Huang Xiaolun, Moore Daniel J, Mohiuddin Mohammad, Lian Moh-Moh, Kim James I, Sonawane Samsher, Wang Jing, Gu Yi, Yeh Heidi, Markmann James F, Deng Shaoping
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Transplantation. 2008 Mar 15;85(5):675-80. doi: 10.1097/TP.0b013e3181663422.
Allogeneic tolerance can be reliably obtained with monoclonal antibody therapy targeting CD45RB. Although regulatory T cells play an important role in the mechanism, we have recently demonstrated the active participation of host B lymphocytes. After anti-CD45RB therapy, B lymphocytes demonstrate phenotypic alterations that include up-regulation of CD54 (intercellular adhesion molecule [ICAM]-1). We have investigated the hypothesis that alteration in ICAM-1 expression is required for tolerance induction.
Recipients of heterotopic allogeneic cardiac grafts (C3H donors into B6 recipients) were treated with anti-CD45RB, anti-ICAM, anti-lymphocyte function-associated antigen-1 (LFA), or the combination of these agents. These data were extended by performing allogeneic cardiac transplants into ICAM or LFA recipients treated with a 5-day course of anti-CD45RB. Finally, B-cell-deficient animals were reconstituted with ICAM splenocytes to create a recipient with a selective deficiency of ICAM-1 restricted to the B-cell compartment.
Anti-CD45RB alone or the combination of anti-LFA/anti-ICAM reliably induced transplantation tolerance. However, the triple combination was routinely unsuccessful and induced long-term graft survival in no recipients. ICAM-deficient or LFA-deficient recipients were also resistant to tolerance induced by anti-CD45RB. Finally, transfer of control splenocytes to B-cell-deficient recipients permitted anti-CD45RB-induced tolerance, whereas transfer of ICAM cells was unable to support tolerance induction.
Expression of ICAM-1 by B lymphocytes and interaction with LFA-1 form a central aspect of transplantation tolerance induced by anti-CD45RB therapy. These data further elucidate the cellular mechanisms used by B lymphocytes in the induction of transplantation tolerance.
通过靶向CD45RB的单克隆抗体疗法能够可靠地诱导同种异体耐受。尽管调节性T细胞在该机制中发挥重要作用，但我们最近证实宿主B淋巴细胞也积极参与其中。抗CD45RB治疗后，B淋巴细胞表现出表型改变，包括CD54（细胞间黏附分子[ICAM]-1）上调。我们研究了ICAM-1表达改变是诱导耐受所必需的这一假说。
将异位同种异体心脏移植物（C3H供体至B6受体）的受体用抗CD45RB、抗ICAM、抗淋巴细胞功能相关抗原-1（LFA）或这些药物的组合进行治疗。通过将同种异体心脏移植到用5天疗程抗CD45RB治疗的ICAM或LFA受体中，扩展了这些数据。最后，用ICAM脾细胞重建B细胞缺陷动物，以创建仅在B细胞区室存在ICAM-1选择性缺陷的受体。
单独使用抗CD45RB或抗LFA/抗ICAM的组合可可靠地诱导移植耐受。然而，三联组合通常不成功，未在任何受体中诱导长期移植物存活。ICAM缺陷或LFA缺陷的受体也对抗CD45RB诱导的耐受具有抗性。最后, 将对照脾细胞转移至B细胞缺陷受体可实现抗CD45RB诱导的耐受，而转移ICAM细胞则无法支持耐受诱导。
B淋巴细胞表达ICAM-1并与LFA-1相互作用是抗CD45RB治疗诱导移植耐受的核心方面。这些数据进一步阐明了B淋巴细胞在诱导移植耐受中所使用的细胞机制。
