MECHANISMS BY WHICH IFN-GAMMA SEPARATES GVHD AND GVL

Massachusetts General Hospital, Boston MA

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Abstract

The inability to selectively prevent GVHD without diminishing graft-vs.-leukemia (GVL) effects limits the[unreadable] success of clinical allogeneic hematopoietic cell transplantation (allo-HCT), an effective therapy for the[unreadable] treatment of many otherwise fatal hematologic malignancies. CD8 T cells are major effector cells that[unreadable] induce both GVHD and GVL effects after allo-HCT. Our previous studies using anti-IFN-gamma mAb and[unreadable] IFN-gamma-deficient mice showed that IFN-gamma restricts donor CD8 T cell activation/expansion through[unreadable] induction of apoptosis and inhibits mononuclear cell infiltration in parenchymal GVHD target tissues in[unreadable] recipients of CD4-depleted allo-HCT, and that donor CD8 T cells induce more severe GVHD but less[unreadable] potent anti-lymphohematopoietic GVH reactions and GVL effects in the absence of IFN-gamma. The goal of[unreadable] this project is to understand the mechanisms by which IFN-gamma regulates the alloreactivity of donor CDS T[unreadable] cells as a prerequisite to the development of approaches that can induce GVL effects without severe[unreadable] GVHD. In Aim 1, we will determine whether or not IFN-gamma restricts expansion of both recipient antigen-specific[unreadable] and -nonspecific (homeostatic proliferation) donor CDS T cells, and identify the mechanisms[unreadable] responsible for IFN-gamma-induced apoptosis of donor CDS T cells in allo-HCT recipients. In Aim 2, we will[unreadable] test the hypothesis that IFN-gamma suppresses the migration, in-situ proliferation and/or survival of donor[unreadable] CDS T cells in parenchymal GVHD target tissues and thereby inhibits GVHD while preserving GVL[unreadable] effects. In Aim 3, we will determine how IFN-gamma mediates GVL effects without promoting GVHD. We will:[unreadable] 1) develop IFN-gamma-unresponsive leukemia models to determine whether or not IFN-gamma can enhance GVL[unreadable] effects by inhibiting tumor cell proliferation and/or sensitizing tumor cells to alloreactive CTLs; 2)[unreadable] assess the role of IFN-gamma in the differentiation of alloreactive CTLs with different cytotoxic mechanisms[unreadable] and the contribution of these cytotoxic mechanisms to the induction of GVHD vs. GVL effects in the[unreadable] presence and absence of IFN-gamma; and 3) determine the role of NK and NKT cells in the induction of GVL[unreadable] effects. Achieving these aims will lead to a better understanding of mechanisms involved in GVHDand[unreadable] GVL-associated alloreactivity of CDS T cells and facilitate the development of novel protocols for[unreadable] the performance of HLA-mismatched allo-HCT in the clinic. In addition to highly-relevant hypotheses to[unreadable] be addressed, collaborative interactions within the PPG can also be established based on the models[unreadable] developed in this project.