In vitro induction of regulatory T cells by anti-CD3 antibody in humans
In vitro induction of regulatory T cells by anti-CD3 antibody in humans
复制标题
DOI：
10.1016/j.jaut.2007.11.007
复制
发表时间：
2008-02-01
影响因子：
12.8
通讯作者：
Weiner, Howard L.
中科院分区：
文献类型：
--
作者：
Abraham, Michal;Karni, Arnon;Weiner, Howard L.
抗CD3抗体治疗在控制自身免疫性疾病模型方面是有效的，可以逆转或防止移植物的排斥反应。我们研究了抗CD3抗体处理的人T细胞的体外免疫调节作用。用平板结合的抗CD3抗体刺激CD4(+)T细胞，培养12天后，与自体外周血单个核细胞(PBMC)共同培养，再用可溶性抗CD3抗体刺激。我们发现抗CD3抗体(T-αCD3)刺激的CD4+T细胞对自体PBMC的增殖和细胞因子的产生有明显的抑制作用。这些调节性T细胞不能通过与同型对照(T对照)抗体孵育或抗CD3与高剂量抗CD28(T-αCD3/CD28)联合诱导。TαCD3调节细胞是无能的，与T对照或T-aCD3/CD28相比，产生的干扰素-γ、肿瘤坏死因子-α和IL-2水平较低，而转化生长因子-β水平较高。CD25或CTLA4在T-αCD3上的表达与T-对照或T-αCD3/CD28无差异，而CD4(+)CD2(5)-T-αCD3细胞的体外抑制特性与CD4(+)CD25(+)T-αCD3细胞相同。体外重组IL-2可阻断T-αCD3的抑制作用。T-αCD3对同种异体PBMCs的抑制作用与细胞凋亡无关，与人类白细胞抗原无关，与可溶性因子无关。最后，当非T细胞从培养物中去除或用平板结合的抗CD3抗体刺激培养物时，没有观察到抑制作用，这与T-αCD3在共培养实验中下调树突状细胞CD80的能力一致。因此，我们已经鉴定出在体外由抗CD3诱导的具有很强的体外调节特性的人T细胞，它似乎通过影响抗原提呈细胞而以非人类白细胞抗原限制性的方式发挥作用。(C)2007爱思唯尔有限公司。保留所有权利。
Therapy with anti-CD3 antibody is effective in controlling models of autoimmune diseases and can reverse or prevent rejection of grafts. We studied the in vitro immunomodulatory effect of anti-CD3 treated human T cells. CD4(+) T cells were stimulated with plate-bound anti-CD3 and cultured for 12 days after which they were cultured with autologous peripheral blood mononuclear cells (PBMCs) and stimulated with soluble anti-CD3. We found that CD4+ T cells that were stimulated with anti-CD3 (T-alpha CD3) markedly suppressed the proliferation and cytokine production of autologous PBMCs. These regulatory T cells were not induced by incubation with isotype control (T-control) antibody or when anti-CD3 was combined with high doses of anti-CD28 (T-alpha CD3/CD28). T alpha CD3 regulatory cells were anergic and produced lower levels of IFN-gamma, TNF-alpha and IL-2, and higher levels of TGF-beta than T-control or T-aCD3/CD28. There were no differences in the expression of CD25 or CTLA4 on T-alpha CD3 as compared to T-control or T-alpha CD3/CD28, and CD4(+) CD2(5)- T-alpha CD3 cells were identical to CD4(+) CD25(+) T-alpha CD3 cells in their in vitro suppressive properties. Recombinant IL-2 in vitro abrogated the suppressive effect of T-alpha CD3. The suppressive effect was not related to apoptosis, was independent of HLA since T-alpha CD3 also suppressed allogeneic PBMCs, and was not related to soluble factors. Finally, no suppression was observed when non-T cells were removed from culture or when cultures were stimulated with plate-bound anti-CD3, consistent with the ability of T-alpha CD3 to downregulate CD80 on dendritic cells in co-culture experiments. Thus, we have identified human T cells with strong in vitro regulatory properties induced in vitro by anti-CD3 which appear to act in a non-HLA restricted fashion by affecting antigen presenting cells. (C) 2007 Elsevier Ltd. All rights reserved.