Chemokines and Graft-versus-Host Disease

移植物抗宿主病(GVHD)是异基因造血干细胞移植的一种并发症，限制了可用的供者池。阻止供者T细胞激活可降低移植物抗白血病(GVL)的发生率和严重程度，但这样做是以移植物抗白血病(GVL)为代价的。事实上，只有有限的靶器官参与急性移植物抗宿主病，这一事实表明这一过程是受调控的。由于趋化因子控制着免疫细胞向特定器官的运输，它们也可能参与其中，在移植物抗宿主病中吸引效应细胞。例如，角化细胞分泌 趋化因子MDC、TARC和CTACK可以吸引表达其受体CCR4或CCR10的效应细胞。阻断这些或其他趋化因子和受体可能会在不损害GVL的情况下改善GVHD，因为这种操作对T细胞激活几乎没有影响。因此，本项目要检验的第一个假设是器官特异性趋化因子的表达与急性移植物抗宿主病的病理生理有关。如果趋化因子在GVHD中起作用，那么调节GVHD结局的干预措施可能会对趋化因子或趋化因子受体的表达产生影响。例如，尽管他克莫司和西罗莫司可能会发挥其作用 通过其强大的免疫抑制活性，它们还可以抑制某些趋化因子的表达。本项目要检验的第二个假设是，他克莫司和西罗莫司以一种改善GVHD的方式调节趋化因子及其受体的表达。为了检验这些假设，我们提出了以下具体目标： 具体目的1：检测趋化因子及其受体在急性移植物抗宿主病(GVHD)模型中的表达和功能。将利用转基因小鼠和特定的拮抗剂来确定表达模式，并研究相关趋化因子及其受体在移植物抗宿主病中的作用。具体目标2：检测人类材料中趋化因子配体和受体的表达和功能。患者的皮肤活检和PBMC将被测试趋化因子配体和受体的表达，拮抗剂的效果将在HU/SCID重建模型中得到测试。具体目标3：检测他克莫司和西罗鲁姆对移植物抗宿主病患者趋化因子系统的影响。他克莫司和西罗莫司的作用将在体外细胞和体内小鼠模型中进行测试。在项目1的试验中，将从患者身上寻找与人体材料相关的材料。

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.