Favorable effects of alemtuzumab on allospecific regulatory T-cell generation
Favorable effects of alemtuzumab on allospecific regulatory T-cell generation
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DOI：
10.1016/j.humimm.2011.11.008
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发表时间：
2012-02-01
期刊：
影响因子：
2.7
通讯作者：
Mathew, James M.
中科院分区：
文献类型：
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作者：
Levitsky, Josh;Leventhal, Joseph R.;Mathew, James M.
我们研究了Alemtuzumab在同种异体活化过程中对T调节细胞（TCRs）的影响，首先通过健康志愿者外周血中各种初始细胞亚群与同种异体活化细胞亚群的耗竭差异，然后通过在混合淋巴细胞反应（MLR）中向人类白细胞抗原（HLA）-DR匹配和不匹配的应答和刺激细胞中添加系列浓度。用流式细胞术检测细胞增殖抑制和增殖的羧基荧光素琥珀酰亚胺酯（CFSE）稀释的CD 4（+）CD 25（高）CD 127（-）FOXP 3（+）（表型）T细胞的形成。此外，还检测了Alemtuzumab处理与未处理MLR产生的CD 4（+）CD 127（-）细胞同种特异性抑制MLR和募集额外应答TlR的能力。我们发现同种活化的CD 4（+）CD 25（高）细胞与初始CD 4（+）CD 25（高）细胞相比，对Alemtuzumab诱导的淋巴细胞耗竭的不应性更明显。Alemtuzumab剂量依赖性地抑制淋巴细胞增殖，同时增加MLR产生的Tcl 3的百分比。这在一定程度上通过人类补体添加而增强。7天后，从Alemtuzumab处理的MLR中免疫选择的CD 127（-）CD 4（+）细胞同种特异性抑制淋巴细胞增殖，并在新鲜MLR应答细胞中招募额外的Tcl 3，与未添加药物的MLR（培养基）衍生的调节剂相似。在Alemtuzumab中添加他克莫司和西罗莫司进一步抑制MLR增殖。然而，西罗莫司组Treg百分比显著更高。这些结果支持以下观点，即Alemtuzumab在经历同种活化（不存在预致敏）的初始T细胞中诱导免疫调节，尤其是与维持SRL联合使用。(C)2012年美国组织相容性和免疫遗传学学会。爱思唯尔公司出版All rights reserved.
We studied the effects of alemtuzumab on T-regulatory cells (Tregs) during alloactivation, first by differences in depletion of various naive versus alloactivated cell subsets in peripheral blood of healthy volunteers, then by adding serial concentrations to human leukocyte antigen (HLA)-DR-matched and -mismatched responding and stimulating cells in mixed lymphocyte reaction (MLR). Lymphoproliferation inhibition and the development of proliferating carboxyfluorescein succinimidyl ester (CFSE)- diluted CD4(+)CD25(high)CD127(-)FOXP3(+) (phenotypic) Tregs by flow cytometry were measured. Also, the ability of alemtuzumab-treated versus nontreated MLR generated CD4(+)CD127(-) cells to allospecifically inhibit MLRs and recruit additional responding Tregs was tested. We found a more pronounced refractoriness of alloactivated versus naive CD4(+)CD25(high) cells to alemtuzumab induced lymphodepletion. Alemtuzumab dose dependently inhibited lymphoproliferation while amplifying percentages of MLR-generated Tregs. This was somewhat augmented by human complement addition. CD127(-)CD4(+) cells immunoselected after 7 days from alemtuzumab-treated MLRs allospecifically inhibited lymphoproliferation and recruited additional Tregs in fresh MLR-responding cells, similar to modulators derived from MLRs without drug addition (media). Addition of tacrolimus and sirolimus to alemtuzumab further inhibited MLR proliferation. However, Treg percentages were markedly higher with sirolimus. These results support the notion that alemtuzumab induces immunoregulation in naive T cells undergoing alloactivation absent presensitization, especially used in conjunction with maintenance SRL. (C) 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.