Onodera K, Lehmann M, Akalin E, Volk H D, Sayegh M H, Kupiec-Weglinski J W
Harvard Medical School, Surgical Research Laboratory, Boston, MA 02115, USA.
J Immunol. 1996 Sep 1;157(5):1944-50.
LBNF1 heart grafts are rejected in an accelerated manner within 36 h by LEW rats that have been sensitized with Brown Norway rat skin grafts on day -7. Treatment with RIB-5/2, a CD4-nondepleting mAb (10 doses of 5 mg/rat/day, i.v., from day -7 to day +21) abrogated rejection at <36 h and produced indefinite (>200 days) cardiac allograft survival. Transplantation tolerance in this model developed within several weeks, and during the maintenance phase (>100 days) it was associated with diminished host circulating allo-Ab responses and induction of peripheral allospecific T cell unresponsiveness both in vitro and in vivo. Tolerant cells in mAb-treated hosts could disable naive or alloimmune cells, so that they failed to trigger graft rejection. Moreover, donor-specific and organ-nonspecific tolerance could be adoptively transferred by spleen cells alone into new sets of primary (100%) and secondary (>40%) test recipients. CD4+ T cells were instrumental for the induction of such readily transferable tolerance. The first and second generation suppressive regulatory cells were also critical for the inhibition of allograft recognition by normal or even alloimmune cells. Hence, the features of an "infectious" tolerance pathway to minor histocompatibility-mismatched skin grafts, originally described in thymectomized mice, may be applied to the euthymic primed rats rendered tolerant to fully MHC-incompatible vascularized organ allografts. Such reprogramming of host cell-mediated regulatory mechanisms following CD4-targeted therapy adds to our appreciation of the potential utility and applicability of infectious tolerance in transplant recipients treated with a perioperative course of CD4-targeted monotherapy.
在第 -7 天用棕色挪威大鼠皮肤移植致敏的 LEW 大鼠会在 36 小时内以加速方式排斥 LBNF1 心脏移植。用 RIB - 5/2（一种非耗竭性 CD4 单克隆抗体，从第 -7 天至第 +21 天，静脉注射，10 剂，5 毫克/大鼠/天）治疗可消除 <36 小时的排斥反应，并使心脏同种异体移植存活期延长至不确定（>200 天）。该模型中的移植耐受在数周内形成，在维持期（>100 天），它与宿主循环中同种异体抗体反应减弱以及外周同种异体特异性 T 细胞在体外和体内的无反应性诱导相关。用单克隆抗体处理的宿主中的耐受细胞可使未致敏或同种免疫细胞失活，从而无法引发移植排斥。此外，供体特异性和器官非特异性耐受可通过单独的脾细胞过继转移到新的一组初次（100%）和二次（>40%）受试受体中。CD4 + T 细胞对诱导这种易于转移的耐受起重要作用。第一代和第二代抑制性调节细胞对于抑制正常甚至同种免疫细胞对同种异体移植的识别也至关重要。因此，最初在胸腺切除小鼠中描述的针对次要组织相容性不匹配皮肤移植的“传染性”耐受途径的特征，可能适用于对完全 MHC 不相容的血管化器官同种异体移植产生耐受的正常胸腺启动大鼠。在针对 CD4 的治疗后宿主细胞介导的调节机制的这种重新编程，增加了我们对传染性耐受在接受围手术期针对 CD4 的单一疗法治疗的移植受者中的潜在效用和适用性的认识。
