髓源抑制性細胞在非腫瘤疾病中的研究進展

喻蓉，于化鵬

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髓源抑制性細胞在非腫瘤疾病中的研究進展

喻蓉，于化鵬

髓源抑制性細胞(MDSCs)是一群在病理條件下產生的具有明顯抑制功能的天然免疫細胞，可通過不同機制對多種免疫細胞產生抑制作用，從而導致機體先天性和獲得性免疫功能低下，促進疾病的發展及惡化。對MDSCs的研究最早集中在腫瘤領域，近年來關于其在非腫瘤疾病中的研究日益增多，現就其在非腫瘤疾病的研究進展作一綜述。

髓源抑制性細胞；非腫瘤疾病；免疫調節

1 髓源抑制性細胞(MDSCs)概述

1984年Hertel-Wulff研究小組在腫瘤組織中發現一群具有抑制先天或獲得性免疫反應作用的細胞，這群細胞主要由不成熟的巨噬細胞、粒細胞、髓樣樹突細胞等髓系細胞組成，故將它們命名為髓源抑制性細胞(myeloid-derived suppressor cells，MDSCs)[1]。

1.1 MDSCs的產生與調節 MDSCs屬于骨髓造血干細胞，該類細胞可產生無抑制功能的未成熟髓樣細胞(immature myeloid cells，IMCs)[2]。在正常情況下，IMCs可遷移至外周淋巴器官，并分化為成熟的樹突細胞、巨噬細胞和(或)粒細胞。在病理條件下(如腫瘤、炎癥、外傷、移植手術及自身免疫性疾病等)，IMCs分化為正常抗原呈遞細胞的能力下降，聚集在外周病理組織及淋巴器官中，逐漸顯示出免疫抑制功能，成為MDSCs[3-4]。因此，在健康人的肝臟和脾臟中，MDSCs所占比例不到5%，從外周血單核細胞中分離到的MDSCs占所有細胞的比例不到1%[2]。

小鼠MDSCs的主要表面標記物是CD11b和Gr-1，后者包括Ly6G和Ly6C[5]，據此有學者將MDSCs分為CD11b+Ly6ClowLy6G+中性粒細胞和CD11b+Ly6ChighLy6G－單核細胞兩種亞型[6]，后續又有學者報道了CD11b+Ly6C－Ly6G+、CD11b+Ly6CLy6G－、CD11b+Ly6C+Ly6G－、CD11b+Ly6C+Ly6G+等多種亞型[7-9]，各亞型的產生時間、功能、代謝產物及在腫瘤中的分布均有所不同。某些小鼠的MDSCs還表達IL-4Rα、F4/80、CD115、CD80等表面標記分子[10-14]。在腫瘤患者中，MDSCs的主要標志為CD11b+、CD33+、CD34+、CD14－HLA-DR－以及CD15[15-18]。新近在黑色素瘤和肝癌患者體內還發現了表面標志為CD14+HLA-DR－/low的細胞群，提示不同的腫瘤可產生不同的MDSCs細胞亞群[15,19]。

MDSCs的調節受多種細胞因子的影響，這些細胞因子主要可以概括為兩大類。第一類由腫瘤細胞產生，可促進MDSCs擴增，如環氧合酶2、前列腺素、干細胞因子、巨噬細胞集落刺激因子、粒巨噬細胞集落刺激因子、白細胞介素6(interleukin-6，IL-6)、血管內皮生長因子等[20-24]，它們主要通過激活蛋白酪氨酸激酶途徑(JAK)和信號轉導與轉錄激活途徑3(STAT3)促進MDSCs擴增[25]。第二類是由活化的T細胞和腫瘤基質產生，直接參與MDSCs的活化[26]。該類細胞因子包括γ干擾素、Toll樣受體、IL-13、IL-4、轉化生長因子β等，它們主要通過STAT1、SAT6和核因子NF-κB途徑促進MDSCs的活化[27]。

1.2 MDSCs的免疫抑制機制 MDSCs主要通過其表面受體和(或)釋放的可溶性介質發揮免疫抑制作用，如精氨酸(Arginine，Arg)、誘導型一氧化氮合酶(inducible nitric oxide synthases，iNOS)、活性氧族(reactive oxygen species，ROS)、過亞硝酸鹽等。Arg通過減少表達CD3ζ[28]和阻止細胞周期蛋白D3以及細胞周期依耐性蛋白激酶4而阻止T細胞增殖[29]。iNOS通過阻斷JAK3和STAT5轉錄激活途徑[30]，阻止主要組織相容性復合物Ⅱ(major histocompatibility complex，MHCⅡ)的表達[31]，從而抑制T細胞功能。ROS和過亞硝酸鹽則通過催化T細胞受體硝化抑制CD8+T細胞，阻斷T細胞與MHC的交互作用[32]。另有研究表明，不同亞型MDSCs抑制T細胞的機制不同，如粒細胞型MDSCs高表達ROS、低表達NO，單核細胞型MDSCs卻與之相反，但是這兩種亞型都表達Arg1[33]。Movahedi等[6]也發現在荷瘤小鼠中，這兩種亞型的細胞對特異性T細胞抗原的抑制機制不同，粒細胞型主要通過Arg1途徑，而單核細胞型則通過STAT1和iNOS途徑抑制T細胞增殖。

2 MDSCs在非腫瘤疾病中的研究進展

MDSCs最初是在腫瘤組織中被發現的，所以目前其研究重點也集中在腫瘤領域。但近年來也有不少學者將其特有的免疫抑制作用運用于非腫瘤疾病中。

2.1 急性感染 一些實驗證明MDSCs在急慢性感染中數量增多，如急性肝炎時，體內的免疫系統被激活，機體通過各種免疫細胞和因子對病原體進行清除。但是，過強的免疫反應對自身的組織和細胞反而會起到破壞作用。小鼠急性肝炎模型中，肝臟特異性糖蛋白130(glycoprotein，gp130)的缺失可導致病死率顯著增加，而gp130可以通過gp130-STAT途徑誘導MDSCs增殖[34]。急性肝炎時，通過輔助性T細胞分泌γ干擾素調節作用，可誘導MDSCs的增殖，因此，MDSCs可能對肝臟起到保護作用。但在肝癌患者體內MDSCs的數量也是增多的[35]，推測可能是MDSCs對急性期肝炎有免疫保護作用，而后期則參與肝纖維化形成和肝癌的進展，但具體機制仍有待研究證實。在脊髓急性損傷患者的外周血標本中，CD11b+Ly6C+Ly6G－亞型MDSCs明顯增多，這些細胞通過上調iNOS和Arg1的表達對T細胞發揮抑制作用，有利于血管生長，加速去除脊髓損傷后的血腫，并有抗炎作用[9]。

2.2 移植免疫 先天固有免疫在啟動同種移植排斥反應和移植物存活中發揮著非常重要的作用。MDSCs通過與細胞接觸并分泌大量iNOS抑制移植物內T細胞活化并誘導T細胞凋亡，抑制移植反應，對宿主起到保護作用。例如在同種異基因腎移植模型中，抗CD28抗體可誘導移植物和外周血中MDSCs擴增，使體內iNOS水平升高，從而建立免疫耐受，若抑制iNOS活性，可打破已建立的免疫耐受[36]。肝星狀細胞中可溶性因子介導的γ干擾素信號途徑可誘導MDSCs增殖，在同種異體肝臟移植中能促使宿主體內CD8+T細胞凋亡和輔助性T細胞增殖，促發免疫抑制，從而使宿主獲得長期存活[37]。另有研究發現，接受粒細胞集落刺激因子(G-CSF)治療的干細胞移植患者，外周血中MDSCs數量顯著增加，在體外將這群細胞與T淋巴細胞共培養后可發現其抑制了T淋巴細胞反應[38]。

2.3 支氣管哮喘/哮喘 哮喘的發病機制復雜，普遍認為Th1/Th2失衡在哮喘的發病機制中發揮了重要作用。但是，新近有研究認為哮喘患者對過敏原存在免疫耐受機制缺陷是導致Th1/Th2失衡的重要原因[39]，過強的先天性免疫和獲得性免疫均可促進哮喘氣道炎癥[40]。研究表明，脂多糖誘導的MDSCs可上調特異性轉錄因子核心堿基序列3或誘導已接觸抗原的Th2細胞STAT5活化，使樹突細胞促進Th2細胞因子產生的能力受到抑制，Th2細胞激活被抑制，氣道炎癥得到緩解[41]。MDSCs還能通過上調CD4+CD25+Foxp3+Treg細胞的數量，抑制嗜酸性粒細胞的產生，從而減輕氣道炎癥[42]。另有研究發現，不同亞型的MDSCs對哮喘氣道炎癥的作用不同，其中CD11b+Ly6C+Ly6G－可下調T細胞活性，募集Treg細胞，減輕氣道高反應性；CD11b+Ly6CLy6G+則與之相反，具有促炎作用，可加重氣道高反應性[8]。小部分CD11b+Ly6C+Ly6G+亞型通過Arg代謝途徑也可抑制T細胞反應[43]。

3 展望

因MDSCs在病理條件下具有特殊的免疫調控作用，其調控及臨床應用已成為目前的研究熱點。針對MDSCs治療的初步成功，為腫瘤及非腫瘤疾病的治療提供了新的思路和方向。但是利用其治療非腫瘤疾病仍有許多未知的情況亟待進一步闡明。首先，MDSCs最先在腫瘤疾病中發現，可促進腫瘤細胞生長，利用其治療非腫瘤疾病是否會導致腫瘤發生？其次，MDSCs的具體免疫機制及其與其他免疫因子的關系目前仍未完全闡明；第三，MDSCs眾多亞型的作用各不相同，如何才能利用其各自優點發揮治療作用？第四，MDSCs是如何從骨髓遷移至脾臟、外周血、淋巴細胞和病理組織的？局部組織在病理情況下是否也會產生MDSCs？第五，過繼轉移MDSCs細胞治療一些非腫瘤疾病初見成效，但哪種過繼轉移方式才能使MDSCs細胞直接聚集于治療的靶器官仍不明確；第六，誘導自身產生與體外過繼相比，哪種方法的治療效果更好，如何才能在體外獲得臨床可用、數量足夠的MDSCs，目前仍是一個難題。這些問題的解決，對MDSCs在非腫瘤疾病中的應用和相關機制的闡釋以及在臨床上的應用將產生重要促進作用。

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Advance in researches on myeloid-derived suppressor cells in non-neoplastic diseases

YU Rong, YU Hua-peng*
Department of Respiratory Diseases, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
*

, E-mail: huapengyu@yahoo.com.cn

Myeloid-derived suppressor cells (MDSCs) are a population of innate immune cells that form under pathological conditions, possess outstanding inhibitory function, and exert immune inhibitory function on many kinds of immune cells by different mechanisms, thus resulting in suppression of innate immune function and acquired immune function, and then promoting progression and deterioration of disease. The earliest researches about MDSCs focused on oncology field. In recent years, the researches about immune inhibition of MSCs in non-neoplastic diseases is increasing. The present paper reviews the research progresses of MDSCs in non-neoplastic diseases.

myeloid derived suppressor cells; non-neoplastic diseases; immunomodulatory

R392.3

A

0577-7402(2013)10-0864-04

10.11855/j.issn.0577-7402.2013.10.018

2013-04-12；

2013-07-17)

(責任編輯：沈寧)

喻蓉，碩士研究生。主要從事哮喘機制方面的研究

510282 廣州 南方醫科大學珠江醫院呼吸內科(喻蓉、于化鵬)

于化鵬，E-mail: huapengyu@yahoo.com.cn