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that decrease GVHD may decrease GVL, which histone deacetylase inhibitor is an undesirable outcome of such therapies. Therefore, it is generally accepted that, in the context of haematopoietic stem cell transplantation, a therapy should decrease or prevent GVHD but ideally should not modify the associated GVL. Although the chemokine system represents a promising system to target to develop new GVHD therapies, it is also important to understand the role of chemokines in GVL response. Evaluation of GVL has not been the major focus of studies involving chemokines and GVHD. However, we have found a few studies showing that, by interfering with the chemokine system, it is possible to decrease GVHD without interfering with GVL. Our group and Choi et al. demonstrated that, despite the important action of CCR1 and its ligands, CCL3, and CCL5, in the GVHD response, neutralization of CCL3, or the absence of CCR1 in donor cells did not interfere with GVL. The capacity of T cells to eliminate tumor cells remained unaltered upon neutralization of CCL3 by evasin 1 in histone deacetylase inhibitor mice subjected

not interfere with GVL responses. The explicit participation of chemokines in the pathophysiology of different diseases has IEM 1754 initiated the development of pharmacological strategies that can interfere with the chemokine system. Chemokines function by signaling through seven transmembrane G protein coupled receptors, which are one of the most druggable classes of receptors in the pharmaceutical industry. Since 1996, interest in targeting the chemokine system has been growing, especially after demonstration of the participation of CCR5 as a co receptor of HIV infection. After those studies, the pharmaceutical industry began investing in the development of molecules that could interfere with chemokine/chemokine receptor interaction. Examples

Evasin 1, CXCR3 antagonists, anti CX3CL1, inhibitor of CCR5 and CCR9, oligopeptides, such as NR58 3143, and inhibitors of molecules involved in downstream signaling of chemokine receptors decrease GVHD in mice and may hence represent an interesting clinical approach in humans. However, to the best of our knowledge, there are no studies conrming the effects of inhibitors of the chemokine system in GVHD in humans. Many experimental studies have not claried the mechanism by which abrogation of inammatory responses occur after use of therapies based on chemokine inhibition. Therefore, more mechanistic studies are needed to understand in greater detail the use of these therapeutic molecules in experimental GVHD. As mentioned above, any therapy for GVHD should decreased clinical disease but not interfere with GVL. In this respect, strategies based on CCL3, CCL5, and CX3CL1 appear to be the PARP most promising approach based on the existing experimental systems. Janus kinase 3 is a key component in the signalling pathways of the type I cytokines interleukin 2, 4, 7, 9, 15 and 21, through its interaction with the common gamma chain subunit of the respective cytokine receptors. Type I cytokines are critically involved