LYMPHOCYTE RECRUITMENT BY VASCULAR ADHESION MOLECULES

淋巴细胞归巢到炎症部位是由血管内皮上的粘附分子与淋巴细胞表面上的配体之间的相互作用指导的。携带适当配体的淋巴细胞归巢到特定器官可以通过血管粘附分子的选择性表达来确定。 我的假设是，皮肤的微血管内皮细胞具有粘附分子E-选择素、VCAM-1和ICAM-1的特征性表达谱，其与其他组织不同，是细胞因子反应性和粘附分子表达持续时间的函数。 我将确定内皮细胞粘附分子表达的这些组织特异性差异是否导致携带特异性粘附分子配体的淋巴细胞亚群的选择性募集。 这将通过1）构建嵌合的人免疫缺陷小鼠模型来实现，其中比较人淋巴细胞与来自皮肤、肺、皮下脂肪和脐静脉的内皮细胞之间的相互作用; 2）系统地表征响应于体外细胞因子刺激的粘附分子表达的组织特异性差异。（在器官和细胞培养中）和体内; 3）通过首先用全细胞或同种异体反应性细胞耗尽的人PBMC接种嵌合动物，确定粘附分子的特定组合是否是体内募集特定T细胞亚群所必需的，然后使用阻断抗体选择性地干扰粘附分子-配体相互作用; 4）在没有其它差异的情况下，通过使用逆转录病毒转导改变内皮粘附分子表达的所有成分，确定这些相互作用是否足以用于选择性淋巴细胞募集，并评估对浸润T细胞表型的影响。一个为期五年的指导计划，提出测试这一假设。该计划将包括在导师（J. Pober）的指导下进行免疫学和分子生物学领域的培训，该导师在免疫生物学和血管生物学方面具有良好的背景，合作者（A. Bothwell和M. Kluger）在分子生物学方面的专业知识，以及从许多课程和研讨会。 在这一时期结束时，我的目标是作为一个独立的研究者，并作出了贡献的皮肤淋巴细胞募集的理解，可以利用在皮肤中的特异性活性的抗炎药的发展。

Lymphocyte homing to sites of inflammation is directed by the interaction between adhesion molecules on the vascular endothelium and their ligands on the surface of the lymphocytes. The homing of lymphocytes bearing the proper ligands to specific organs may be determined by the selective expression of vascular adhesion molecules. It is my hypothesis that the microvascular endothelium of the skin has a characteristic profile expression of the adhesion molecules E-Selectin, VCAM-1, and ICAM-1 that differs from other tissues as a function of cytokine responsiveness and duration of adhesion molecule expression. I will determine whether these tissue specific differences in endothelial adhesion molecule expression result in the selective recruitment of subsets of lymphocytes bearing specific adhesion molecule ligands. This will be accomplished by 1) constructing a chimeric human-immunodeficient mouse model in which to compare the interactions between human lymphocytes and endothelial cells derived from skin, lung, subcutaneous fat and umbilical vein; 2) systematically characterizing tissue specific differences in adhesion molecule expression in response to cytokine stimulation in vitro (in both organ and cell culture) and in vivo; 3) determining whether specific combinations of adhesion molecules are necessary for the recruitment of specific T cell subsets in vivo by first inoculating the chimeric animals with whole or alloreactive cell depleted human PBMC, then using blocking antibodies to selectively interfere with adhesion molecule-ligand interactions; 4) determining whether these interactions are sufficient, in the absence of other differences, for selective lymphocyte recruitment by using retroviral transduction to alter the repertoire of endothelial adhesion molecule expression, and assessing the effect on the phenotype of infiltrating T-cells. A five year mentored program is proposed test this hypothesis. This program will incorporate training in the fields of immunology and molecular biology under the guidance of a mentor (J. Pober) with a well established background in immunobiology and vascular biology, collaborators (A. Bothwell and M. Kluger) with expertise in molecular biology, as well as from numerous courses and seminars. At the end of this period it is my goal to be well established as an independent investigator, and to have made a contribution to the understanding of cutaneous lymphocyte recruitment which could be exploited in the development of anti inflammatory agents with specific activity in the skin.