Data_Sheet_1_ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions.PDF

Activated leukocyte cell adhesion molecule (ALCAM, CD166) is a cell adhesion molecule of the immunoglobulin superfamily and has been implicated in diverse pathophysiological processes including T cell activation, leukocyte trafficking, and (lymph)angiogenesis. However, exploring the therapeutic potential of ALCAM blockade in immune-mediated inflammatory disorders has been difficult due to the lack of antibodies with blocking activity toward murine ALCAM. In this study, we identified and characterized a monoclonal antibody with high affinity and specificity for murine ALCAM. This antibody reduced in vitro T cell activation induced by antigen-presenting dendritic cells (DCs) as well as (trans)migration of murine DCs across lymphatic endothelial monolayers. Moreover, it reduced emigration of DCs from in vitro-cultured human skin biopsies. Similarly, antibody-based blockade of ALCAM reduced (lymph)angiogenic processes in vitro and decreased developmental lymphangiogenesis in vivo to levels observed in ALCAM-deficient mice. Since corneal allograft rejection is an important medical condition that also involves (lymph)angiogenesis, DC migration and T cell activation, we investigated the therapeutic potential of ALCAM blockade in murine corneal disease. Blocking ALCAM lead to DC retention in corneas and effectively prevented corneal allograft rejection. Considering that we also detected ALCAM expression in human corneal DCs and lymphatics, our findings identify ALCAM as a potential novel therapeutic target in human corneal allograft rejection.

活化白细胞黏附分子（Activated leukocyte cell adhesion molecule，ALCAM，CD166）属于免疫球蛋白超家族的细胞黏附分子，已被证实参与多种病理生理过程，包括T细胞活化、白细胞迁移以及（淋巴）血管生成。然而，由于缺乏对鼠源ALCAM具有阻断活性的抗体，探索ALCAM阻断在免疫介导性炎症疾病中的治疗潜力一直面临困难。本研究中，我们鉴定并表征了一种对鼠源ALCAM具有高亲和力与特异性的单克隆抗体。该抗体可抑制由抗原呈递树突状细胞（dendritic cells，DCs）诱导的体外T细胞活化，同时可抑制鼠源DCs跨淋巴内皮单层的迁移。此外，该抗体可减少体外培养的人皮肤活检组织中DCs的迁出。类似地，基于抗体的ALCAM阻断可在体外抑制（淋巴）血管生成过程，并在体内将发育性淋巴管生成降低至ALCAM缺陷小鼠中的观测水平。鉴于角膜同种异体移植排斥反应是一种同样涉及（淋巴）血管生成、DC迁移与T细胞活化的重要临床病症，我们探究了ALCAM阻断在鼠源角膜疾病中的治疗潜力。阻断ALCAM可导致DCs在角膜内滞留，并有效阻止角膜同种异体移植排斥反应。考虑到我们还在人角膜DCs与淋巴管中检测到ALCAM的表达，本研究结果证实ALCAM可作为人类角膜同种异体移植排斥反应中一种潜在的新型治疗靶点。