Bestard Oriol, Cruzado Josep M, Mestre Mariona, Caldés Anna, Bas Jordi, Carrera Marta, Torras Joan, Rama Inés, Moreso Francesc, Serón Daniel, Grinyó Josep M
Department of Nephrology, Hospital de Bellvitge, Barcelona, Spain.
J Immunol. 2007 Oct 1;179(7):4901-9. doi: 10.4049/jimmunol.179.7.4901.
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 humoral 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 hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.
探索诱导供体特异性低反应性的新型免疫抑制策略是移植领域的一项重要挑战。为此，必须进行仔细的免疫监测和移植物组织学评估。在此，我们报告了一项针对20名肾移植受者开展的初步研究结果，分析了基于低剂量兔抗胸腺细胞球蛋白诱导治疗、西罗莫司和霉酚酸酯的方案的免疫调节作用。评估了供体特异性细胞和体液同种免疫反应、外周血淋巴细胞亚群及细胞凋亡的演变情况。进行了为期6个月的方案活检，以评估组织学病变以及间质浸润中FOXP3 +调节性T细胞（Tregs）的存在情况。移植后，出现了早期短暂的凋亡效应，主要发生在CD8 + HLA - DR + T细胞内，同时外周血中CD4 + CD25（+高）淋巴细胞持续增加。急性排斥反应的发生率为35%，均对类固醇敏感。重要的是，只有移植前供体特异性细胞同种异体反应性能够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，且这种免疫状态的达成并未因先前的急性排斥反应而被消除。值得注意的是，供体特异性低反应者的肾功能更好，慢性肾损伤更少。耗竭显示供体抗原特异性的CD4 + CD25（+高）T细胞可抑制供体特异性低反应性。供体特异性低反应者外周血和肾浸润中的FOXP3 + CD4 + CD25（+高）Tregs均高于非低反应者，这表明同种异体移植物中Tregs的募集对肾脏接受起着重要作用。总之，肾移植后达到供体特异性低反应性是可行的，且与移植物中Tregs的募集有关。
