The Role of CCR4 in Skin Lymphocyte Homing and Immunity

描述（由申请人提供）：趋化因子受体CCR 4及其配体CCL 17在人体中的表达模式表明，这两种分子之间的相互作用可能有助于皮肤特异性T淋巴细胞归巢和皮肤炎症。然而，这一假设依赖于间接证据，需要直接检验。幸运的是，CCR 4表达也与小鼠皮肤淋巴细胞归巢有关，这使得CCR 4在皮肤特异性T细胞归巢中的作用可以直接在动物模型中进行测试。目前研究趋化因子受体在小鼠皮肤特异性T细胞归巢中的作用的努力在很大程度上依赖于局部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细胞缺陷型小鼠中，其强度与野生型（WT）小鼠相同。这表明DNFB模型（至少其当前使用的读数）是T细胞非依赖性的，因此可能与人类T细胞介导的皮肤炎症无关。因此，我们开发了一种真正的T细胞依赖性皮肤炎症模型，其中我们将使用靶向基因缺陷小鼠和药理学抑制剂来精确确定CCR 4和其他皮肤相关归巢分子（包括CCR 10和E-和P-选择素）在皮肤T细胞运输和炎症中的作用。我们将：1）使用抗OVA-TCR转基因过继转移模型来检查皮肤相关T细胞归巢分子在皮肤炎症中的作用; 2）使用直接皮肤OVA致敏和激发方案来确定这些归巢分子在对皮肤抗原的T细胞记忆应答的发展中的作用;和3）使用竞争性过继转移方法来确定缺乏皮肤相关归巢受体的T细胞是否可以在竞争性WT细胞存在下参与皮肤炎性皮肤反应。这些研究可能有助于确定人类皮肤炎症性疾病（如过敏性皮炎和银屑病）的最佳药物干预候选者。

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.