Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans
Treatment with depleting CD4 monoclonal antibody results in a preferential loss of circulating naive T cells but does not affect IFN-gamma secreting TH1 cells in humans
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DOI：
10.1172/jci119396
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发表时间：
1997-05-01
影响因子：
15.9
通讯作者：
vanLier, RAW
中科院分区：
文献类型：
--
作者：
Rep, MHG;vanOosten, BW;vanLier, RAW
CD 4（pos）TH 1 T细胞被认为在许多人类自身免疫性疾病如类风湿性关节炎（RA）和多发性硬化症中起核心作用。迄今为止，旨在选择性消除CD 4（pos）T细胞的实验性治疗方案产生了令人失望的临床结果。我们在一项随机、双盲、安慰剂对照、磁共振成像监测的II期试验中分析了嵌合CD 4 mAb cM-T412治疗多发性硬化患者循环T细胞的表型和功能。治疗导致CD 4（pos）T细胞的长期耗竭，但不影响CD 8（pos）T细胞数量。CD 4（pos）亚群分析显示，未致敏的CD 45 RA（pos）/ROpos淋巴细胞对mAb的敏感性约为致敏的CD 45 RA（neg）/ROpos T细胞的3倍。值得注意的是，在CD 45 RA（pos）亚群中，具有先前活化的表型证据的T细胞，即，与Fas（neg）细胞相比，表达Fas的细胞对cM-T412相对不敏感。值得注意的是，虽然在抗-CD 4处理组中观察到产生IL-4的辅助性T细胞2（TH 2）-型细胞的数量减少，但产生IFN-γ的辅助性T细胞1（TH 1）-型细胞的数量保持稳定，导致TH 1/TH 2比率显著增加。我们的数据表明，用消耗性CD 4 mAb治疗不能消除与疾病过程最密切相关的细胞，即，致敏的、产生IFN-γ的TH 1型细胞，因此可以解释在人类慢性自身免疫性疾病中缺乏消耗CD 4 mAb的有益临床效果。
CD4(pos) TH1 T cells are considered to play a central role in a number of human autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis. Experimental treatment protocols aimed at selectively eliminating CD4(pos) T cells thus far have yielded disappointing clinical results. Here we analyzed phenotype and function of circulating T cells in multiple sclerosis patients treated with the chimeric CD4 mAb cM-T412 in a randomized, double-blind, placebo-controlled, magnetic resonance imaging-monitored phase II trial. Treatment resulted in a long-lasting depletion of CD4(pos) T cells but did not affect CD8(pos) T cell numbers. Analysis of CD4(pos) subpopulations showed that unprimed, CD45RA(pos)/ROneg lymphocytes were approximately three times more sensitive to the mAb than primed, CD45RA(neg)/ROpos T cells. Notably, within the CD45RA(pos) subset, T cells with phenotypic evidence of prior activation, i.e., expressing Fas, were relatively insensitive to cM-T412, compared with Fas(neg) cells. Remarkably, while a decrease in the number of IL-4-producing T helper 2 (TH2)-type cells in the anti-CD4 treated group was observed, numbers of IFN-gamma-producing T helper 1 (TH1)-type cells remained stable, resulting in a significant increase in the TH1/TH2 ratio. Our data show that treatment with depleting CD4 mAb does not eliminate the cells most strongly involved in the disease process, i.e., primed, IFN-gamma-producing TH1-type cells, and may therefore give an explanation for the lack of beneficial clinical effects of depleting CD4 mAb in human chronic autoimmune disease.