Graft-versus-host (GVH) alloresponses mediated by donor lymphocyte infusions (DLI) administered toestablished murine mixed hematopoietic chimeras eliminate normal and malignant host hematopoietic cellswithout causing graft-versus-host disease (GVHD). Administration of similar DLI immediately followingconditioning leads to severe GVHD. More potent graft-versus-tumor (GVT) effects are achieved fromdelayed DLI given to mixed hematopoietic chimeras than are achieved in fully allogeneic chimeras. We haveobserved that GVH-reactive T cells are activated, expand, produce cytokines and adopt the 'memory'phenotype when administered as DLI to established mixed allogeneic chimeras. Therefore, the lack ofGVHD cannot be attributed to global suppression of the alloresponse by regulatory cells. This potent GVHreaction is largely confined to the lymphohematopoietic system, as T cells do not accumulate in GVHD targettissues. We refer to this as a lymphohematopoietic GVH reaction (LGVHR). We have obtained evidencethat a similar phenomenon can occur clinically when DLI are given to patients in whom mixed chimerism isestablished with non-myeloablative conditioning. The ability to achieve LGVHR without GVHD across MHCbarriers provides an approach to achieving powerful GVT effects against lymphohematopoietic malignancieswithout GVHD. In order to identify the mechanisms whereby GVHR are confined to thelymphohematopoietic system following DLI, we will: 1) Compare the kinetics of GVH-reactive CD4 and CDST cell activation, proliferation, differentiation, tissue accumulation and death in mice receiving DLIimmediately following irradiation or with a delay following establishment of mixed allogeneic chimerism; wewill address the significance and mechanisms of increased apoptosis and other differences in mixedchimeras vs freshly irradiated mice. 2) Compare the survival, proliferation, migratory properties and GVHDeffector function of effector/memory T cells generated in a non-inflammatory environment (i.e. following DLIadministration to established mixed chimeras) versus a pro-inflammatory environment (i.e. following DLIadministration to freshly irradiated mice) when the cells are adoptively transferred to either type ofenvironment. These studies will determine the extent to which T cell-intrinsic versus extrinsic environmentalfactors determine the capacity of a given effector/memory cell population to induce GVHD; 3) Examine therole of regulatory cell populations and of T cell homeostatic proliferation in modulating susceptibility toGVHD. The studies will synergize with those in Projects 2 and 3, and will make extensive use of Cores A, B,and C. An improved understanding of the mechanisms of LGVHR in delayed DLI recipients will advance thestudies in Project 3 and ultimately the clinical use of this approach to separating GVHD and GVT effects inHLA-mismatched hematopoietic cell transplantation.
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