of allogeneic chimerism, suggesting that another cell population with this property remains to be identified.
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