Recent studies in mice have demonstrated that high doses of IL-2, when given for a few days beginning on the day of BMT, mediate a potent protective effect against both acute and chronic GVHD induced across complete MHC barriers. This demonstrated for T cell depleted syngeneic marrow. Complete allogeneic chimerism is attained in such mice. The main goal of the proposed studies is to determine the mechanism of this protective effect of IL-2 and TCD syngeneic marrow, so that a rational approach for the application of these results to clinical BMT can be developed.
The specific aims i nclude: 1) phenotypic and functional analyses of the influence of IL-2 on developing donor and host-type cell populations in irradiated mice; 2) analysis of the influence of IL-2 on the production of cytokines which might modulate GVHD; 3) evaluation of the possible role of host-type T cells in mediating the protective effect of IL-2; 4) evaluation of the role of NK1.1+ cells in the anti-GVHD effect of IL-2; and 5) evaluation of the effect of IL-2 treatment on host resistance to alloengraftment and on the ability of allogeneic T cells to promote engraftment. Understanding the mechanism whereby IL-2 plus TCD syngeneic marrow protect against GVHD will be important in determining the clinical applicability of this approach. In clinical BMT, the beneficial reduction in the incidence of GVHD associated with T cell depletion of allogeneic bone marrow has been offset by an increased rate of failure of alloengraftment and of leukemic relapse. The problems of GVHD and engraftment failure are further amplified when transplant are attempted across HLA barriers, so that the lack of suitable HLA-matched donors continues to limit the application of BMT for the treatment of leukemia. New approaches are therefore needed to exploit the beneficial effects of allogeneic T cells while avoiding their major harmful effect, GVHD.
