髓系来源抑制细胞的功能及其与自身免疫性疾病关系的研究进展

髓系来源抑制细胞(MDSC)是一群具有异质性的髓系细胞,在肿瘤、感染、创伤和自身免疫性疾病等病理状态下,会异常扩增并发挥免疫抑制作用。MDSC主要通过上调诱导型一氧化氮合酶(iNOS)和精氨酸酶(Arg)的表达,增加一氧化氮(NO)、活性氧(ROS)和过氧化硝酸盐(ONOO-)浓度,诱导调节性T细胞(Treg)分化等途径抑制获得性免疫;通过削弱自然杀伤(NK)细胞功能等途径抑制固有免疫。近年来MDSC在自身免疫性疾病中的作用日渐受到关注,参与了多发性硬化等多种自身免疫性疾病的免疫调控。现就MDSC及其与自身免疫性疾病关系的研究进展进行综述。     

人类免疫缺陷病毒1感染与髓源性抑制细胞相关性研究进展

人类免疫缺陷病毒1型(HIV-1)感染者自身的持续免疫活化程度是决定疾病进展的关键。过度免疫活化导致机体免疫系统功能亢进,多种免疫细胞功能改变。髓源性抑制细胞(MDSC)是具有免疫抑制作用的细胞,参与机体免疫调节。在HIV-1感染者中,MDSC显著增多且与CD4+T细胞绝对数等疾病进展指标有关。随着高效抗逆转录病毒治疗的实施,MDSC也发生相应变化。疫苗诱导的MDSC对保护性细胞免疫应答有抑制作用,提示阻止MDSC的诱导可能提高HIV疫苗的有效性。因此,了解MDSC在HIV-1感染者中功能的改变有利于进一步探究HIV-1感染者免疫活化状态的成因,为HIV-1的治疗以及疫苗的研制提供新思路。     

肿瘤微环境中髓系来源抑制细胞对T细胞免疫活性抑制的分子机制

髓系来源抑制细胞(MDSC)根据其起源和功能而命名,由巨噬细胞、树突状细胞(DC)及粒细胞等细胞的前体细胞组成。肿瘤免疫逃逸与肿瘤微环境中MDSC介导的抗肿瘤免疫抑制相关,肿瘤微环境中的MDSC主要通过抑制T细胞的免疫活性来发挥免疫抑制作用。根据MDSC与T细胞之间的接触方式,肿瘤微环境中的MDSC抑制T细胞免疫功能的分子机制可分为直接抑制和间接抑制两类,其中MDSC通过产生细胞因子影响T细胞功能和细胞之间膜受体配体相互作用发挥抑制T细胞功能的方式为直接抑制,而MDSC通过影响T细胞代谢从而影响T细胞功能及通过其他细胞发挥抑制T细胞功能的方式为间接抑制。制定针对MDSC的治疗策略时,需综合考虑上述多种分子机制共存的可能性。     

MDSC对免疫系统的抑制机制

机体的免疫系统是一个复杂的网络调控系统,由固有免疫和适应性免疫组成,其中包括了固有免疫细胞、抗原递呈细胞、适应性免疫细胞等之间的相助作用和调节。越来越多的证据表明一群骨髓来源的具有CD11b和Gr-1标志的抑制性细胞在各种感染、肿瘤、急慢性炎症等疾病中大量存在,并且负向调节机体的免疫功能。这就是具有负向调节机体免疫反应的髓系抑制性细胞(MDSC),近年来被广泛研究。MDSC是免疫系统调节机体免疫反应的一群独特的细胞群体,可以对多种免疫细胞通过多种不同的机制发挥免疫抑制功能,从而导致机体固有免疫和适应性免疫功能的低下,促进疾病的发展和恶化。本文着重就MDSC对参与机体免疫反应的几种炎性细胞的抑制     

舒尼替尼对转移性肾癌患者髓系来源抑制细胞的影响

舒尼替尼是一种口服的多靶点酪氨酸激酶抑制剂,具有抗血管生成和抑制肿瘤增殖的作用.与IFN-α相比,舒尼替尼明显提高了转移性肾癌(mRCC)患者的无进展生存期,并成为治疗mRGC的一线治疗方案.近期有研究报道,舒尼替尼还可以通过抑制髓系来源抑制细胞(MDSC)调节肿瘤免疫.MDSC是一群来源于髓系细胞谱系的异质细胞,其通...     

髓源性抑制细胞诱导调节性T细胞产生的机制

髓源性抑制细胞(MDSC)是一群具有免疫抑制功能的未成熟细胞,通过抑制效应T细胞和自然杀伤(NK)细胞等抗肿瘤免疫细胞的功能介导肿瘤免疫逃逸。调节性T细胞(Treg)则在维持自身免疫稳态、控制移植排斥反应中发挥着非常重要的作用,但肿瘤微环境中的Treg却能够减弱机体的抗肿瘤免疫,而且肿瘤抗原和相关细胞因子对Treg的募集、扩增以及诱导产生有重要作用。肿瘤发生时,MDSC对Treg具有正向调控作用,抑制机体正常的抗肿瘤免疫。本文就MDSC促进Treg产生的机制进行综述,以进一步了解MDSC抗肿瘤免疫的机制,为肿瘤的免疫治疗提供新视角。     

荷瘤小鼠肿瘤组织髓系抑制性细胞的比例变化及意义

研究荷瘤小鼠肿瘤组织中髓系抑制性细胞(myeloid-derived suppressor cell,MDSC)的比例变化及分布特点,探讨其在机体抗肿瘤免疫中发挥的作用。采用肝癌细胞原位移植法建立小鼠原位肝癌模型,流式细胞仪检测荷瘤小鼠不同时间肿瘤组织中MDSC的比例;免疫组织化学法检测MDSC在肿瘤组织中的分布情况,以正常小鼠作对照。MDSC的比例在荷瘤小鼠肿瘤组织中比正常小鼠肝组织中明显升高,差别具有统计学意义(P0.05),且随着荷瘤时间的延长,MDSC的比例逐渐增加。正常小鼠肝组织中仅有极少量MDSC,而荷瘤后大量增加的MDSC主要分布于肿瘤组织与正常组织交界处。可见荷瘤小鼠肿瘤组织中MDSC的比例与肿瘤进展密切相关,提示荷瘤小鼠体内MDSC增多可能参与肿瘤的免疫逃逸,促进肿瘤细胞的生长。     

髓系来源抑制细胞促进肿瘤免疫逃逸的研究进展

髓系来源抑制细胞(MDSC)是髓系来源的一群异质细胞,在荷瘤小鼠模型及肿瘤患者均发挥免疫抑制作用.肿瘤MDSC免疫逃逸作用的机制目前已取得了很多进展,这群细胞可以通过上调精氨酸酶1(ARN1),诱导一氧化氮合酶(iNOS or NOS-2)表达,增加一氧化氮(NO)、活化氧自由基(ROS)等的释放,分解肿瘤微环境中的半...     

肿瘤源性因子对肿瘤相关免疫抑制细胞的影响

肿瘤相关树突状细胞(TADC)、髓系来源抑制细胞(MDSC)和肿瘤相关巨噬细胞(TAM)等免疫抑制细胞在肿瘤免疫逃逸过程中能够诱导免疫抑制反应.肿瘤源性因子不仅影响这些细胞的分化和功能,而且影响这些细胞的迁移.这些在肿瘤免疫中的研究进展能够为发展新的抗肿瘤免疫治疗策略提供依据.     

髓系来源的抑制性细胞在肿瘤进展过程中的研究

进展性肿瘤显著的特性是逃避机体免疫系统的监视、躲避免疫系统的杀伤、抑制自体免疫系统。肿瘤在进展过程中一群髓系来源的抑制性细胞（MDSC）在肿瘤微环境、引流区淋巴结大量聚集,其能够促进肿瘤的发展同时抑制机体的免疫作用。其机制概括为：髓系细胞向正常树突状细胞或巨噬细胞的分化受阻,分泌促进肿瘤生长的细胞因子,参与肿瘤血管的形成,诱导调节性T淋巴细胞（Treg）的产生,从而抑制了T淋巴细胞的抗肿瘤作用。     

Role of myeloid-derived suppressor cells in autoimmune disease

Myeloid-derived suppressor cells(MDSCs) represent an important class of immunoregulatory cells that can be activated to suppress T cell functions. These MDSCs can inhibit T cell functions through cell surface interactions and the release of soluble mediators. MDSCs accumulate in the inflamed tissues and lymphoid organs of patients with autoimmune diseases. Much of our knowledge of MDSC function has come from studies involving cancer models, however many recent studies have helped to characterize MDSC involvement in autoimmune diseases. MDSCs are a heterogeneous group of immature myeloid cells with a number of different functions for the suppression of T cell responses. However, we have yet to fully understand their contributions to the development and regulation of autoimmune diseases. A number of studies have described beneficial functions of MDSCs during autoimmune diseases, and thus there appears to be a potential role for MDSCs in the treatment of these diseases. Nevertheless, many questions remain as to the activation, differentiation, and inhibitory functions of MDSCs. This review aims to summarize our current knowledge of MDSC subsets and suppressive functions in tissue-specific autoimmune disorders. We also describe the potential of MDSC-basedcell therapy for the treatment of autoimmune diseases and note some of hurdles facing the implementation of this therapy.     

Atorvastatin promotes the expansion of myeloid‐derived suppressor cells and attenuates murine colitis

Statins, widely prescribed as cholesterol‐lowering drugs, have recently been extensively studied for their pleiotropic effects on immune systems, especially their beneficial effects on autoimmune and inflammatory disorders. However, the mechanism of statin‐induced immunosuppression is far from understood. Here, we found that atorvastatin promoted the expansion of myeloid‐derived suppressor cells (MDSCs) both in vitro and in vivo. Atorvastatin‐derived MDSCs suppressed T‐cell responses by nitric oxide production. Addition of mevalonate, a downstream metabolite of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, almost completely abrogated the effect of atorvastatin on MDSCs, indicating that the mevalonate pathway was involved. Along with the amelioration of dextran sodium sulphate (DSS) ‐induced murine acute and chronic colitis, we observed a higher MDSC level both in spleen and intestine tissue compared with that from DSS control mice. More importantly, transfer of atorvastatin‐derived MDSCs attenuated DSS acute colitis and T‐cell transfer of chronic colitis. Hence, our data suggest that the expansion of MDSCs induced by statins may exert a beneficial effect on autoimmune diseases. In summary, our study provides a novel potential mechanism for statins‐based treatment in inflammatory bowel disease and perhaps other autoimmune diseases.     

Human fibrocytic myeloid‐derived suppressor cells express IDO and promote tolerance via Treg‐cell expansion

By restraining T‐cell activation and promoting Treg‐cell expansion, myeloid‐derived suppressor cells (MDSCs) and tolerogenic DCs can control self‐reactive and antigraft effector T cells in autoimmunity and transplantation. Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor‐free donors. In the present study, we describe and characterize a novel population of human myeloid suppressor cells, named fibrocytic MDSC, which are differentiated from umbilical cord blood precursors by 4‐day culture with FDA‐approved cytokines (recombinant human‐GM‐CSF and recombinant human‐G‐CSF). This MDSC subset, characterized by the expression of MDSC‐, DC‐, and fibrocyte‐associated markers, promotes Treg‐cell expansion and induces normoglycemia in a xenogeneic mouse model of Type 1 diabetes. In order to exert their protolerogenic function, fibrocytic MDSCs require direct contact with activated T cells, which leads to the production and secretion of IDO. This new myeloid subset may have an important role in the in vitro and in vivo production of Treg cells for the treatment of autoimmune diseases, and in either the prevention or control of allograft rejection.     

Negative Regulation of Myeloid-derived Suppressor Cells in Cancer

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with suppressive function on immune response. In this review, we discuss recent studies about mechanisms of expansion and suppressive function of MDSCs during inflammation, infection and autoimmune diseases, as well as pro-angiogenic and pro-metastatic functions of these cells in tumor development. Further, we focus on novel studies of MDSCs and therapeutic approaches to eliminate these cells in cancer.     

Myeloid derived suppressor cells and autoimmunity

Myeloid-derived suppressor cells are a heterogeneous group of immature myeloid cells with immunoregulatory function. When activated and expanded, these cells can suppress T cell functions via cell-to cell interactions as well as soluble mediators. Recent studies investigated the involvement of MDSC in autoimmune diseases. Some papers have described beneficial effect of MDSC during the course of autoimmune diseases, and suggest a potential role as a treatment option, while others failed to detect these effects. Their contributions to autoimmune diseases are not fully understood, and many questions and some controversies remain as to the expansion, activation, and inhibitory functions of MDSC. This review aims to summarize current knowledge of MDSC in autoimmune disorders.     

Myeloid-derived suppressor cells expansion is closely associated with disease severity and progression in HBV-related acute-on-chronic liver failure

Dysregulation of the host immune responses induced by host hepatitis B virus (HBV) interactions has been observed in acute-on-chronic liver failure (ACLF). Myeloid-derived suppressor cells (MDSCs), well known for their immunomodulatory properties, can suppress T-cell function by regulating the expression of CD3 ζ chain in cancer and autoimmune/infectious diseases while rarely have been studied in ACLF. In this study, MDSCs, CD4⁺/CD8⁺ T cells, and CD3 ζ chain were analyzed by flow cytometry in peripheral blood mononuclear cells obtained from HBV-related ACLF patients, chronic hepatitis B (CHB) patients and healthy controls. ACLF patients were followed up for dynamic detection of MDSCs and observation of outcomes after treatment. Interestingly, peripheral CD14⁺CD33⁺CD11b⁺HLA-DR^−/low MDSCs from ACLF patients were significantly increased compared to those from CHB patients and healthy controls. CD4⁺/CD8⁺ T cell frequency and CD3 ζ chain expression in T cells were decreased in ACLF patients compared to those of healthy controls and were negatively correlated with matched MDSC frequency. Meanwhile, the frequency of MDSCs was closely correlated with biochemical parameters that are relevant for liver injury rather than virological parameters. Moreover, a lower level of MDSCs was correlated with a better short-term prognosis (within 4 weeks but not at 8 weeks), and MDSCs remained high in ACLF patients whose conditions worsened within a 4-week follow-up period after treatment. These results suggest that MDSCs are closely involved in cell-mediated immunity in HBV-related ACLF and that peripheral MDSC expansion is closely associated with disease severity and progression in HBV-related ACLF, which may serve as a predictor of short-term prognosis.     

Myeloid-derived suppressor cells: Important communicators in systemic lupus erythematosus pathogenesis and its potential therapeutic significance

Systemic lupus erythematosus (SLE) is a recognized chronic condition associated with immune system disorders that affect women nine times more commonly than men. SLE is characterized by over-secretion and release of autoantibodies in response to different cellular compartments and self-tolerance breaks to its own antigens. The detailed immunological dysregulation as an associated event that elicits the onset of clinical manifestations of SLE has not been clarified yet. Though, research using several animal models in the last two decades has indicated the role of the immune system in the pathogenesis of this disease. Myeloid-derived suppressor cells (MDSCs) as heterogeneous myeloid cells, are responsible for severe pathological conditions, including infection, autoimmunity, and cancer, by exerting considerable immunosuppressive effects on T-cells responses. It has been reported that these cells are involved in the regulation process of the immune response in several autoimmune diseases, particularly SLE. The function of MDSC is deleterious in infection and cancer diseases, though their role is more complicated in autoimmune diseases. In this review, we summarized the role and function of MDSCs in the pathogenesis and progression of SLE and its possible therapeutic approach.     

Myeloid-derived suppressor cells (MDSC): Another player in the orchestra

The simplest and most extended definition of myeloid-derived suppressor cells (MDSC) refers to them as immature myeloid cells with the ability to downregulate adaptative immune responses, a definition that reflects both their origin and function. Although initially described in experimental models and patients with cancer, accumulations of MDSC have also been found in other pathological conditions such as chronic/acute infections, autoimmune diseases and different types of stress. In all these situations MDSC may play their physiological role by modulating normal immune responses, both adaptive and innate. The mechanisms of action of MDSC are diverse requiring either cell to cell contact or the release of soluble factors. A better understanding of MDSC biology will open new windows of therapeutic opportunities, either by inhibiting their function (i.e. in cancer patients), or by enhancing their suppressive effects and promoting their expansion (i.e. in inflammation or autoimmunity).     

Cover Picture: Eur. J. Immunol. 11'14

Our cover features a light micrograph of hematoxylin and eosin‐stained human myeloid‐derived suppressor cells (MDSCs). These CD33⁺IL‐4Rα⁺ cells were derived from umbilical cord blood precursors by culturing with hGM‐CSF and hG‐CSF, and the histology confirms a fibrocyte‐like morphology characterized by extended cytoplasm, multiple nucleoli in the nucleus, phagocytic extensions and high adhesion to plastic. The image is taken from Zoso et al., in which the authors show that this novel population of fibrocytic MDSCs drives Treg‐cell expansion and induces normoglycemia in a xenogeneic mouse model of Type 1 diabetes. The authors also show that direct contact between the fibrocyte‐like MDSCs and T cells is required for the tolerogenic effect, and that this process involves IDO production. This new MDSC subset may prove useful in the production of Treg cells for the treatment of autoimmune diseases.     

Myeloid-derived suppressor cells are increased in frequency but not maximally suppressive in peripheral blood of Type 1 Diabetes Mellitus patients

Type 1 Diabetes Mellitus (T1D) results from the destruction of insulin-producing beta cells in the pancreas by autoreactive T cells. Myeloid derived suppressor cells (MDSCs) are a recently identified immune cell subset that down-regulate T cells. Whether defects in MDSC numbers or function may contribute to T1D pathogenesis is not known. We report here that MDSCs are unexpectedly enriched in peripheral blood of both mice and patients with autoimmune diabetes. Peripheral blood MDSCs from T1D patients suppressed T cell proliferation in a contact-dependent manner; however, suppressive function could be enhanced with in vitro cytokine induction. These findings suggest that native T1D MDSCs are not maximally suppressive and that strategies to promote MDSC suppressive function may be effective in preventing or treating T1D.