來自上海交通大學(xué)醫(yī)學(xué)院,，中科院上海生科院健康科學(xué)研究所的研究人員利用同種異基因小鼠骨髓移植模型研究,，發(fā)現(xiàn)了移植物抗宿主病治療新策略，這一研究成果公布在國(guó)際重要學(xué)術(shù)期刊Blood上,。
領(lǐng)導(dǎo)這一研究的是張雁云教授，其早年畢業(yè)于蘇州醫(yī)學(xué)院,，曾在日本東京大學(xué)醫(yī)學(xué)部進(jìn)修學(xué)習(xí),，目前任中國(guó)科學(xué)院上海生命科學(xué)研究院/上海交通大學(xué)醫(yī)學(xué)院健康科學(xué)研究所研究員，研究組長(zhǎng),。
移植物抗宿主?。╣raft-versus-host disease, GVHD）是骨髓/造血干細(xì)胞移植后發(fā)生的最主要的排斥反應(yīng)，是由于移植物中成熟的淋巴細(xì)胞被受者抗原遞呈細(xì)胞活化后攻擊受者組織,，產(chǎn)生的全身性組織損傷,。GVHD的高發(fā)病率和高致死率嚴(yán)重制約了造血干細(xì)胞移植的臨床應(yīng)用。移植前對(duì)受者的預(yù)處理所造成的受者體內(nèi)炎癥性環(huán)境被認(rèn)為是GVHD發(fā)生的重要條件,，而其中的機(jī)制尚不明確,。
研究人員利用同種異基因小鼠骨髓移植模型研究發(fā)現(xiàn)，移植后受鼠體內(nèi)細(xì)胞因子osteopontin（OPN）出現(xiàn)持續(xù)性的上調(diào)表達(dá),，以研制的中和性抗體體內(nèi)阻斷OPN能夠顯著抑制移植后GVHD的發(fā)生和發(fā)展,。進(jìn)一步研究發(fā)現(xiàn)，阻斷OPN后能夠抑制異體反應(yīng)性T細(xì)胞的活化,、遷移以及生存,，從而減少致病細(xì)胞在靶組織中的駐留。更為重要的是,，體內(nèi)阻斷OPN并不影響異體反應(yīng)性T細(xì)胞介導(dǎo)的移植物抗白血病效應(yīng),，這將有助于降低造血干細(xì)胞移植后的白血病復(fù)發(fā)幾率。這一研究首次闡述了OPN與GVHD發(fā)生發(fā)展之間的相關(guān)機(jī)制,，發(fā)現(xiàn)了GVHD治療的重要靶點(diǎn),，為臨床GVHD的防治提供了新的手段。
張雁云教授研究組曾獲得多項(xiàng)重要成果,，今年3月曾發(fā)文發(fā)現(xiàn)了脂代謝調(diào)節(jié)影響神經(jīng)再生修復(fù)和神經(jīng)機(jī)體免疫功能,，首次揭示了CNS小膠質(zhì)細(xì)胞的非經(jīng)典激活形式及抗炎癥效應(yīng)及其相關(guān)分子機(jī)制。
脂代謝調(diào)節(jié)的紊亂會(huì)導(dǎo)致多種疾病的發(fā)生,，但是其對(duì)神經(jīng)再生修復(fù)和神經(jīng)免疫功能的影響目前還尚不清楚,。內(nèi)固醇受體輔激活因子(SRC-3)是機(jī)體脂代謝調(diào)節(jié)中重要轉(zhuǎn)錄因子，研究人員發(fā)現(xiàn),，SRC3基因敲除小鼠較野生型小鼠瘦小,，且其脂代謝水平較高,。
研究人員利用SRC-3基因敲除小鼠構(gòu)建實(shí)驗(yàn)性自身免疫性腦脊髓炎(EAE)模型，發(fā)現(xiàn)基因敲除小鼠表現(xiàn)出對(duì)EAE誘導(dǎo)的耐受,。其原因是SRC3基因敲除促進(jìn)了炎癥條件下中樞神經(jīng)系統(tǒng)(CNS)中小膠質(zhì)細(xì)胞處于一種非經(jīng)典的激活狀態(tài),，這些非經(jīng)典激活的小膠質(zhì)細(xì)胞通過上調(diào)抗炎癥細(xì)胞因子IL-10的表達(dá)來對(duì)抗EAE誘導(dǎo)引起的CNS炎癥，并促進(jìn)了CNS少突膠質(zhì)細(xì)胞誘導(dǎo)的髓鞘再生,。
進(jìn)一步分析相關(guān)的機(jī)制,，發(fā)現(xiàn)這種非經(jīng)典激活的小膠質(zhì)細(xì)胞是由于SRC3基因敲除誘導(dǎo)了炎癥條件下CNS中PPAR-β的升高引起的，也調(diào)節(jié)了神經(jīng)干細(xì)胞的活化,、增殖和分化,。在此研究中，首次揭示了CNS小膠質(zhì)細(xì)胞的非經(jīng)典激活形式及抗炎癥效應(yīng)及其相關(guān)分子機(jī)制,，也發(fā)現(xiàn)了調(diào)節(jié)影響神經(jīng)干細(xì)胞活化,、增殖分化及再生修復(fù)病理?yè)p傷的重要代謝分子信號(hào)途徑，為神經(jīng)干細(xì)胞再生修復(fù)損傷提供了新的思路,。（生物谷Bioon.com）
生物谷推薦原文出處：
Blood DOI 10.1182/blood-2010-04-281659
Blockade of osteopontin reduces alloreactive CD8+ T cell-mediated graft-versus-host disease
Fang Zhao1, Yi Zhang1, Hao Wang2, Min Jin1, Shan He1, Yufang Shi3, Yajun Guo2 and Yanyun Zhang1,*
1 Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Science, Chinese Academy of Sciences and SJTUSM, Shanghai, China; 2 International Joint Cancer Institute, Second Military Medical University, Shanghai, China; 3 Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, United States
Abstract
Graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is caused by alloreactive donor T cells that trigger host tissue damage. The inflammatory environment inside recipients is critical for GVHD pathogenesis, but the underpinning mechanisms remain elusive. Using mouse model of human GVHD, we demonstrate osteopontin (OPN), a potent proinflammatory cytokine, plays important role in regulating activation, migration and survival of alloreactive T cells during GVHD. OPN was significantly elevated after irradiation and persisted throughout the course of GVHD. Blockade of OPN attenuated GVHD with reduced accumulation of donor T cells in recipient organs. Amelioration was the result of migration and survival suppression caused by anti-OPN treatment on donor-derived T cells for two reasons. First, OPN promoted the migration and infiltration of na?ve and alloreactive CD8+ T cells into host organs. Second, it also facilitated activation and viability of donor-derived CD8+ T cells via synergizing with T cell receptor/CD3 signaling. Finally, anti-OPN treatment retained graft-versus-leukemia effect of alloreactive CD8+ T cells. This study demonstrates, to our knowledge for the first time, the critical effect of OPN in the initiation and persistence of CD8+ T cell-mediated GVHD, and validates OPN as a potential target in GVHD prevention.
