The Role of CCR4 in Skin Lymphocyte Homing and Immunity

CCR4 在皮肤淋巴细胞归巢和免疫中的作用

• 批准号: 6755999
• 负责人: James J. Campbell
• 金额: $ 31.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6755999
• 关键词: B lymphocyte; T lymphocyte; antireceptor antibody; cell migration; cellular immunity; chemokine; chemotaxis; clinical research; cytokine receptors; delayed hypersensitivity; disease /disorder model; human subject; inflammation; laboratory mouse; laboratory rat; lymphocyte; natural killer cells; psoriasis; receptor expression; skin

DESCRIPTION (provided by applicant): Chemoattractant cytokines (chemokines) are important mediators of lymphocyte trafficking from the circulation into sites of tissue damage and inflammation, and into secondary lymphoid organs. Certain chemokines rapidly trigger lymphocyte integrins, causing increased avidity with endothelial ligands, resulting in arrest of the lymphocyte on endothelial cells close to the chemokine source. Gradients of chemokine molecules can also attract arrested cells through the endothelium and into the surrounding tissue. A variety of chemokines are differentially expressed in various tissue types, suggesting a role in the differential homing of specific lymphocyte subsets to various types of tissue. We have found (in the human system) that the chemokines TARC and MDC efficiently attract circulating systemic memory T cells, especially skin-homing T cells expressing the cutaneous lymphocyte antigen, CLA. In contrast, intestinal (a4B7+) memory and naive T cells respond poorly. Immunohistochemistry reveals anti-TARC reactivity with venules involved in lymphocyte trafficking in chronically inflamed skin, but not in the gastrointestinal lamina propria, suggesting a potential role in circulating CLA+ lymphocyte recognition of skin vasculature. Consistent with this, TARC triggers integrin-dependent adhesion of CLA+ (but not a4B7hi intestinal) memory T cells to ICAM-1; and mediates rapid integrin-dependent arrest of lymphocytes rolling on the vascular CLA receptor, E-selectin, under physiologic flow conditions. The results suggest a fundamental role for TARC and its lymphocyte receptor CCR4 in lymphocyte-endothelial cell recognition and in differential trafficking of lymphocyte populations responsible for systemic vs. intestinal immunity. In order to define this role in detail, here we shall characterize CCR4 expression and responsiveness to TARC and MDC among specialized subsets of lymphocytes in man (Aim 1). We will determine if the preferential effects of TARC and MDC on systemic vs. mucosal lymphocytes are also observed in the mouse, and will ask if these responses are CCR4-dependent (Aim 2). The availability of a mutant CCR4-deficient mouse line will allow us to explore the role of this receptor in targeted lymphocyte homing to inflamed skin (Aim 3) and its role in the inflammation process in models of DTH and autoimmune psoriasis (Aim 4). Monoclonal antibodies to mouse CCR4 and its ligands will facilitate these studies (Aim 5). These studies promise to define a critical component of lymphocyte recruitment to systemic sites inflammation, and may lead to novel therapeutic approaches in cutaneous (i.e. psoriasis) and other inflammatory diseases.

描述（由申请人提供）：趋化剂细胞因子（趋化因子）是 淋巴细胞贩运的重要介质从循环到部位 组织损伤和炎症，以及次级淋巴器官。肯定 趋化因子迅速触发淋巴细胞整合素，导致与 内皮配体，导致淋巴细胞在内皮细胞上停滞 接近趋化因子来源。趋化因子分子的梯度也可以 通过内皮吸引被捕的细胞进入周围的组织。 多种趋化因子在各种组织类型中差异表达， 暗示在特定淋巴细胞亚群的差分归位中发挥作用 各种类型的组织。我们发现（在人类系统中） 趋化因子TARC和MDC有效吸引循环的全身记忆t 细胞，尤其是表达皮肤淋巴细胞的皮肤的T细胞 抗原，CLA。相反，肠道（A4B7+）记忆和天真的T细胞反应 差。免疫组织化学揭示了抗tarc的反应性 在慢性发炎的皮肤中淋巴细胞贩运中，但没有 胃肠道层植物层，表明在循环中具有潜在的作用 CLA+淋巴细胞对皮肤脉管系统的识别。与此一致，TARC 触发CLA+（但不是A4B7HI肠）内存的整合素依赖性粘附 T细胞到ICAM-1；并介导淋巴细胞的快速整联蛋白依赖性停滞 在生理流动下，在血管CLA受体E-选择蛋白上滚动 状况。结果表明TARC及其淋巴细胞的基本作用 淋巴细胞 - 内皮细胞识别和差异的受体CCR4 负责全身性与肠道的淋巴细胞种群的贩运 免疫。为了详细定义此角色，我们将在这里表征 CCR4表达和对TARC和MDC的反应性 人类中的淋巴细胞（AIM 1）。我们将确定是否优先影响 在全身性与粘膜淋巴细胞上的TARC和MDC也观察到 鼠标，并将询问这些响应是否依赖于CCR4（AIM 2）。这 突变CCR4缺陷鼠标线的可用性将使我们能够探索 该受体在靶向淋巴细胞中的作用对皮肤发炎（AIM 3） 及其在DTH和自身免疫模型中的炎症过程中的作用 牛皮癣（目标4）。小鼠CCR4及其配体的单克隆抗体将 促进这些研究（目标5）。这些研究有望定义关键 淋巴细胞募集到全身性部位炎症的成分，可能 导致皮肤（即牛皮癣）和其他的新型治疗方法 炎症性疾病。