來自美國國家衛(wèi)生研究院的研究人員發(fā)現(xiàn)一種獨(dú)特類型的免疫細(xì)胞促進(jìn)多發(fā)性硬化癥(multiple sclerosis, MS)產(chǎn)生。他們的發(fā)現(xiàn)有助于確定研究作為最新藥物之一的達(dá)利珠單抗(daclizumab)的療效,，而且還可能導(dǎo)致人們開發(fā)出一類新藥來治療多發(fā)性硬化癥和其他自身免疫疾病,。在這些疾病中，免疫系統(tǒng)攻擊身體自己的組織,。正在進(jìn)行的臨床試驗(yàn)已證實(shí)達(dá)利珠單抗似乎有助于壓制多發(fā)性硬化癥病人的自身免疫反應(yīng),，但是它對組成免疫系統(tǒng)的大批量免疫細(xì)胞的精確影響仍然尚未充分理解。
根據(jù)這項(xiàng)于2012年8月1日在線發(fā)表在Science Translational Medicine期刊上的新研究,，研究人員發(fā)現(xiàn)達(dá)利珠單抗的一種影響就是降低淋巴組織誘導(dǎo)細(xì)胞(lymphoid tissue inducer cell, LTi)的數(shù)量,。已知在胎兒期間，這些細(xì)胞促進(jìn)淋巴結(jié)和相關(guān)組織的發(fā)育,，但是它們在成年時(shí)的作用仍然是個(gè)謎,。這項(xiàng)新研究是第一次證實(shí)LTi細(xì)胞參與任何一種人自身免疫疾病的產(chǎn)生。
論文通信作者Bibiana Bielekova博士和她的研究團(tuán)隊(duì)發(fā)現(xiàn)在參與臨床試驗(yàn)的多發(fā)性硬化癥病人當(dāng)中,，沒有接受達(dá)利珠單抗治療的病人體內(nèi)LTi細(xì)胞的數(shù)量比服用這種藥物的病人體內(nèi)的要高,。對接受達(dá)利珠單抗治療的病人而言，他們腦脊髓液中的炎癥癥狀減輕,。此外,，研究人員發(fā)現(xiàn)達(dá)利珠單抗似乎阻止身體產(chǎn)生LTi細(xì)胞，并促進(jìn)另一種對抗自身免疫反應(yīng)的細(xì)胞類型產(chǎn)生,。
在這項(xiàng)新研究中,，Bielekova博士和她的研究團(tuán)隊(duì)發(fā)現(xiàn)達(dá)利珠單抗對自然殺傷細(xì)胞的促進(jìn)效應(yīng)是與它對LTi細(xì)胞的抑制效應(yīng)同時(shí)存在的。他們發(fā)現(xiàn)這種藥物通過它對IL-2信號的影響,，作用于一類干細(xì)胞,。該藥物似乎降低這種干細(xì)胞產(chǎn)生LTi細(xì)胞而讓它變成自然殺傷細(xì)胞的可能性。
研究人員解釋道,，達(dá)利珠單抗通過抑制LTi細(xì)胞,，應(yīng)當(dāng)能夠降低淋巴濾泡的生長。因?yàn)榭茖W(xué)家們不可能在活的大腦組織中可視化觀察這些淋巴濾泡,，所以研究人員測量這種藥物對腦脊髓液中炎癥標(biāo)記物的影響,。他們發(fā)現(xiàn)在服用這種藥物6.5個(gè)月的臨床試驗(yàn)病人體內(nèi)，一種與淋巴生長相關(guān)聯(lián)的蛋白CXCL13和一種用來測量抗體產(chǎn)生的指標(biāo)IgG指數(shù)(IgG index)分別平均下降了50.4%和13.5%,。
不過Bielekova提醒道,，這些數(shù)據(jù)只是表明LTi細(xì)胞與多發(fā)性硬化癥病人大腦中的炎癥之間存在間接聯(lián)系。如果進(jìn)一步研究證實(shí)這些細(xì)胞在多發(fā)性硬化癥和其他自身免疫疾病中發(fā)揮著重要作用,，那么尋求開發(fā)新的藥物來選擇性地抑制LTi細(xì)胞可能是一種非常有用的治療策略,。(生物谷：Bioon.com)
本文編譯自Researchers implicate unique cell type in multiple sclerosis
doi: 10.1126/scitranslmed.3004140
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Inhibition of LTi cell development by CD25 blockade is associated with decreased intrathecal inflammation in multiple sclerosis
Justin S. A. Perry1,*, Sungpil Han1,2,*, Quangang Xu1,3, Matthew L. Herman1, Lucy B. Kennedy1, Gyorgy Csako4 and Bibiana Bielekova
Genetic polymorphisms in the interleukin-2 receptor α (IL-2Rα) chain (CD25) locus are associated with several human autoimmune diseases, including multiple sclerosis (MS). Blockade of CD25 by the humanized monoclonal antibody daclizumab decreases MS-associated inflammation but has surprisingly limited direct inhibitory effects on activated T cells. The present study describes unexpected effects of daclizumab therapy on innate lymphoid cells (ILCs). The number of circulating retinoic acid receptor–related orphan receptor γt–positive ILCs, which include lymphoid tissue inducer (LTi) cells, was found to be elevated in untreated MS patients compared to healthy subjects. Daclizumab therapy not only decreased numbers of ILCs but also modified their phenotype away from LTi cells and toward a natural killer (NK) cell lineage. Mechanistic studies indicated that daclizumab inhibited differentiation of LTi cells from CD34+ hematopoietic progenitor cells or c-kit+ ILCs indirectly, steering their differentiation toward immunoregulatory CD56bright NK cells through enhanced intermediate-affinity IL-2 signaling. Because adult LTi cells may retain lymphoid tissue–inducing capacity or stimulate adaptive immune responses, we indirectly measured intrathecal inflammation in daclizumab-treated MS patients by quantifying the cerebrospinal fluid chemokine (C-X-C motif) ligand 13 and immunoglobulin G index. Both of these inflammatory biomarkers were inhibited by daclizumab treatment. Our study indicates that ILCs are involved in the regulation of adaptive immune responses, and their role in human autoimmunity should be investigated further, including their potential as therapeutic targets.
