Chemokines and Graft-versus-Host Disease

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Graft versus host disease (GVHD) is a complication of allogeneic hematopoietic stem cell transplantation that limits the available donor pool. Preventing donor T cell activation reduces the incidence and severity of GVHD but does so at the expense of graft versus leukemia (GVL). The fact that only a limited set of target organs is involved in acute GVHD suggests that this process is regulated. Since chemokines control the trafficking of immune cells to specific organs, they may also be involved, attracting effector cells in GVHD. For example, keratinoeytes secrete the chemokines MDC, TARC, and CTACK which could attract effector cells expressing their receptors, CCR4 or CCR10. Blockade of these or other chemokines and receptors might ameliorate GVHD without impairing GVL since this maneuver would have little influence on T cell activation. Thus the first hypothesis to be tested in this project is that organ-specific chemokine expression contributes to acute GVHD pathophysiology. If chemokines play a role in GVHD, then interventions that modulate GVHD outcomes may have effects on chemokine or chemokine receptor expression. For example, although tacrolimus and sirolimus are likely to exert their effects on GVHD through their potent immunosuppressive activities, they also inhibit the expression of some chemokines. The second hypothesis to be tested in this project is that tacrolimus and sirolimus modulate chemokine and chemokine receptor expression in a manner that ameliorates GVHD. To test these hypotheses, the following specific aims are proposed: Specific Aim 1: Examine the expression and function of chemokines and chemokine receptors in murine acute GVHD models. Expression patterns will be determined and the roles of relevant chemokines and their receptors in GVHD will be examined using genetically modified mice and specific antagonists. Specific Aim 2: Examine human material for chemokine ligand and receptor expression and function. Skin biopsies and PBMCs from patients will be tested for chemokine ligand and receptor expression and the effect of antagonists will be tested in a hu/SCID reconstitution model. Specific Aim 3: Examine effects of tacrolimus and sirolumus on the chemokine system in GVHD. Effects of tacrolimus and sirolimus will be tested on cells in vitro and in mouse models in vivo. Correlates will be sought with human material from patients on trials in Project #1.