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J immunol:共刺激信号调节Treg活性有助于抑制免疫排斥反应

  1. Treg
  2. 免疫排斥
  3. 共刺激信号

来源:生物谷 2016-06-15 20:31

共刺激信号(co-stimulation)对于T细胞的激活具有重要的作用,阻断这一信号会导致一些与T细胞有关的疾病的发生。对于共刺激信号通路研究的比较清楚的包括CD28以及CD40。CTLA-4Ig是一个融合了CTLA-4胞外段以及抗体的

2016615日 讯 /生物谷BIOON/ -- 最近,来自比利时鲁文盖斯堡大学的Jan L. Ceuppens课题组研究了Treg细胞在共刺激因子信号通路阻断的情况下如何减缓免疫排斥效应的分子机制,发现结合MR1以及低浓度的CTLA-4Ig能够起到最佳的免疫抑制效果,相关结果发表在最近一期的《Journal of Immunology》杂志上。

共刺激信号(co-stimulation)对于T细胞的激活具有重要的作用,阻断这一信号会导致一些与T细胞有关的疾病的发生。对于共刺激信号通路研究的比较清楚的包括CD28以及CD40CTLA-4Ig是一个融合了CTLA-4胞外段以及抗体的Fc片段的融合蛋白,它能够特异性地与CD80/CD86结合,从而抑制其与CD28的相互作用。目前该蛋白已经获得了美国FDA的批准,用以治疗系统性红斑狼疮。第二代的这类融合蛋白被用于抑制器官移植术后的免疫排斥反应。在小鼠模型试验中,anti-B7单抗或CTLA-4Ig均能够有效降低免疫排斥引发的致死效应。然而,直到目前为止,阻断CD28CD40通路能够减缓免疫排斥的内在分子机制还不太清楚。一般认为,在没有共刺激因子的影响下,T细胞在激活会后会处于过度激活状态,进而引发细胞凋亡反应。这一过程中可能有Treg的参与。此前研究发现:CTLA-4Ig的刺激能够引发Treg数量的上升,而且在CD28CD40信号被阻断的前提下Treg细胞的活性并不会受到抑制。但这一现象是否在体内具有生理学意义仍不得而知。

首先,作者分别比较了CD40抗体MR1CTLA4-IgCD4以及CD8 T细胞异体移植的影响。结果显示,MR1能够有效地抑制CD4细胞移植引起的免疫排斥反应,而CTLA-4Ig则能够有效抑制CD8 T细胞抑制引发的免疫排斥。进一步,作者发现MR1能够特异性地降低与宿主有反应的供体CD4 T细胞的增殖。

之后,作者发现MR1的刺激能够有效促进供体来源的Treg细胞的增殖,而CTLA-4Ig则对Treg的增殖存在剂量依赖性:低浓度的CTLA-4Ig能够促进Treg数量的增加,而浓度一旦上升,则会反向地降低Treg的数量。体内试验也验证了上述结果。

综上,作者认为结合MR1以及低浓度的CTLA-4Ig能够起到最佳的免疫抑制效果。(生物谷Bioon.com

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doi: 10.4049/jimmunol.1600286

PMC:

PMID:

Regulatory T Cell–Dependent and –Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade

Isabel Vogel, Bert Verbinnen, Stefaan Van Gool, and Jan L. Ceuppens

Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4+ T cells, or CD8+ T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4+ T cells, but not of CD8+ T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8+ T cells but had only a weak effect on CD4+ T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4+ and CD8+ T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation.

 

 

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