树突状细胞在角膜移植免疫排斥反应中的作用

角膜移植术后的免疫排斥反应是导致手术失败的主要原因,树突状细胞在角膜移植免疫排斥反应中起着多方面作用,其作用机制成为研究热点.近年来,通过角膜移植动物模型发现,树突状细胞能够诱导不同类型的免疫反应.通过减少树突状细胞数量、抑制树突状细胞提供双信号的能力以及通过树突状细胞诱导免疫耐受等防治角膜移植免疫排斥反应的研究方法,目前取得了一定进展.     

调节性T细胞在角膜移植排斥反应中的研究进展

角膜移植术是治疗终末期角膜疾病的常用方式,虽然角膜移植的成功率较其它器官移植高,但是术后排斥仍然是手术失败的主要原因。器官移植后排斥反应高度依赖于免疫细胞向淋巴组织或炎症部位的定向迁移和归巢,并受粘附分子和趋化因子的调控。调节性T细胞在免疫调节中起着关键性作用,通过诱导免疫耐受维持内环境稳定,在器官移植排斥反应、自身免疫性疾病及肿瘤相关研究中发挥重要作用。本篇综述主要介绍调节性T细胞参与眼部免疫耐受的相关研究,着重阐述调节性T细胞在角膜移植排斥过程中的作用、机制和应用。     

细胞与角膜移植免疫耐受

角膜移植术后免疫排斥反应是角膜移植失败的主要原因。免疫耐受是指抗原特异性的免疫无应答。诱导受体产生针对移植物的免疫耐受是彻底克服移植排斥反应的根本方法。角膜移植排斥反应是一个复杂且有多因素参与的过程。多种免疫细胞在抑制角膜移植术后排斥反应、诱导免疫耐受中,发挥着关键作用。因此,我们就近几年通过细胞诱导角膜移植免疫耐受的机制作一综述。     

角膜内树突状细胞及其在角膜移植免疫排斥反应中的作用

树突状细胞是目前已知的体内功能最强的抗原呈递细胞。成熟树突状细胞可引发机体免疫反应,而未成熟树突状细胞则会诱导机体免疫耐受。最近研究表明,角膜中央区内的树突状细胞完全处于未成熟状态,而角膜周边区内的树突状细胞则大多处于成熟状态;树突状细胞在角膜移植免疫排斥反应中发挥着重要作用。本文就角膜内的树突状细胞以及其在角膜移植免疫排斥反应中的作用作一综述。     

角膜移植免疫耐受的研究进展

排斥反应是角膜移植失败的主要原因.临床治疗中常用的非特异性免疫抑制剂,如糖皮质激素、环孢素A等,存在着许多全身副作用.因此诱导受体建立针对供体角膜的特异性免疫耐受是治疗排斥反应的理想方法.免疫耐受的机制主要包括T细胞克隆失活(anergy)、克隆清除(delete)、细胞因子介导的抑制及免疫平衡等.现就目前人工诱导免疫耐受的方法作一综述.     

角膜移植排斥反应中调节性T细胞的发展及应用

角膜移植术是角膜盲的有效治疗方式,是角膜盲患者复明的唯一希望。角膜无血管、无淋巴管,被称为免疫赦免器官,因此角膜移植术的成功率明显高于其他器官移植术,但角膜移植术后的排斥反应仍然是角膜移植术失败的主要原因。器官移植术后的免疫反应主要是免疫细胞向淋巴组织、炎症部位的定向移动,而调节性T细胞(regulatory T cells,Treg)在免疫调节中起着关键性作用,其可以通过调节和抑制效应T细胞的活化来诱导免疫耐受,从而减轻角膜移植术后的排斥反应。据此,文章对在角膜移植术后发生免疫排斥反应中Treg的来源、作用机制以及治疗等多方面做简单综述,同时也探讨了应用冬虫夏草提取物FTY720增强Treg的有效性,以期为后续针对性开展临床应用转化及基础研究提供一定的参考。     

免疫耐受对角膜移植片长期存活的价值

穿透性角膜移植是治疗角膜盲的主要手段,尽管角膜是器官移植的免疫赦免部位,但同种异体免疫排斥反应仍是角膜移植片失败的主要原因.据统计,18%的常规角膜移植或75%的高危角膜移植患者会发生排斥反应.目前临床使用的各种免疫抑制剂主要通过作用于T淋巴细胞达到抑制免疫排斥反应的目的,但长期使用费用昂贵,且为非特异性免疫抑制.当免疫抑制剂不足时就会发生排斥反应,而抑制过强易诱发感染或肿瘤,并且阻断受体形成免疫耐受.     

角膜移植免疫排斥反应防治研究进展

角膜移植术后发生免疫排斥反应是导致移植手术失败的主要原因。角膜移植与其他器官移植相比，不易发生免疫排斥反应，主要原因：前房的相关免疫偏离状态；血．房水屏障；角膜缺乏血管、淋巴组织；角膜中央区不含成熟抗原提呈细胞；房水中有大量免疫调节分子；眼前节有Fas配基表达等。角膜移植免疫排斥反应是一个复杂的反应过程，一般包括宿主对异体组织抗原的致敏和宿主对异体组织抗原的反应两方面。相应的治疗措施应围绕三方面：（1）阻断宿主对异源组织抗原的敏感性；（2）诱导免疫耐受，使淋巴不激活或活性减低；（3）降低或阻断免疫效应因素对角膜植片的破坏。随着对角膜移植排斥反应机制的深入研究，将有新的治疗措施出现，特别是诱导免疫耐受防治角膜移植排斥反应的研究前景乐观。     

TGF-β与角膜移植诱导的免疫耐受

角膜移植术后免疫排斥反应是角膜移植失败的主要原因.如何诱导免疫耐受是角膜移植成功的关键.许多研究表明,TGF(转化生长因子)-β不仅与角膜移植免疫耐受有密切关系,而且在其它器官移植免疫耐受中也发挥重要作用.本文就TGF-β的生物学特性及其角膜移植中TGF-β的作用作一综述.     

角膜移植与B7分子

随着角膜移植手术技巧的改进,移植成功率明显提高,移植术后的免疫排斥反应越来越成为移植失败的主要原因。角膜移植免疫排斥反应是一个复杂的反应过程,受多种因素的调节。致敏T淋巴细胞在角膜移植排斥反应中起着重要的作用,是角膜排斥过程中的主要效应细胞。而T淋巴细胞的激活需要两个信号刺激,即除了通过APC递呈MHC处理过的抗原给抗原特异性T细胞提供第1信号外,还需协同刺激分子作为辅助信号的协同作用,才能使T细胞产生正常的免疫应答。如果缺少协同刺激分子的第2信号,将会导致调节性T细胞的无反应性或特异性免疫耐受。随着研究的深入,协同刺激信号已逐渐成为角膜移植免疫学研究的热点领域。B7分子作为重要的协同刺激分子,在角膜移植免疫排斥反应的发生及其治疗中起着重要作用。     

重视调控眼免疫稳定的调节性T细胞

调节性T细胞是近年来免疫学研究的热点,由于其具有免疫抑制的特点,在多种免疫性疾病的发生发展中发挥免疫调节作用,在眼部的初步研究已发现其参与眼局部免疫微环境的稳定调节,并在角膜移植免疫排斥反应、葡萄膜炎、过敏性结膜炎、感染性眼病以及干眼等疾病中发挥调节作用,有望为免疫性眼病的治疗提供新的手段.

Abstract：

T regulatory cells (Tregs) have been recognized as the hotspot in recent immunology research. Because of the capability of immune suppression, they play an important role in regulating many immune associated diseases. It has been reported that they are involved in stabilizing local immune microenvironment of the eye and regulating many eye diseases such as corneal transplantation immune rejection, uveitis, allergic conjunctivitis, infectious keratitis and dry eye. Treatment with Tregs may provide novel method for immune related eye diseases.     

New thoughts on the immunology of corneal transplantation

Significant advances derived from rodent models of penetrating keratoplasty have transformed our understanding of the pathogenesis of rejection of orthotopic corneal transplants. The high rate of success of corneal allografts placed in low-risk eyes without cover of immunosuppression arises from immune privilege of the cornea graft itself, and of the anterior chamber where it forms the anterior wall. Immune privilege owes its existence in penetrating keratoplasty to an absence of blood and lymph vessels in the graft and its bed, the absence of MHC class II(+) antigen presenting cells in the graft, reduced expression of MHC-encoded alloantigens on graft cells, constitutive expression of T cell-deleting CD95 ligand on corneal graft endothelium, the existence of an immunosuppressive local microenvironment (aqueous humor), and the capacity of the graft to induce anterior chamber associated immune deviation (ACAID). The results of recent experiments provide answers to pertinent questions regarding cornea graft failure: How does the cornea as a graft suppress inflammation and angiogenesis locally? How does the graft promote ACAID to the alloantigens it expresses? and How do corneal cells reduce their vulnerability as targets of effector T cells? The answers offer the possibilities of novel strategies for preventing immune-based corneal allograft failure.     

Corneal allograft rejection: risk factors, diagnosis, prevention, and treatment

Recent advances in corneal graft technology, including donor tissue retrieval, storage and surgical techniques, have greatly improved the clinical outcome of corneal grafts. Despite these advances, immune mediated corneal graft rejection remains the single most important cause of corneal graft failure. Several host factors have been identified as conferring a "high risk" status to the host. These include: more than two quadrant vascularisation, with associated lymphatics, which augment the afferent and efferent arc of the immune response; herpes simplex keratitis; uveitis; silicone oil keratopathy; previous failed (rejected) grafts; "hot eyes"; young recipient age; and multiple surgical procedures at the time of grafting. Large grafts, by virtue of being closer to the host limbus, with its complement of vessels and antigen-presenting Langerhans cells, also are more susceptible to rejection. The diagnosis of graft rejection is entirely clinical and in its early stages the clinical signs could be subtle. Graft rejection is largely mediated by the major histocompatibility antigens, minor antigens and perhaps blood group ABO antigens and some cornea-specific antigens. Just as rejection is mediated by active immune mediated events, the lack of rejection (tolerance) is also sustained by active immune regulatory mechanisms. The anterior chamber associated immune deviation (ACAID) and probably, conjunctiva associated lymphoid tissue (CALT) induced mucosal tolerance, besides others, play an important role. Although graft rejection can lead to graft failure, most rejections can be readily controlled if appropriate management is commenced at the proper time. Topical steroids are the mainstay of graft rejection management. In the high-risk situations however, systemic steroids, and other immunosuppressive drugs such as cyclosporin and tacrolimus (FK506) are of proven benefit, both for treatment and prevention of rejection.     

Corneal graft rejection

Penetrating keratoplasty is the most widely practiced type of transplantation in humans. Irreversible immune rejection of the transplanted cornea is the major cause of human allograft failure in the intermediate and late postoperative period. This immunological process causes reversible or irreversible damage to the grafted cornea in several cases despite the use of intensive immunosuppressive therapy. Corneal graft rejection comprises a sequence of complex immune responses that involves the recognition of the foreign histocompatibility antigens of the corneal graft by the host's immune system, leading to the initiation of the immune response cascade. An efferent immune response is mounted by the host immune system against these foreign antigens culminating in rejection and graft decompensation in irreversible cases. A variety of donor- and host-related risk factors contribute to the corneal rejection episode. Epithelial rejection, chronic stromal rejection, hyperacute rejection, and endothelial rejection constitute the several different types of corneal graft rejection that might occur in isolation or in conjunction. Corneal graft failure subsequent to graft rejection remains an important cause of blindness and hence the need for developing new strategies for suppressing graft rejection is colossal. New systemic pharmacological interventions recommended in corneal transplantation need further evaluation and detailed guidelines. Two factors, prevention and management, are of significant importance among all aspects of immunological graft rejection. Preventive aspects begin with the recipient selection, spread through donor antigenic activity, and end with meticulous surgery. Prevention of corneal graft rejection lies with reduction of the donor antigenic tissue load, minimizing host and donor incompatibility by tissue matching and suppressing the host immune response. Management of corneal graft rejection consists of early detection and aggressive therapy with corticosteroids. Corticosteroid therapy, both topical and systemic, is the mainstay of management. Addition of immunosuppressive to the treatment regimen helps in quick and long term recovery. Knowledge of the immunopathogenesis of graft rejection may allow a better understanding of the immunological process thus helping in its prevention, early detection and management.     

Rejection of corneal allografts

Corneal graft rejection is the major cause of penetrating keratoplasty failure. It is a complex immunological process that involves recognition of alloantigens from the corneal graft by the host's immune system, leading to an efferent immune response against the graft. Each layer of the cornea can undergo rejection, endothelial rejection being the most severe form. In some cases, rejection will lead to corneal graft failure. Many donor- and host-related risk factors contribute to corneal graft rejection. Corticosteroid therapy, topical or systemic, is the gold-standard in the preventive and curative treatment of rejection. Other immunosuppressive agents are promising but require further evaluation. Early detection of rejection is essential to establish an aggressive treatment and reduce the risk of graft failure. Prevention of rejection is also based on tissue matching between donor and recipient. In high-risk patients, ABO compatibility decreases the risk of rejection. HLA compatibility could positively influence corneal graft survival in some cases.