Chemokines and Graft-versus-Host Disease

趋化因子和移植物抗宿主病

• 批准号: 7393103
• 负责人: Barrett J. Rollins
• 金额: $ 38.08万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7393103
• 关键词: Acute; Acute Disease; Acute Graft Versus Host Disease; Affect; Alloantigen; Allogenic; Antibodies; Antigens; Biopsy; CC chemokine receptor 4; CCL17 gene; CCL27 gene; Cells; Cessation of life; Characteristics; Chemokine, Other; Chemotactic Factors; Complication; Cutaneous; Cytoplasmic Granules; Disease Outcome; Disease model; Effector Cell; Epithelial Cells; Functional disorder; G-Protein-Coupled Receptors; GPR2 gene; Hematopoietic Stem Cell Transplantation; Human; Immune; Immunosuppressive Agents; In Vitro; Incidence; Infiltration; Inflammation; Intervention; Intestines; Leukocytes; Ligands; Liver; Lymphocyte; Lymphocyte Activation; Measures; Minor Histocompatibility Antigens; Modeling; Molecular Weight; Mus; Numbers; Organ; Pathway interactions; Patients; Pattern; Play; Process; Reactive Oxygen Species; Research Personnel; Role; Role playing therapy; Severities; Sirolimus; Site; Skin; System; T memory cell; T-Cell Activation; T-Lymphocyte; Tacrolimus; Testing; Tissues; Toxic effect; chemokine; chemokine receptor; graft vs host disease; human CCL25 protein; in vivo; keratinocyte; leukemia; macrophage-derived chemokine; mouse model; prevent; programs; receptor; receptor expression; reconstitution; research study; trafficking

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.

移植物抗宿主病（GVHD）是异基因造血干细胞移植的并发症，限制了可用的供体库。防止供体T细胞活化降低了GVHD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，只有有限的一组靶器官参与急性GVHD表明，这一过程是受调控的。由于趋化因子控制免疫细胞向特定器官的运输，因此它们也可能参与GVHD中吸引效应细胞。 例如，角质形成细胞分泌 趋化因子MDC、TARC和CTACK，其可以吸引表达其受体CCR 4或CCR 10的效应细胞。 阻断这些或其他趋化因子和受体可能会改善GVHD而不损害GVL，因为这种操作对T细胞活化的影响很小。因此，在本项目中要检验的第一个假设是器官特异性趋化因子表达有助于急性GVHD病理生理学。 如果趋化因子在GVHD中发挥作用，那么调节GVHD结果的干预可能对趋化因子或趋化因子受体表达有影响。例如，虽然他克莫司和西罗莫司可能发挥其 通过其有效的免疫抑制活性对GVHD的作用，它们还抑制一些趋化因子的表达。第二个假设是，他克莫司和西罗莫司调节趋化因子和趋化因子受体表达的方式，改善GVHD。为了检验这些假设，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小鼠急性GVHD模型中的表达和功能。将确定表达模式，并使用遗传修饰小鼠和特异性拮抗剂检查相关趋化因子及其受体在GVHD中的作用。 具体目标2：检测人体材料的趋化因子配体和受体表达和功能。将测试来自患者的皮肤活组织检查和PBMC的趋化因子配体和受体表达，并且将在hu/SCID重建模型中测试拮抗剂的作用。具体目标3：检查他克莫司和西罗莫司对GVHD中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。将从项目1试验患者的人体材料中寻找相关性。