Dendritic Cell Therapy in Transplantation, Phenotype Governs Destination and Function.
Dendritic Cell Therapy in Transplantation, Phenotype Governs Destination and Function.
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移植中的树突状细胞治疗，表型决定目的地和功能。
DOI：
10.1097/tp.0000000000002238
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发表时间：
2018
期刊：
影响因子：
6.2
通讯作者：
Brennan,ToddV
中科院分区：
文献类型：
--
作者：
Samy,KannanP;Brennan,ToddV
尽管药理学方法是移植免疫抑制的主要方法，但基于细胞的疗法作为一种潜在的替代方法正在被越来越多地研究。目前可用的免疫抑制药物缺乏特异性，使移植受者易受感染，恶性肿瘤和药物相关毒性的影响，同时仍易受慢性排斥反应的影响。供体特异性耐受性明显上级整体免疫抑制，但仍然是一个难以捉摸的目标。细胞疗法的最新进展沿着对中枢和外周耐受机制的进一步理解，为供体特异性免疫调节提供了新的可能性。在迄今为止测试的许多类型的基于细胞的疗法中，一些迄今为止最成功的疗法涉及活体供者肾移植受者的供者干细胞移植。然而，需要离体细胞操作沿着T细胞耗竭和骨髓调节使得这些方法对于许多移植受体来说是困难的，并且对于那些接受死亡供体器官的人来说是不切实际的。作为一种替代的细胞疗法，树突状细胞（DC）是特别有吸引力的，因为它们的作用作为免疫反应的中央调节器。2在本期《移植》杂志中，罗森及其同事3对DC在产生同种异体移植耐受中的作用进行了全面综述，重点介绍了最近的研究，这些研究表明，负载供体抗原的树突状细胞衍生的DC，而不是供体衍生的DC，可用于移植免疫治疗。受体来源的DC在自身主要组织相容性复合体（间接呈递）的背景下呈递供体抗原，与供体主要组织相容性复合体的直接呈递相比，其在移植的背景下产生更强的同种异体特异性效应子应答。4因此，自体DC是有吸引力的，因为当与抑制性巨噬细胞或髓源性抑制细胞相比时，它们也产生有效的调节性T细胞应答。5同种异体移植的小鼠模型表明，这些作用进一步延长了移植物的存活时间，同时具有最小的药理学免疫抑制作用。6-8自体DC也可能在转移后更容易维持未成熟表型，因为它们本身不会被直接抗原呈递途径靶向，直接抗原呈递途径可能导致它们的消除，或者更糟的是，诱导它们的成熟并使受体对供体抗原敏感。如罗森等人的综述所示，DC的表面表型和位置影响其对免疫系统的作用。DC被认为是最有效的抗原递呈细胞类型，是先天免疫系统的高度移动的哨兵，收集外周抗原并将其递呈给适应性免疫系统。DC呈递抗原的背景受到一系列复杂的刺激和抑制信号的调节，这些信号协调免疫应答的方向和幅度。在局部炎症信号的存在下，组织驻留DC成熟（mDC）并表达水平增加的抗原提呈分子、共刺激分子和炎症细胞因子，这些分子将T细胞分化为效应子表型。在没有炎症的情况下，未成熟DC（imDC），包括迁移性常规DC（SIRPα+，CD 11 c+，B220阴性）和浆细胞样DC（PDCA-1+，CD 11 c+，B220+），其抗原呈递潜力降低，有助于维持对外周抗原的自身耐受。虽然DCs的迁移途径还不完全清楚，但有证据表明，它们的表型决定了它们的目的地，并最终决定了它们在调节免疫系统中的功能。
Although pharmacological methods are the mainstay for transplant immunosuppression, cell-based therapies are being increasingly studied as a potential alternative. Currently available immunosuppressive medications lack specificity, leaving transplant recipients vulnerable to infection, malignancy, and drug-related toxicities while still being susceptible to chronic rejection. Donor-specific tolerance would be clearly superior to global immunosuppression yet remains an elusive goal. Recent advances in cell-based therapies along with an improved understanding of central and peripheral tolerance mechanisms offer new possibilities for donor-specific immunomodulation. Among the many types of cell-based therapies tested to date, some of the most successful thus far have involved donor stem cell transplantation in livingdonor kidney transplant recipients. 1 However, the need ex vivo cell manipulation along with T-cell depletion and bone marrow conditioning makes these methods arduous for many transplant recipients and impractical for those receiving deceased donor organs. As an alternative cellular therapy, dendritic cells (DCs) are particularly attractive because of their role as central regulators of immune responses. 2 In this edition of Transplantation, Rosen and colleagues3 present a comprehensive review of the role DCs play in producing allograft tolerance, highlighting recent studies demonstrating the utility of recipient-derived DCs loaded with donor antigen, rather than donor-derived DCs for transplant immunotherapy. Recipient-derived DCs present donor antigen in the context of self major histocompatibility complex (indirect presentation), which in the setting of transplantation produces stronger allospecific effector responses when compared with direct presentation of donor major histocompatibility complex. 4 Thus, autologous DCs are attractive because they also generate potent regulatory T-cell responses when compared with suppressive macrophages or myeloid derived suppressor cells. 5 Murine models of allotransplantation demonstrate that these effects further extend graft survival with minimal pharmacologic immunosuppression. 6-8 Self-DCs may also be easier to maintain in an immature phenotype after transfer as they will not themselves be targeted by pathways of direct antigen presentation that can lead to their elimination or, even worse, induce their maturation and sensitize the recipient against donor antigen. As illustrated in the review by Rosen et al, the surface phenotype and location of DCs influence their effects on the immune system. Considered to be the most potent of the antigen-presenting cell types, DCs are highly mobile sentinels of the innate immune system that collect peripheral antigens and present them to the adaptive immune system. The context in which DCs present antigen is regulated by a complex array of stimulatory and inhibitory signals that orchestrate the direction and magnitude of the immune response. In the presence of local inflammatory signals, tissue resident DCs mature (mDCs) and express increased levels of antigenpresenting molecules, costimulation molecules, and inflammatory cytokines that differentiate T cells into effector phenotypes. In the absence of inflammation, immature DCs (imDCs), including migratory conventional DCs (SIRPα+, CD11c+, B220neg) and plasmacytoid DCs (PDCA-1+, CD11c+, B220+) with decreased antigen-presenting potential, help maintain self-tolerance to peripheral antigens. Although the migratory routes of DCs are incompletely understood, there is evidence that their phenotype governs their destination and ultimately their function in regulating immune …