細(xì)胞毒性T細(xì)胞和自然殺傷細(xì)胞互補(bǔ)性作用的示意圖,，圖片來(lái)自維基共享資源。
來(lái)自西班牙Bellvitge生物醫(yī)學(xué)研究所(Bellvitge Biomedical Research Institute)的研究人員首次研究人自然殺傷細(xì)胞(natural killer cell, NK)抗豬軟骨細(xì)胞的反應(yīng),。研究結(jié)果于2012年1月27日發(fā)表在Journal of Immunology期刊上,，表明作為天然免疫系統(tǒng)特征之一的自然殺傷細(xì)胞在排斥豬軟骨細(xì)胞異種移植(xenotransplantation)中發(fā)揮著重要的作用。
自然殺傷細(xì)胞
自然殺傷細(xì)胞連同嗜中性白細(xì)胞和巨噬細(xì)胞,，是細(xì)胞第一道防御體系的一部分,。自然殺傷細(xì)胞參與非獲得性免疫反應(yīng)，即天然免疫反應(yīng),。它們負(fù)責(zé)鑒定特異性的細(xì)胞類型(腫瘤,、感染或者外來(lái)物)并利用細(xì)胞毒性將之摧毀。
這項(xiàng)研究的通訊作者Cristina Costa說(shuō),，自然殺傷細(xì)胞數(shù)量雖少,，但是它們?cè)谝浦差I(lǐng)域中的重要性越來(lái)越大，“我們觀察到天然免疫在調(diào)節(jié)獲得性免疫中發(fā)揮著重要的作用,，而獲得性免疫在身體排斥移植器官中起著比較關(guān)鍵的作用,。”
異種移植
Costa領(lǐng)導(dǎo)的研究小組正在實(shí)現(xiàn)將豬軟骨細(xì)胞移植到人身上以便修復(fù)軟骨損傷。研究小組研究了在豬細(xì)胞存在下人自然殺傷細(xì)胞“在體外”產(chǎn)生的反應(yīng),。他們注意到在移植條件下和在高水平抗體和細(xì)胞因子存在時(shí),，人自然殺傷細(xì)胞產(chǎn)生細(xì)胞毒性反應(yīng)，然后裂解(摧毀)外源細(xì)胞,，在這項(xiàng)研究中,，外源細(xì)胞指的是豬軟骨細(xì)胞。
研究人員解釋道,，“在這項(xiàng)研究中,，我們闡明了幾種分子參與自然殺傷細(xì)胞的附著過(guò)程和細(xì)胞毒性。”他們相信這項(xiàng)研究為科學(xué)家繼續(xù)深入研究指明方向,，“[在進(jìn)行移植時(shí)],，一方面我們不得不阻止抗體儲(chǔ)存,，因?yàn)榭贵w是增加細(xì)胞毒性的一個(gè)關(guān)鍵性因子，另一方面我們必須努力通過(guò)修復(fù)相關(guān)的分子來(lái)降低細(xì)胞附著,。”
就Costa提出的軟骨異種移植的臨床應(yīng)用而言,，下一步實(shí)驗(yàn)將是“對(duì)豬軟骨細(xì)胞進(jìn)行基因修飾”，這樣人自然殺傷細(xì)胞就不能將它們識(shí)別為外來(lái)者,，因而避免產(chǎn)生移植排斥,。
軟骨移植
人之間的軟骨移植在診所并未得到廣泛地應(yīng)用，但是科學(xué)家已經(jīng)成功地讓遭受創(chuàng)傷性損傷的組織再生,。自體移植(autologous transplant)是用來(lái)自同一個(gè)人的細(xì)胞進(jìn)行的,，而異基因移植(allogenic transplant)是用來(lái)自另一個(gè)人的細(xì)胞開(kāi)展的。
Costa說(shuō),，“在這兩種情形中,，人們遇到的限制就是可獲得的細(xì)胞數(shù)量。如果我們能夠進(jìn)行軟骨異種移植,，它將需要增加可獲得的用于移植的細(xì)胞數(shù)量和質(zhì)量,。”在未來(lái)，“我們可能能夠?qū)⒇i軟骨細(xì)胞異種移植到骨關(guān)節(jié)炎患者或者甚至是類風(fēng)濕性關(guān)節(jié)炎患者身上”,，但是“在這些情形中,，其他的發(fā)炎和免疫過(guò)程也可能會(huì)影響移植的最終結(jié)果。”(生物谷：towersimper編譯)
doi:10.4049/jimmunol.1100433
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Multiple Receptors Trigger Human NK Cell-Mediated Cytotoxicity against Porcine Chondrocytes
Roberta Sommaggio, André Cohnen, Carsten Watzl and Cristina Costa
Xenotransplantation of genetically engineered porcine chondrocytes may provide a therapeutic solution for the repair of cartilage defects of various types. However, the mechanisms underlying the humoral and cellular responses that lead to rejection of xenogeneic cartilage are not well understood. In this study, we investigated the interaction between human NK cells and isolated porcine costal chondrocytes (PCC). Our data show that freshly isolated NK cells adhere weakly to PCC. Consequently, PCC were highly resistant to cytolysis mediated by freshly isolated NK cells. However, the presence of human natural Abs in the coculture was often sufficient to trigger cytotoxicity against PCC. Furthermore, IL-2 stimulation of NK cells or activation of PCC with the proinflammatory cytokines TNF-α or IL-1α resulted in increased adhesion, which was paralleled by increased NK cell-mediated lysis of PCC. NK cell adhesion to PCC could be blocked by Abs against human LFA-1 and porcine VCAM-1. NKG2D and NKp44 were involved in triggering cytotoxicity against PCC, which expressed ligands for these activating NK cell receptors. Our data further suggest that NKp30 and NKp46 may contribute to the activation of NK cells by PCC under certain conditions. Finally, comparative studies confirmed that PCC are more resistant than porcine aortic endothelial cells to human NK cell-mediated lysis. Thus, the data demonstrate that human NK cells can kill pig chondrocytes and may therefore contribute to rejection of xenogeneic cartilage. In addition, we identify potential targets for intervention to prevent the NK cell response against pig xenografts.
