喻蓉，于化鹏

·综 述·

髓源抑制性细胞在非肿瘤疾病中的研究进展

喻蓉，于化鹏

髓源抑制性细胞(MDSCs)是一群在病理条件下产生的具有明显抑制功能的天然免疫细胞，可通过不同机制对多种免疫细胞产生抑制作用，从而导致机体先天性和获得性免疫功能低下，促进疾病的发展及恶化。对MDSCs的研究最早集中在肿瘤领域，近年来关于其在非肿瘤疾病中的研究日益增多，现就其在非肿瘤疾病的研究进展作一综述。

髓源抑制性细胞；非肿瘤疾病；免疫调节

1 髓源抑制性细胞(MDSCs)概述

1984年Hertel-Wulff研究小组在肿瘤组织中发现一群具有抑制先天或获得性免疫反应作用的细胞，这群细胞主要由不成熟的巨噬细胞、粒细胞、髓样树突细胞等髓系细胞组成，故将它们命名为髓源抑制性细胞(myeloid-derived suppressor cells，MDSCs)[1]。

1.1 MDSCs的产生与调节 MDSCs属于骨髓造血干细胞，该类细胞可产生无抑制功能的未成熟髓样细胞(immature myeloid cells，IMCs)[2]。在正常情况下，IMCs可迁移至外周淋巴器官，并分化为成熟的树突细胞、巨噬细胞和(或)粒细胞。在病理条件下(如肿瘤、炎症、外伤、移植手术及自身免疫性疾病等)，IMCs分化为正常抗原呈递细胞的能力下降，聚集在外周病理组织及淋巴器官中，逐渐显示出免疫抑制功能，成为MDSCs[3-4]。因此，在健康人的肝脏和脾脏中，MDSCs所占比例不到5%，从外周血单核细胞中分离到的MDSCs占所有细胞的比例不到1%[2]。

小鼠MDSCs的主要表面标记物是CD11b和Gr-1，后者包括Ly6G和Ly6C[5]，据此有学者将MDSCs分为CD11b+Ly6ClowLy6G+中性粒细胞和CD11b+Ly6ChighLy6G－单核细胞两种亚型[6]，后续又有学者报道了CD11b+Ly6C－Ly6G+、CD11b+Ly6CLy6G－、CD11b+Ly6C+Ly6G－、CD11b+Ly6C+Ly6G+等多种亚型[7-9]，各亚型的产生时间、功能、代谢产物及在肿瘤中的分布均有所不同。某些小鼠的MDSCs还表达IL-4Rα、F4/80、CD115、CD80等表面标记分子[10-14]。在肿瘤患者中，MDSCs的主要标志为CD11b+、CD33+、CD34+、CD14－HLA-DR－以及CD15[15-18]。新近在黑色素瘤和肝癌患者体内还发现了表面标志为CD14+HLA-DR－/low的细胞群，提示不同的肿瘤可产生不同的MDSCs细胞亚群[15,19]。

MDSCs的调节受多种细胞因子的影响，这些细胞因子主要可以概括为两大类。第一类由肿瘤细胞产生，可促进MDSCs扩增，如环氧合酶2、前列腺素、干细胞因子、巨噬细胞集落刺激因子、粒巨噬细胞集落刺激因子、白细胞介素6(interleukin-6，IL-6)、血管内皮生长因子等[20-24]，它们主要通过激活蛋白酪氨酸激酶途径(JAK)和信号转导与转录激活途径3(STAT3)促进MDSCs扩增[25]。第二类是由活化的T细胞和肿瘤基质产生，直接参与MDSCs的活化[26]。该类细胞因子包括γ干扰素、Toll样受体、IL-13、IL-4、转化生长因子β等，它们主要通过STAT1、SAT6和核因子NF-κB途径促进MDSCs的活化[27]。

1.2 MDSCs的免疫抑制机制 MDSCs主要通过其表面受体和(或)释放的可溶性介质发挥免疫抑制作用，如精氨酸(Arginine，Arg)、诱导型一氧化氮合酶(inducible nitric oxide synthases，iNOS)、活性氧族(reactive oxygen species，ROS)、过亚硝酸盐等。Arg通过减少表达CD3ζ[28]和阻止细胞周期蛋白D3以及细胞周期依耐性蛋白激酶4而阻止T细胞增殖[29]。iNOS通过阻断JAK3和STAT5转录激活途径[30]，阻止主要组织相容性复合物Ⅱ(major histocompatibility complex，MHCⅡ)的表达[31]，从而抑制T细胞功能。ROS和过亚硝酸盐则通过催化T细胞受体硝化抑制CD8+T细胞，阻断T细胞与MHC的交互作用[32]。另有研究表明，不同亚型MDSCs抑制T细胞的机制不同，如粒细胞型MDSCs高表达ROS、低表达NO，单核细胞型MDSCs却与之相反，但是这两种亚型都表达Arg1[33]。Movahedi等[6]也发现在荷瘤小鼠中，这两种亚型的细胞对特异性T细胞抗原的抑制机制不同，粒细胞型主要通过Arg1途径，而单核细胞型则通过STAT1和iNOS途径抑制T细胞增殖。

2 MDSCs在非肿瘤疾病中的研究进展

MDSCs最初是在肿瘤组织中被发现的，所以目前其研究重点也集中在肿瘤领域。但近年来也有不少学者将其特有的免疫抑制作用运用于非肿瘤疾病中。

2.1 急性感染 一些实验证明MDSCs在急慢性感染中数量增多，如急性肝炎时，体内的免疫系统被激活，机体通过各种免疫细胞和因子对病原体进行清除。但是，过强的免疫反应对自身的组织和细胞反而会起到破坏作用。小鼠急性肝炎模型中，肝脏特异性糖蛋白130(glycoprotein，gp130)的缺失可导致病死率显著增加，而gp130可以通过gp130-STAT途径诱导MDSCs增殖[34]。急性肝炎时，通过辅助性T细胞分泌γ干扰素调节作用，可诱导MDSCs的增殖，因此，MDSCs可能对肝脏起到保护作用。但在肝癌患者体内MDSCs的数量也是增多的[35]，推测可能是MDSCs对急性期肝炎有免疫保护作用，而后期则参与肝纤维化形成和肝癌的进展，但具体机制仍有待研究证实。在脊髓急性损伤患者的外周血标本中，CD11b+Ly6C+Ly6G－亚型MDSCs明显增多，这些细胞通过上调iNOS和Arg1的表达对T细胞发挥抑制作用，有利于血管生长，加速去除脊髓损伤后的血肿，并有抗炎作用[9]。

2.2 移植免疫 先天固有免疫在启动同种移植排斥反应和移植物存活中发挥着非常重要的作用。MDSCs通过与细胞接触并分泌大量iNOS抑制移植物内T细胞活化并诱导T细胞凋亡，抑制移植反应，对宿主起到保护作用。例如在同种异基因肾移植模型中，抗CD28抗体可诱导移植物和外周血中MDSCs扩增，使体内iNOS水平升高，从而建立免疫耐受，若抑制iNOS活性，可打破已建立的免疫耐受[36]。肝星状细胞中可溶性因子介导的γ干扰素信号途径可诱导MDSCs增殖，在同种异体肝脏移植中能促使宿主体内CD8+T细胞凋亡和辅助性T细胞增殖，促发免疫抑制，从而使宿主获得长期存活[37]。另有研究发现，接受粒细胞集落刺激因子(G-CSF)治疗的干细胞移植患者，外周血中MDSCs数量显著增加，在体外将这群细胞与T淋巴细胞共培养后可发现其抑制了T淋巴细胞反应[38]。

2.3 支气管哮喘/哮喘 哮喘的发病机制复杂，普遍认为Th1/Th2失衡在哮喘的发病机制中发挥了重要作用。但是，新近有研究认为哮喘患者对过敏原存在免疫耐受机制缺陷是导致Th1/Th2失衡的重要原因[39]，过强的先天性免疫和获得性免疫均可促进哮喘气道炎症[40]。研究表明，脂多糖诱导的MDSCs可上调特异性转录因子核心碱基序列3或诱导已接触抗原的Th2细胞STAT5活化，使树突细胞促进Th2细胞因子产生的能力受到抑制，Th2细胞激活被抑制，气道炎症得到缓解[41]。MDSCs还能通过上调CD4+CD25+Foxp3+Treg细胞的数量，抑制嗜酸性粒细胞的产生，从而减轻气道炎症[42]。另有研究发现，不同亚型的MDSCs对哮喘气道炎症的作用不同，其中CD11b+Ly6C+Ly6G－可下调T细胞活性，募集Treg细胞，减轻气道高反应性；CD11b+Ly6CLy6G+则与之相反，具有促炎作用，可加重气道高反应性[8]。小部分CD11b+Ly6C+Ly6G+亚型通过Arg代谢途径也可抑制T细胞反应[43]。

3 展望

因MDSCs在病理条件下具有特殊的免疫调控作用，其调控及临床应用已成为目前的研究热点。针对MDSCs治疗的初步成功，为肿瘤及非肿瘤疾病的治疗提供了新的思路和方向。但是利用其治疗非肿瘤疾病仍有许多未知的情况亟待进一步阐明。首先，MDSCs最先在肿瘤疾病中发现，可促进肿瘤细胞生长，利用其治疗非肿瘤疾病是否会导致肿瘤发生？其次，MDSCs的具体免疫机制及其与其他免疫因子的关系目前仍未完全阐明；第三，MDSCs众多亚型的作用各不相同，如何才能利用其各自优点发挥治疗作用？第四，MDSCs是如何从骨髓迁移至脾脏、外周血、淋巴细胞和病理组织的？局部组织在病理情况下是否也会产生MDSCs？第五，过继转移MDSCs细胞治疗一些非肿瘤疾病初见成效，但哪种过继转移方式才能使MDSCs细胞直接聚集于治疗的靶器官仍不明确；第六，诱导自身产生与体外过继相比，哪种方法的治疗效果更好，如何才能在体外获得临床可用、数量足够的MDSCs，目前仍是一个难题。这些问题的解决，对MDSCs在非肿瘤疾病中的应用和相关机制的阐释以及在临床上的应用将产生重要促进作用。

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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)

(责任编辑：沈宁)

喻蓉，硕士研究生。主要从事哮喘机制方面的研究

510282 广州 南方医科大学珠江医院呼吸内科(喻蓉、于化鹏)

于化鹏，E-mail: huapengyu@yahoo.com.cn