抑制性树突状细胞诱导移植免疫耐受的研究进展

树突状细胞（DC）是功能强大的专职抗原呈递细胞。在器官或细胞移植中，DC通过直接或间接识别途径呈递抗原活化T细胞，引起移植免疫排斥反应，但某些特殊类型的DC也可以产生抑制免疫应答，促进免疫耐受的作用。基于DC这种生物学特性的异质性，目前有多种生物学策略诱生抑制性DC诱导移植免疫耐受。     

基因修饰树突状细胞诱导移植免疫耐受研究进展

在移植免疫反应中 ,树突状细胞 (DC)作为专职抗原提呈细胞 ,既可活化T、B细胞生产免疫应答 ,同时某些类型DC由于缺乏共刺激分子或表达某些抑制性细胞因子而能诱导移植免疫耐受。针对DC提呈抗原及活化T、B细胞的多个环节 ,目前有许多策略将不同目的基因转染不同来源的DC ,让其表达不同的表面分子或分泌免疫抑制因子 ,以诱导移植免疫耐受     

069 基因修饰树突状细胞诱导移植免疫耐受研究进展

在移植免疫反应中,树突状细胞(DC)作为专职抗原提呈细胞,既可活化T、B细胞生产免疫应答,同时某些类型DC由于缺乏共刺激分子或表达某些抑制性细胞因子而能诱导移植免疫耐受.针对DC提呈抗原及活化T、B细胞的多个环节,目前有许多策略将不同目的基因转染不同来源的DC,让其表达不同的表面分子或分泌免疫抑制因子,以诱导移植免疫耐受.     

基因修饰树突状细胞诱导移植免疫耐受研究进展

在移植免疫反应中，树突状细胞(DC)作为专职抗原提呈细胞，既可活化T、B细胞生产免疫应答，同时某些类型DC由于缺乏共刺激分子或表达某些抑制性细胞因子而能诱导移植免疫耐受。针对DC提呈抗原及活化T、B细胞的多个环节，目前有许多策略将不同目的基因转染不同来源的DC，让其表达不同的表面分子或分泌免疫抑制因子，以诱导移植免疫耐受。     

树突状细胞诱导外周免疫耐受的机制

树突状细胞既能启动免疫应答 ,又能诱导免疫耐受。目前对树突状细胞诱导外周耐受方面的研究进展迅速 ,本文就未成熟树突状细胞、免疫抑制因子处理的树突状细胞及转基因树突状细胞在诱导外周免疫耐受中的作用作一综述 ,这可能是治疗自身免疫性疾病和移植排斥反应的新途径     

树突状细胞在移植免疫耐受诱导中的作用

移植排斥是异体/种组织和器官移植中长期存在而尚未克服的医学难题.目前临床应用的免疫抑制剂虽能使移植排斥反应得到有效控制,但由于其对受者免疫系统非选择性的广泛抑制而常引起感染、肿瘤发生等诸多并发症.因此诱导供者特异性免疫耐受被认为是最终克服移植排斥的有效途径.树突状细胞(dendriticcell,DC)由于来源、发育阶段不同而存在的功能异质性,使其成为诱导移植免疫耐受的重要靶细胞.     

树突状细胞和免疫耐受

树突状细胞 (DC)是职业抗原递呈细胞 ,既可触发排斥反应 ,又能够调节T细胞反应而产生外周免疫耐受。尽管其诱导外周免疫耐受的确切机制尚不清楚 ,但DC在诱导供体特异性T无反应细胞 (Treg)凋亡 ,供体特异T调整细胞 ,转基因诱导耐受DC以及T辅助细胞转化方向等方面都取得了明显进展。进一步研究DC在诱导自身抗原耐受的作用机理 ,可以揭示DC诱导移植免疫耐受 ,以实现人类在不依赖免疫抑制剂的条件下产生供体特异性免疫耐受 ,本文拟就有关内容作一综述。     

树突状细胞与移植免疫耐受研究进展

诱导供者特异性免疫耐受是最终克服移植排斥提高受者生存质量的有效途径之一。近年随着对树突状细胞发育成熟过程的认识步步深入，树突状细胞在移植排斥和移植耐受平衡中的双向调节作用引入注目。     

树突状细胞诱导免疫耐受的研究进展

树突状细胞(dendritic cells,DC)因其成熟时表面有许多树突样或伪足样突起而得名,一直以来,大家所关注的都是其发挥专业的抗原递呈细胞(antigen presenting cell,APC)的功能和引起T细胞和B细胞介导的免疫应答的出色能力。近年的研究发现,DC不仅是最强的抗原递呈细胞,而且DC本身具有调节免疫反应、诱导免疫耐受的作用,更有证据显示外周DC具有天生的遗传耐受特性(inherent tolerogen ic ity)。DC如何诱导外周免疫耐受的机制尚需进一步研究,这对自身免疫性疾病、移植排斥和过敏性疾病的治疗都具有重要意义。1 DC的分类和作用DC分为多种…     

树突状细胞和免疫耐受

树突状细胞（DC）是职业抗原递呈细胞，即可触发排斥反应，又能够调节T细胞反应而产生外周免疫耐受。尽管其诱导外周免疫耐受的确切机制尚不清楚，但DC在诱导供体特异性T无反应细胞（Treg）凋亡，供体特异T调整细胞，转基因诱导耐受DC以及T辅助细胞转化方向等方面都取得了明显进展。进一步研究DC在诱导自身抗原耐受的作用机理，可以揭示DC诱导移植免疫耐受，以实现人类在不依赖免疫抑制剂的条件下产生供体特异性免疫耐受，本文拟就有关内容作一综述。     

IL-10上调PD-1配体的表达诱导耐受性树突状细胞形成

目的 探讨IL-10诱导耐受性树突状细胞（DCs）形成的机制。方法 用30ng／mL的IL-10处理Balb／c小鼠骨髓DCs，分别用RT-PCR和流式细胞术分析DCs的PD-1配体分子的表达，用MTF法测定DCs激活T细胞的能力，并用IL-10-DCs免疫荷瘤小鼠，观察H22肝癌细胞的生长情况。结果 IL-10-DCs对T细胞的激活能力降低；在注射了IL-10-DCs的小鼠体内，H22肝癌细胞的生长速度快于对照组；免疫抑制性受体PD-1的配体分子在IL-10-DCs上的表达上调。结果提示，在H22肝癌模型上，IL-10上调PD-1的配体分子表达可能是免疫耐受的一个机制。结论 减少IL-10的产生或封闭PD-1／PD-L路径可能是一个很有前景的肝癌生物学治疗策略。     

IL-10 gene modified dendritic cells inhibit T helper type 1-mediated alloimmune responses and promote immunological tolerance in diabetes

Dendritic cells （DCs） have the potency to regulate the outcome of autoimmunity through the modulation of immune responses. The induction of antigen specific tolerance is critical for prevention and treatment of allograft rejection. In the present Study, we transfected IL-10 gene into DCs and investigated their effect on inhibition of lymphocyte activity in vitro and induction of immune tolerance on islet allograft in mice. An IDDM C57BL/6 mouse model was induced by streptozotocin. The islet cells isolated from the BALB/c mice were transplanted into the kidney capules of the model mice followed by injection of IL-10 modified DCs （mDCs）. The results showed that mDCs could significantly inhibit T lymphocyte proliferation mediated by allotype cells and induce its apoptosis, whereas, unmodified DCs （umDCs） could promote the murine lymphocyte proliferation markedly. The injection of mDCs could prolong the survival of allotype islet transplanted IDDM mice. The average plasma glucose （PG） level in mDCs treated mice returned to normal within 3 days and lasted for about 2 weeks. The rejection response in control mice occurred for 5 days after transplantation. The level of IFN-γ was lower while IL-4 was higher in mDCs treated mice than that in umDCs treated mice, which indicated that Thl/Th2 deviation occurred. Our studies suggest that IL-10 gene modified DCs can induce the immune tolerance to islet graft and prolong survival of the recipients by the inhibiting of T cell proliferation in allotype mice. Cellular ＆ Molecular Immunology.     

IL-10 gene modified dendritic cells induced antigen-specific tolerance in experimental autoimmune myocarditis

Experimental autoimmune myocarditis (EAM) in rats is a T-cell-mediated disorder, and the involvement of Th1/Th2 unbalance has been demonstrated. The induction of antigen-specific tolerance is critical for the treatment of EAM and maintenance of immune tolerance. IL-10 is a pleiotrophic immunomodulatory cytokine that functions at different levels of the immune response, so it has emerged as a promising therapeutic factor for the treatment of autoimmune/inflammatory diseases. This study was designed to explore the effects of IL-10 gene modified bone-marrow-derived immature dendritic cells (iDCs) on the in vitro and in vivo immune response to cardiac myosin in EAM. EAM was induced using the classic methods of cardiac myosin immunization on day 0 and day 7. 2 x 10(6)/per rat mature DC (mDC), immature DC (iDC), pcDNA3 transfected iDC, pcDNA3-IL-10 transfected iDC or PBS were injected intravenously for treatment 5 days after the first immunization. On day 21, transthoracic echocardiogram and HE staining were performed to detect the cardiac function and myocardial inflammation. Th1/Th2 cytokines were detected by ELISA and MHC-II molecules, costimulatory molecules were identified by flow cytometry. In vitro T lymphocyte proliferation assay and adoptive transfer of DCs were performed to determine the antigen-specific tolerance induced by IL-10 gene modified iDCs. IL-10 gene modified iDC-treated EAM rats showed improved cardiac function and reduced infiltration of inflammatory cell into myocardium. Serum cytokines data indicated lower Th1 while higher Th2-type responses were induced in the pcDNA3-IL-10-iDC-treated group, suggesting a Th2 polarization. Moreover, IL-10 gene modified iDCs down-regulated MHC-II and costimulatory molecules on the surface of splenocytes and inhibited the antigen-specific immunological responses towards cardiac myosin. Adoptive transfer of IL-10 producing DCs prevented EAM induction. IL-10 gene modified iDCs ameliorates EAM histopathologically and functionally. The underlying mechanisms may be related to the IL-10 induced Th2 polarization and down-regulation of MHC-II molecules and costimulatory molecules expression.     

Induction of IL-10 producing CD4+ T cells with regulatory activities by stimulation with IL-10 gene-modified bone marrow derived dendritic cells

Dendritic cells (DCs) can induce both tolergenic as well as effective immune responses in the lung. Pulmonary DCs producing interleukin (IL)-10 mediated tolerance induced by respiratory exposure to antigen. IL-10 is an important immunosuppressive cytokine, which inhibits maturation and function of DC. To assess whether IL-10 producing DCs can exert the tolergenic effect through the differentiation of regulatory T cells, bone marrow derived DCs were genetically modified by IL-10 expressing adenovirus. IL-10 gene modified DCs (Ad-IL-10-DC) displayed a characteristic phenotype of immature DCs. Here we showed that in vitro repetitive stimulation of naïve DO11·10 CD4⁺ T cells with Ad-IL-10-DCs resulted in a development of IL-10 producing T-cell regulatory cells. These T cells could not proliferate well but also lost their ability to produce interferon-γ upon restimulation with irradiated splenocytes and ovalbumin peptide. Furthermore, in co-culture experiments these T cells inhibited the antigen-driven proliferation of naïve CD4+ T cells in a dose-dependent manner. Our findings demonstrated that IL-10 producing DCs had the potential to induce the differentiation of Tr1-like cells and suggested their therapeutic use.     

TLR2激动剂Pam3CK逆转IL-10转染小鼠髓样树突状细胞免疫功能的研究

目的:观察TLR2激活剂Pam3CK对IL-10转染小鼠髓样树突状细胞免疫功能影响。方法:转染IL-10至小鼠髓样树突状细胞(mDC),TLR2配体Pam3CK刺激48小时,利用流式细胞仪检测DC表面标志MHCⅡ、CD80、CD86及FasL等分子的表达;ELISA检测细胞产生IL-6、TNF-α。结果:IL-10抑制mDC表达CD80、CD86、MHCⅡ类分子,降低其分泌IL-6、TNF-α,促进其表达FasL,而TLR2激动剂刺激增加了IL-10转染DC表达MHC-Ⅱ类分子及CD80、CD86,促进其产生IL-6及TNF-α,抑制了FasL表达。结论:TLR2激动剂可逆转IL-10诱发的DC免疫应答低下。     

IL-10诱导小鼠树突状细胞耐受的分子机制

目的：研究白细胞介素-10 (interleukin-10，IL-10)诱导小鼠来源的树突状细胞(DC)耐受及其与配对免疫球蛋白样受体（PIR-A/B）的关系。方法: 以IL-10（20 μg/L）诱导小鼠来源的树突状细胞系（DC2.4）6 d，即IL-10-DC组，脂多糖（LPS）刺激其48 h为成熟DC2.4细胞（LPS-DC），体外化学合成特异性针对PIR-B的小干扰RNA片段，以脂质体2 000转染IL-10组（Si-DC组）。分别应用半定量RT-PCR和流式细胞仪（FCM）检测DC2.4、IL-10组、LPS组及Si-DC组细胞PIR-A/B的表达。以［3H］-TdR标记法检测上述各组细胞刺激同种异体淋巴细胞的增殖反应(MLR)，ELISA方法测混合培养上清中IFN-γ的水平变化。结果: RT- PCR结果表明，IL-10诱导PIR-B表达升高、PIR-A表达下降，LPS则下调PIR-B、上调PIR-A的表达。FCM检测IL-10组和LPS组的PIR-A/B胞外区PIR表达均升高，且前者明显高于后者。同正常DC2.4和LPS组相比，IL-10可抑制MLR，小干扰RNA沉默PIR-B表达可增强MLR，伴随MLR反应上清中IFN-γ的水平升高。结论: IL-10诱导DC高度表达免疫抑制性受体PIR-B，使其获得耐受，上调PIR-B的表达是IL-10诱导DC耐受的分子机制之一。     

Acquired thymic tolerance to autoimmune encephalomyelitis is associated with activation of peripheral IL-10-producing macrophages/dendritic cells

Antigen injection into the thymus of adult animals induces systemic tolerance and protects animals from subsequent challenge for the autoimmune disease. However, its mechanisms are not well understood. In this study, we analyzed tolerance to experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats by intrathymic (i.t.) injection of myelin basic protein (MBP). Intrathymic injection of MBP 7 days before immunization with MBP/complete Freund's adjuvant resulted in complete suppression of clinical signs of EAE in most animals and markedly reduced the histological severity in the central nervous system lesion. However, immunohistochemical examination and the TCR repertoire analysis revealed that there was no significant difference in the T cell composition in the lesion and the TCR spectratype pattern between MBP and saline i.t. rats, suggesting that encephalitogenic T cell activation occurs equally in both protected and symptomatic rats. In contrast, quantitative analysis of cytokine mRNA and flow cytometry revealed a marked increase of IL-10 production in the splenic macrophages/dendritic cell (M?/DC) population of MBP i.t. rats. Adoptive transfer of this population significantly suppressed the clinical course of EAE in recipients. Taken together, IL-10-secreting M?/DC in peripheral lymphoid organs activated by MBP i.t. injection may play a critical role in the induction and maintenance of tolerance.     

hIL-10修饰树突状细胞对实验动物淋巴细胞增殖及胞毒效应的影响

目的：探讨hIL-10修饰DC对实验动物免疫功能的影响。方法：将经IL-10基因修饰或未修饰DC腹腔注射C57BL／6致敏小鼠，以致敏或未致敏C57BL／6单个核细胞作为反应细胞，以未修饰DC细胞及修饰DC为刺激细胞。共培养6天，MTT检测细胞增殖，乳酸脱氢酶法测定细胞毒活性。结果：hIL-10对未修饰DC致敏或未致敏小鼠的同种细胞刺激的增殖反应有明显的抑制作用。hIL-10修饰DC诱导不同组小鼠淋巴细胞增殖反应显著低于未修饰DC细胞诱导小鼠淋巴细胞增殖反应，hIL-10修饰DC对不同组小鼠CTL细胞毒活性具有抵抗作用。结论：hIL-10修饰的DC诱导同种小鼠淋巴细胞的增殖反应显著降低和对CTL胞毒活性抵抗。     

IL-10 from plasmacytoid dendritic cells promotes angiogenesis in the early stage of endometriosis

An elevated level of IL-10 has been considered a critical factor for the development of endometriosis; however, its detailed mechanism and causal relationship remain unclear. This study explored the cellular source and angiogenic activity of local IL-10 during the early stage of endometriosis. Using a surgical murine model, we found that localised treatment with exogenous recombinant IL-10 on the day of surgery significantly enhanced endometriotic lesion growth and angiogenesis, whereas blocking local IL-10 activity using mAbs significantly suppressed those effects. Adoptive transfer of Il10^+/+ plasmacytoid dendritic cells into mice significantly enhanced lesion development, whereas Il10^−/− plasmacytoid dendritic cells significantly inhibited lesion development. Furthermore, in vitro angiogenesis analyses demonstrated that the IL-10 and IL-10 receptor pathway stimulated the migratory and tube formation ability of HUVECs as well as ectopic endometrial mesenchymal stem cells through, at least in part, a VEGF-dependent pathway. We also found that recombinant IL-10 directly stimulated angiogenesis, based on a Matrigel plug assay as well as a zebrafish model. Pathological results from human endometrioma tissues showed the increased infiltration of CD123⁺ plasmacytoid dendritic cells and higher percentages of cells that express the IL-10 receptor and CD31 as compared with the corresponding normal counterparts. Taken together, these results show that IL-10 secreted from local plasmacytoid dendritic cells promotes endometriosis development through pathological angiogenesis during the early disease stage. This study provides a scientific basis for a potential therapeutic strategy targeting the IL-10—IL-10 receptor pathway in the endometriotic milieu. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen

Respiratory exposure to allergen induces T cell tolerance and protection against the development of airway hyperreactivity and asthma. However, the specific mechanisms by which tolerance is induced by respiratory allergen are not clear. We report here that pulmonary dendritic cells (DCs) from mice exposed to respiratory antigen transiently produced interleukin 10 (IL-10). These phenotypically mature pulmonary DCs, which were B-7(hi) as well as producing IL-10, stimulated the development of CD4(+) T regulatory 1--like cells that also produced high amounts of IL-10. In addition, adoptive transfer of pulmonary DCs from IL-10(+/+), but not IL-10(-/-), mice exposed to respiratory antigen induced antigen-specific unresponsiveness in recipient mice. These studies show that IL-10 production by DCs is critical for the induction of tolerance, and that phenotypically mature pulmonary DCs mediate tolerance induced by respiratory exposure to antigen.