2012年8月20日 訊 /生物谷BIOON/ --對多發(fā)性硬化癥而言,，免疫系統(tǒng)攻擊大腦和脊髓中的神經(jīng)，從而導(dǎo)致運(yùn)動問題,，肌肉無力和視力喪失,。科學(xué)家們之前曾認(rèn)為被稱作樹突細(xì)胞的免疫細(xì)胞促進(jìn)多發(fā)性硬化癥的發(fā)生和發(fā)展,，然而根據(jù)一篇刊登在Immunity期刊上的論文,，在模式小鼠中，這些細(xì)胞實(shí)際上抵抗這種疾病的產(chǎn)生,。這些新發(fā)現(xiàn)有助于改變我們對多發(fā)性硬化癥起源的基本理解,，而且可能導(dǎo)致我們開發(fā)出更加有效的療法來治療這種疾病。
論文通信作者,、德國美因茨市約翰內(nèi)斯古騰堡大學(xué)醫(yī)學(xué)中心研究員Ari Waisman說,，“通過將樹突細(xì)胞注入到血液中，它可能能夠降低自身免疫反應(yīng),。除了多發(fā)性硬化癥之外,，我能夠輕松地想象到這種方法可能適用于其他自身免疫疾病,，比如炎癥性腸病和銀屑病。”
在被稱作實(shí)驗(yàn)性自身免疫性腦脊髓炎(experimental autoimmune encephalomyelitis, EAE)的多發(fā)性硬化癥模式動物中,，當(dāng)T細(xì)胞被抗原呈遞細(xì)胞(antigen-presenting cells, APCs)激活之后,，它們就觸發(fā)這種疾病產(chǎn)生。樹突細(xì)胞是能夠激活T細(xì)胞的APCs,，但是科學(xué)家們并不知道樹突細(xì)胞是否是誘導(dǎo)EAE產(chǎn)生的APCs,。
在這項(xiàng)新研究中，Waisman和他的研究小組利用遺傳方法剔除小鼠體內(nèi)的樹突細(xì)胞,。出乎人意料之外的是,，這些小鼠仍然對EAE敏感，并且患上更糟糕的自身免疫反應(yīng)和較低的疾病臨床評分,，這就提示著樹突細(xì)胞并不是誘導(dǎo)EAE產(chǎn)生所必需的，而且還提示著其他的APCs激活T細(xì)胞從而觸發(fā)這種疾病的產(chǎn)生,。研究人員也發(fā)現(xiàn)樹突細(xì)胞通過增加T細(xì)胞表面上PD-1受體的表達(dá)而降低T細(xì)胞的反應(yīng)性和降低對EAE的敏感性,。
論文第一作者Nir Yogev說，“剔除樹突細(xì)胞改變T細(xì)胞調(diào)節(jié)的自身免疫反應(yīng)的局面,。我們的發(fā)現(xiàn)提示著樹突細(xì)胞抑制免疫反應(yīng),，因而將樹突細(xì)胞轉(zhuǎn)移到多發(fā)性硬化癥病人體內(nèi)可能能夠治療T細(xì)胞缺陷并且作為一有效的干預(yù)療法來治療這種疾病。”(生物谷Bioon.com)
本文編譯自Discovery of immune cells that protect against multiple sclerosis offers hope for new treatment
doi: 10.1016/j.immuni.2012.05.025
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Dendritic Cells Ameliorate Autoimmunity in the CNS by Controlling the Homeostasis of PD-1 Receptor+ Regulatory T Cells
Nir Yogev, Friederike Frommer, Dominika Lukas, Kordula Kautz-Neu, Khalad Karram, Daniele Ielo, Esther von Stebut, Hans-Christian Probst, Maries van den Broek, Dieter Riethmacher, Tal Birnberg, Thomas Blank, Boris Reizis, Thomas Korn, Heinz Wiendl, Steffen Jung, Marco Prinz, Florian C. Kurschus, Ari Waisman
Mature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T cell tolerance. Using various genetic approaches, we depleted CD11c+ DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice. Furthermore, when we engineered DCs to present a CNS-associated autoantigen in an induced manner, we found robust tolerance that prevented disease, which coincided with an upregulation of the PD-1 receptor on antigen-specific T cells. Additionally, we showed that PD-1 was necessary for DC-mediated induction of regulatory T cells. Our results show that a reduction of DCs interferes with tolerance, resulting in a stronger inflammatory response, and that other APC populations could compensate for the loss of immunogenic APC function in DC-depleted mice.
