Department of Surgery, University of Western Ontario, London, ON, Canada.
Transplantation. 2010 Dec 27;90(12):1286-93. doi: 10.1097/TP.0b013e3182007bbf.
Tolerogenic dendritic cells (Tol-DCs) play a critical role in inducing and maintaining tolerance. Recognizing that both T-cell inactivation and activation are contingent on signals provided by DCs and that graft-specific activated T cells are major mediators of transplant rejection, we aimed to create an environment favoring Tol-DCs with a novel reagent, human soluble CD83 (hsCD83).
Life-supporting orthotopic kidney transplantation was performed in a C57BL/6-to-BALB/c mouse model. The study group was treated with hsCD83 (100 μg/mouse/day, postoperative days -1 to +7, intravenously) and compared with untreated controls.
Treatment with hsCD83 achieved kidney allograft tolerance (>100 days), with negligible antidonor antibody detected. In contrast, kidney grafts in untreated recipients demonstrated severe rejection after 35 days, characterized by cellular infiltration, interstitial hemorrhage and edema, and glomerular and tubular necrosis, as well as high antidonor antibody titers. In addition, splenic DCs of tolerant recipients exhibited significantly decreased levels of surface major histocompatibility complex class II, CD40, CD80, and intracellular interleukin-12, as well as reduced allogeneic stimulatory capacity. Adoptive transfer of CD11c+ DCs from tolerant hsCD83-treated animals induced kidney allograft tolerance in syngeneic recipients. Blocking indoleamine 2,3-dioxygenase with 1-methyl-tryptophan (15 mg/mouse/day; gavage) prevented the immunosuppressive effect of hsCD83, abrogating hsCD83-induced Tol-DCs and graft tolerance, and leading to acute kidney graft rejection in 22 days.
hsCD83 alone was capable of inducing kidney allograft tolerance through a mechanism involving Tol-DC generation and, at least in part, indoleamine 2,3-dioxygenase activity. Because sCD83 is of human origin, the therapeutic approach used in our mouse transplant model holds significant promise for clinical transplantation.
耐受原性树突状细胞（Tol-DC）在诱导和维持免疫耐受中发挥关键作用。鉴于 T 细胞失能和激活都依赖于 DC 提供的信号，且移植物特异性激活的 T 细胞是移植排斥的主要介导者，我们旨在通过一种新型试剂——人可溶性 CD83（hsCD83）创造有利于 Tol-DC 的环境。
在 C57BL/6 到 BALB/c 小鼠模型中进行了支持生命的原位肾脏移植。实验组接受 hsCD83（100μg/只/天，术后第-1 天至+7 天，静脉内）治疗，并与未治疗的对照组进行比较。
hsCD83 治疗实现了肾脏同种异体移植物耐受（>100 天），检测到的抗供体抗体可忽略不计。相比之下，未治疗的受者的肾脏移植物在 35 天后表现出严重的排斥反应，特征为细胞浸润、间质出血和水肿、肾小球和肾小管坏死，以及高抗供体抗体滴度。此外，耐受受者的脾 DC 表面主要组织相容性复合体 II、CD40、CD80 和细胞内白细胞介素-12 的水平显著降低，并且同种异体刺激能力降低。从耐受的 hsCD83 治疗的动物中过继转移 CD11c+DC 可诱导同基因受者的肾脏同种异体移植物耐受。用 1-甲基色氨酸（15mg/只/天；灌胃）阻断吲哚胺 2,3-双加氧酶可防止 hsCD83 的免疫抑制作用，消除 hsCD83 诱导的 Tol-DC 和移植物耐受，并导致 22 天内急性肾脏移植物排斥。
hsCD83 本身通过诱导 Tol-DC 生成的机制能够诱导肾脏同种异体移植物耐受，并且至少部分通过吲哚胺 2,3-双加氧酶活性。由于 sCD83 是人源的，因此我们在小鼠移植模型中使用的治疗方法为临床移植提供了重要的前景。
