Onodera K, Chandraker A, Volk H D, Ritter T, Lehmann M, Kato H, Sayegh M H, Kupiec-Weglinski J W
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Transplantation. 1999 Jul 27;68(2):288-93. doi: 10.1097/00007890-199907270-00022.
CD4-targeted therapy or blocking of CD28-B7 T-cell costimulation may produce indefinite cardiac allograft survival in presensitized rats. This study analyzes the immune events associated with tolerance pathways after the blockade of activation signal 1 (CD4 monoclonal antibody [mAb]) or signal 2 (CTLA4Ig).
Lewis rats sensitized with Brown Norway skin grafts reject LBNF1 cardiac allografts in <36 hr. Animals were treated with RIB-5/2, a nondepleting CD4 mAb, or with CTLA4Ig + LBNF1 spleen cells. RIB-5/2 monotherapy uniformly produced permanent cardiac graft acceptance, whereas CTLA4Ig produced indefinite graft survival in about 50% of sensitized rats. Spleen cells (100 x 10(6)) from CD4 mAb-treated rats conferred donor-specific tolerance after transfer into new sets of recipients. This tolerant state could be then transferred with regulatory cells in an infectious manner into new cohorts of engrafted rats. In contrast, features of infectious tolerance could be detected in CTLA4Ig-treated hosts after infusion of >300 x 10(6) of splenocytes. CD4 mAb therapy abolished the transcription of both T helper (Th)1 and Th2 cytokines compared with rejecting controls. In contrast, CTLA4Ig treatment resulted in a selective sparing of Th2-type cytokines. Surviving grafts in both groups were largely protected from signs of chronic rejection.
CD4 mAb-induced blockage of activation signal 1 or CTLA4Ig-mediated blockage of costimulatory signal 2 may induce a true transplantation tolerance in sensitized rats, as documented by permanent graft acceptance and attenuation of chronic injury. The infectious pathway operates in a cell dose-dependent manner. Th2-type deviation in the graft itself is not required for tolerance maintenance, and it does not necessarily lead to chronic injury.
针对CD4的治疗或阻断CD28 - B7 T细胞共刺激可能使致敏大鼠的心脏移植长期存活。本研究分析了激活信号1（CD4单克隆抗体[mAb]）或信号2（CTLA4Ig）阻断后与耐受途径相关的免疫事件。
用挪威棕色大鼠皮肤移植致敏的Lewis大鼠在<36小时内排斥LBNF1心脏移植。动物接受非清除性CD4 mAb RIB - 5/2治疗，或接受CTLA4Ig + LBNF1脾细胞治疗。RIB - 5/2单药治疗均能使心脏移植永久被接受，而CTLA4Ig能使约50%的致敏大鼠移植长期存活。来自接受CD4 mAb治疗大鼠的脾细胞（100×10⁶）在转移到新的受体组后赋予供体特异性耐受。这种耐受状态随后可通过调节性细胞以感染性方式转移到新的移植大鼠群体中。相比之下，在输注>300×10⁶脾细胞后，可在接受CTLA4Ig治疗的宿主中检测到感染性耐受的特征。与排斥对照组相比，CD4 mAb治疗消除了辅助性T细胞（Th）1和Th2细胞因子的转录。相比之下，CTLA4Ig治疗导致Th2型细胞因子选择性保留。两组中存活的移植心脏在很大程度上免受慢性排斥迹象的影响。
CD4 mAb诱导的激活信号1阻断或CTLA4Ig介导的共刺激信号2阻断可能在致敏大鼠中诱导真正的移植耐受，永久移植接受和慢性损伤减轻证明了这一点。感染途径以细胞剂量依赖方式起作用。移植自身的Th2型偏向对于耐受维持不是必需的，并且不一定导致慢性损伤。
