Induction of Donor-Specific Tolerance Using Superagonistic CD28 Antibody in Rat Renal Allografts: Regulatory T-Cell Expansion Before Engraftment May Be Important
Induction of Donor-Specific Tolerance Using Superagonistic CD28 Antibody in Rat Renal Allografts: Regulatory T-Cell Expansion Before Engraftment May Be Important
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DOI：
10.1097/tp.0b013e3182007b59
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发表时间：
2010-12-27
期刊：
影响因子：
6.2
通讯作者：
Takahara, Shiro
中科院分区：
文献类型：
--
作者：
Azuma, Haruhito;Isaka, Yoshitaka;Takahara, Shiro
背景。我们假设，针对 CD28 (CD28SA) 特异的超激动单克隆抗体可在体内扩增调节性 T 细胞 (Treg)，从而防止急性排斥反应并延长肾同种异体移植物的存活时间。方法。我们使用我们建立的大鼠肾同种异体移植模型（Wistar-Lewis）检查了 CD28SA 治疗是否诱导供体特异性耐受。结果。所有对照大鼠均在 13 天内死亡，原因是严重的氮质血症和移植组织的明显破坏。相比之下，接受三次注射 CD28SA（第 3 天、第 0 天和第 3 天）治疗的受者表现出良好的移植物组织学和功能保存，Treg 细胞大量浸润到同种异体移植物中； 92% 的接受者存活超过 100 天，77% 的接受者在 180 天收获当天存活。这些存活时间较长的受者在肾移植后 120 天同时接受来自供体匹配的 Wistar 和第三方 Brown挪威大鼠的二次异位双心同种异体移植物，八只大鼠中的七只（87.5%）表现出供体特异性耐受性，接受 Wistar 心脏，但强烈排斥 Brown挪威心脏。有趣的是，移植前 3 天（第 3 天）而不是移植后 3 天（第 3 天）单次注射 CD28SA 也会在一些受者中诱导供体特异性耐受。然后，我们对从 CD28SA 处理的 Lewis 大鼠中纯化的非特异性 CD4(+) CD25(+) Tregs 进行过继转移，同时注射肝细胞生长因子（500 μg/kg/天，静脉注射）。治疗诱导移植物存活时间显着延长（与对照组相比，P < 0.0001），八名受者中的五名 (62.5%) 存活到 180 天的收获日，并成功诱导供体特异性耐受。结论。我们已经建立了一种新的治疗方法，用于诱导同种异体肾移植大鼠的供体特异性耐受。
Background. We hypothesized that a superagonistic monoclonal antibody specific for CD28 (CD28SA), which expands regulatory T cells (Tregs) in vivo, would prevent acute rejection and prolong the survival of renal allograft.Methods. We examined whether CD28SA treatment induce donor-specific tolerance using our established rat renal allograft model (Wistar-Lewis).Results. All control rats died within 13 days because of severe azotemia with marked destruction of graft tissue. In contrast, recipients treated with a triple injection of CD28SA (days - 3, 0, and 3) showed good preservation of graft histology and function, with considerable infiltration of Tregs into the allografts; 92% of recipients survived for more than 100 days, and 77% survived by the day of harvest at 180 days. These long-surviving recipients received secondary heterotopic bicardiac allografts from both donor-matched Wistar and third-party Brown Norway rats simultaneously 120 days after kidney transplantation, and seven of eight (87.5%) rats exhibited donor-specific tolerance, accepting the Wistar heart, but acutely rejecting the Brown Norway heart. Interestingly, a single injection of CD28SA 3 days before (day - 3), but not 3 days after (day 3), transplantation also induced donor-specific tolerance in some recipients. We then performed adoptive transfer of nonspecific CD4(+) CD25(+) Tregs, purified from CD28SA-treated Lewis rats, with simultaneous injection of hepatocyte growth factor (500 mu g/kg/day, intravenously). The treatment induced significant prolongation of graft survival (P < 0.0001 vs. control group), and five of eight (62.5%) recipients survived until the day of harvest at 180 days with successful induction of donor-specific tolerance.Conclusions. We have established a novel therapeutic approach for inducing donor-specific tolerance in rats with renal allografts.