Achieving donor-specific hyporesponsiveness is associated with FOXP3+ regulatory T cell recruitment in human renal allograft infiltrates
Achieving donor-specific hyporesponsiveness is associated with FOXP3+ regulatory T cell recruitment in human renal allograft infiltrates
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DOI：
10.4049/jimmunol.179.7.4901
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发表时间：
2007-10-01
影响因子：
4.4
通讯作者：
Grinyo, Josep M.
中科院分区：
文献类型：
--
作者：
Bestard, Oriol;Cruzado, Josep M.;Grinyo, Josep M.
探索新的免疫抑制策略诱导供体特异性低反应是移植中的重要挑战。为此，必须进行仔细的免疫监测和移植物组织学评估。在这里，我们报告了一项在20名肾移植受者中进行的初步研究的结果，分析了基于兔抗胸腺细胞球蛋白低剂量、西罗莫司和吗替麦考酚酯诱导治疗的方案的免疫调节作用。评价了供者特异性细胞和不道德同种免疫反应、外周血淋巴细胞亚群和细胞凋亡的演变。进行6个月的方案活检以评估组织学病变和间质浸润中FOXP3（+）调节性T细胞（T细胞）的存在。移植后，有早期和短暂的凋亡效应，主要是在CD8（+）HLADR（+）T细胞内，并伴有外周血中CD4（+）CD25（+high）淋巴细胞的持续增强。急性排斥反应发生率为35%，均为激素敏感型。重要的是，只有移植前供者特异性细胞同种异体反应性可以区分有发生急性排斥反应风险的患者。三分之二的患者在6个月和24个月时成为供体特异性低反应者，并且这种免疫状态的实现并没有被先前的急性排斥事件所废除。值得注意的是，供者特异性低反应者的肾功能更好，慢性肾损害更少。供体特异性低反应性通过耗尽CD4（+）CD25（+high）T细胞而被抑制，这显示出供体抗原特异性。外周血和肾浸润组织中FOXP3（+）CD4（+）CD25（+high）T细胞亚群在供者特异性低应答者中均高于非低应答者，表明同种异体移植物中T细胞亚群的募集在肾接受中起重要作用。总之，在肾移植后达到供体特异性低反应是可行的，并且与移植物中Treg募集相关。
Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and Immoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3(+) regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8(+)HLADR(+) T cells, combined with a sustained enhancement of CD4(+)CD25(+high) lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4(+)CD25(+high) T cells, which showed donor-Ag specificity. FOXP3(+)CD4(+)CD25(+high) Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporespionsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.