Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts
Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts
复制标题
DOI：
10.1111/j.1600-6143.2008.02358.x
复制
发表时间：
2008-10-01
影响因子：
8.8
通讯作者：
Takahara, S.
中科院分区：
文献类型：
--
作者：
Azuma, H.;Isaka, Y.;Takahara, S.
器官移植的最终目标是建立移植耐受，其中CD4+CD25+FOXP3+调节性T细胞(Treg)发挥重要作用。我们利用我们建立的大鼠急性肾移植模型(Wistar To Lewis)，研究了一种针对CD28(CD28 SA)的超激动型单抗(CD28 SA)，它可以在体内扩大Treg细胞，是否可以防止急性排斥反应和诱导耐受。在未经治疗或接受小鼠免疫球蛋白治疗的受体中，移植肾功能显著恶化，肾组织明显破坏，所有大鼠在13天后死亡，并伴有严重的氮质血症。相比之下，接受CD28 SA治疗的受者中，90%的人存活超过100天，70%的人存活下来，移植物功能保存良好，直到180天移植物恢复。流式细胞仪和免疫组织化学分析表明，CD28 SA可诱导FOXP3+Treg细胞向移植物中明显渗透。此外，这些长期存活的受体表现出供者特异性的耐受性，接受二次(供者匹配的)Wistar心脏移植，但强烈排斥第三方BN同种异体移植。我们进一步证明，过继转移CD28 SA处理的Lewis大鼠的CD4+CD25+Treg细胞可以显著延长同种异体移植物的存活时间，并成功地诱导供者特异性耐受。总之，CD28 SA治疗在Treg细胞的参与下成功地诱导了供者特异性耐受，因此该方法的治疗价值值得进一步研究和临床前研究。
The ultimate goal of organ transplantation is to establish graft tolerance where CD4+CD25+FOXP3+ regulatory T (Treg) cells play an important role. We examined whether a superagonistic monoclonal antibody specific for CD28 (CD28 SA), which expands Treg cells in vivo, would prevent acute rejection and induce tolerance using our established rat acute renal allograft model (Wistar to Lewis). In the untreated or mouse IgG-treated recipients, graft function significantly deteriorated with marked destruction of renal tissue, and all rats died by 13 days with severe azotemia. In contrast, 90% of recipients treated with CD28 SA survived over 100 days, and 70% survived with well-preserved graft function until graft recovery at 180 days. Analysis by flow cytometry and immunohistochemistry demonstrated that CD28 SA induced marked infiltration of FOXP3+ Treg cells into the allografts. Furthermore, these long-surviving recipients showed donor-specific tolerance, accepting secondary (donor-matched) Wistar cardiac allografts, but acutely rejecting third-party BN allografts. We further demonstrated that adoptive transfer of CD4+CD25+ Treg cells, purified from CD28 SA-treated Lewis rats, significantly prolonged allograft survival and succeeded in inducing donor-specific tolerance. In conclusion, CD28 SA treatment successfully induces donor-specific tolerance with the involvement of Treg cells, and thus the therapeutic value of this approach warrants further investigation and preclinical studies.