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: 7151962
• 负责人: James J. Campbell
• 金额: $ 38.84万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7151962
• 关键词: Adoptive Transfer; Animal Model; Antigens; Atopic Dermatitis; Biological Models; Blood; Blood Vessels; CCL17 gene; Cells; Chemicals; Cutaneous; Development; Disease; E-Selectin; Edema; Fluorobenzenes; GPR2 gene; Gene Targeting; Genes; Genetic; Homing; Human; Immune response; Immunity; Immunologic Memory; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Intestines; Ligands; Lymphocyte; Mediating; Medical; Memory; Modeling; Mus; Numbers; P-Selectin; Pattern; Pharmacologic Substance; Population; Positioning Attribute; Protocols documentation; Psoriasis; Role; Skin; Surface; Swelling; T memory cell; T-Cell Development; T-Lymphocyte; Testing; Tissues; Topical application; Transgenic Organisms; Wild Type Mouse; cell type; chemokine; chemokine receptor; concept; in vivo; inhibitor/antagonist; prevent; receptor; response; small molecule; trafficking; venule

DESCRIPTION (provided by applicant): Expression patterns of the chemokine receptor CCR4 and its ligand CCL17 in humans suggests that interaction between these two molecules may contribute to skin-specific T lymphocyte homing and cutaneous inflammation. However, this assumption relies upon circumstantial evidence, and requires direct testing. Fortunately, CCR4 expression is also associated with cutaneous lymphocyte homing in the mouse, which allows the role of CCR4 in skin-specific T cell homing to be directly tested animal models. Current efforts to study the role of chemokine receptors in murine skin-specific T cell homing have relied largely upon a topical DNFB-induced inflammation model. We have recently demonstrated that DNFB-induced cutaneous edema occurs in T cell-deficient mice with the same intensity as it occurs in wild type (WT) mice. This suggests that the DNFB model (at least with its currently-used readout) is T cell independent, and therefore may not be relevant to human T cell-mediated skin inflammation. We have therefore developed a truly T cell-dependent model of skin inflammation, in which we will use targeted-gene-deficient mice and pharmacological inhibitors to precisely determine the roles of CCR4 and other skin-associated homing molecules (including CCR10 and E- and P-selectin) in cutaneous T cell trafficking and inflammation. We will: 1) use an anti-OVA-TCR-transgenic adoptive-transfer model to examine the role of skin-associated T cell homing molecules in cutaneous inflammation; 2) use a direct cutaneous OVA sensitization-and-challenge protocol to determine the role of these homing molecules in development of T cell memory responses to cutaneous antigens; and 3) use a competitive adoptive transfer approach to determine whether T cells lacking skin-associated homing receptors can participate in cutaneous inflammatory skin responses in the presence of competing WT cells. These studies may help determine the best candidates for medical intervention in human cutaneous inflammatory disorders, such as allergic dermatitis and psoriasis.

描述（由申请人提供）：人类中趋化因子受体CCR4及其配体CCL17的表达模式表明，这两个分子之间的相互作用可能有助于皮肤特异性T淋巴细胞托管和皮肤炎症。但是，该假设依赖于间接证据，需要直接测试。幸运的是，CCR4表达也与小鼠中的皮肤淋巴细胞寄养有关，这使得CCR4在皮肤特异性T细胞中的作用可以直接测试。当前研究趋化因子受体在鼠皮肤特异性T细胞寄养中的作用的努力主要依赖于局部DNFB诱导的炎症模型。我们最近证明，DNFB诱导的皮肤水肿发生在T细胞缺陷的小鼠中，其强度与野生型（WT）小鼠相同。这表明DNFB模型（至少具有目前使用的读数）是独立的，因此可能与人类T细胞介导的皮肤炎症无关。因此，我们已经开发了一种真正的T细胞炎症模型的皮肤炎症模型，在该模型中，我们将使用靶向基因的小鼠和药理学抑制剂精确确定CCR4和其他皮肤相关的寄居分子（包括CCR10和E-和P-SELECTIN）在皮细胞运输和炎症中的作用。我们将：1）使用抗OVA-TCR转基因的收养转移模型来检查皮肤相关的T细胞归巢分子在皮肤炎症中的作用； 2）使用直接皮肤的OVA敏化和挑战方案来确定这些归巢分子在T细胞记忆对皮肤抗原的反应发展中的作用； 3）使用竞争性的收养转移方法来确定缺乏皮肤相关的归巢受体的T细胞是否可以在存在竞争性WT细胞的情况下参与皮肤炎症性皮肤反应。这些研究可能有助于确定人皮肤炎症性疾病（例如过敏性皮炎和牛皮癣）中医疗干预的最佳候选者。