The role of cytokines, CTLA-4 and costimulation in transplant tolerance and rejection.

T cell costimulation and cytokine production play an important role in generating the alloimmune responses that lead to allograft rejection. Recent data, however, provide evidence that costimulatory molecules, such as B7-1 and B7-2, and T cell activating cytokines, such as IFN-gamma and IL-2, also trigger negative feedback mechanisms in T lymphocytes which limit alloimmune responses. These feedback mechanisms are essential for the induction of long-term allograft acceptance and, in certain situations, transplantation tolerance.     

细胞因子在心脏移植排斥反应中的作用研究进展

器官移植技术的发展突飞猛进,但宿主移植排斥反应是限制器官移植的一大障碍,其本质上是一种针对异型移植抗原的特异性免疫应答,已成为目前研究的热点.移植排斥反应过程机理复杂,涉及众多细胞因子的参与,白细胞介素(IL)-2、IL-4、干扰素(INF)-γ、IL-10等均在其过程中发挥重要作用.了解细胞因子与移植排斥反应的关系很有意义.     

Innate immunity in transplant tolerance and rejection

Historically, research on transplant rejection and tolerance has focused on cells of the adaptive immune system, especially T cells. Anti-graft effector T cells are necessary and sufficient for the rejection of most allografts, while regulatory T cells, either arising naturally or as a result of a specific treatment regimen, are crucial to long-term graft tolerance. Although the role of T cells in transplant rejection and tolerance is well-established, the role that the innate immune system plays in these processes is only recently being appreciated. Cells of the innate immune system, such as dendritic cells (DCs) and natural killer cells, can become activated by microbial products or endogenous pro-inflammatory ligands released during the mechanical and ischemia-reperfusion injury associated with transplantation surgery, promoting the initiation of T-cell responses against the graft. In addition, innate immune cells are required for acute and chronic rejection in certain animal transplant models and by extension perhaps in clinical transplantation. However, innate immune cells are also implicated in the establishment of transplant tolerance through mechanisms including elimination or inhibition of activated host effector T cells and killing of donor DCs. A deeper understanding of the functions of the innate immune system during transplantation may lead to more successful tolerance strategies.     

A role for eosinophils in transplant rejection

Eosinophils release inflammatory mediators and cationic proteins that are instrumental in the pathogenesis of allergic diseases such as bronchial asthma. Here, we review experimental observations indicating that eosinophils are also involved in the rejection of allografts. We propose that their role as effectors of transplant damage becomes crucial when classical pathways of rejection are inhibited and T helper 2 (Th2) cells dominate the alloimmune response.     

Loss of tolerance to self after transplant

Organ transplantation is the widely accepted treatment for end-stage organ failure. Since the first successful kidney transplant from an identical twin donor in 1954, researchers have been studying the effects of the immune system on transplantation outcomes. Although the surgery is technically successful, the majority of grafts from genetically disparate donors are rejected due to a number of factors that stimulate recipient immune responses, ultimately resulting in graft loss despite the chronic use of immunosuppressive (IS) drugs. Unfortunately, while short-term success has greatly improved with the development of novel IS drugs, the long-term graft survival of solid organs has not improved significantly over the last few decades. The problem of late graft loss is mainly attributed to development of chronic rejection. Therefore, understanding all of the immune mechanisms involved in transplant rejection is important to prevent graft dysfunction, and eventually, graft loss. In this review, we will give an overview of allograft rejection, the progression from acute to chronic rejection, and in addition, the recent discovery of a critical role for loss of self-tolerance and development of IL-17-dependent autoimmunity in chronic rejection.     

The coin toss of B cells in rejection and tolerance: danger versus defense

Transplantation is the preferred therapy for the end stage organ disease. Since the introduction of organ transplantation into medical practice in 1953 [1], significant progress has been achieved in patient and graft survival rates due to improvements in surgical techniques and more targeted immunosuppressive medications [2]. Nevertheless, current gaps in the management of the transplant patient stem from an incomplete understanding about the heterogeneity of the injury response in organ transplantation, at different rates and different time points after transplantation, as well as our inability to monitor the immunologic threshold of risk versus safety in each individual patient. Recent advances in immunology/transplantation biology with the advent of high throughput "omic" assays such as gene microarrays, proteomics, metabolomics, antibiomics, chemical genomics and functional imaging with nanoparticles, offers us unique methods to interrogate and decipher the variability and unpredictability of the immune response in organ transplantation (Fig. 1) [3]. Recent studies using these applications [3-8] have uncovered a critical and pivotal role for specific B cell lineages in organ injury [9] and organ acceptance [10,11] (Fig. 2). The availability of specific therapies against some of these defined B cell populations provides for an exciting new field of B cell targeted manipulation that can both abrogate the allospecific injury response, as well as promote allospecific graft accommodation and health.     

IL-17及IL-22在大鼠肝移植排斥反应中的表达及意义

目的探讨IL-17及IL-22在大鼠肝移植排斥模型及耐受模型中的表达差异及意义。方法建立大鼠原位肝移植动物模型,分为排斥组和耐受组(各15只),取术后1、3、5、7 d大鼠血浆及肝组织标本,应用ELISA检测其血浆IL-17浓度,应用免疫组化染色、Western blot及荧光定量PCR检测其肝组织内IL-17及IL-22的细胞、蛋白及mRNA的表达情况。结果大鼠原位肝移植模型建立成功,结果显示排斥组IL-17血浆浓度显著高于耐受组;在肝组织中,IL-17及IL-22的淋巴细胞阳性率、蛋白表达水平及mRNA表达水平排斥组显著高于耐受组,且排斥组肝组织中STAT3 mRNA表达水平升高。结论 IL-17及IL-22参与肝移植术后急性排斥反应的发生过程,并推测其通过激活STAT3通路发挥效应。     

The dichotomous role of IL-2: tolerance versus immunity

Interleukin-2 (IL-2) is a well-known T-cell growth factor, which is traditionally implicated in the agonistic stimulation of immune responses. Recent work, however, has uncovered an unexpected function of this cytokine. In particular, IL-2 appears crucial to maintaining peripheral tolerance by supporting the survival and function of CD25+ CD4+ regulatory T cells. A recent study examining the role of IL-2 in the peripheral generation of regulatory T cells from apparently na?ve T cells has gone some way to reconciling the seemingly opposing functions of this cytokine.     

A role for Th2 cytokines in the suppression of CD8+ T cell-mediated graft rejection

A major histocompatibility complex (MHC) class I-specific T cell receptor (TCR)-transgenic mouse was used to study classical-type transplantation tolerance in the adult. Engraftment of MHC class I-incompatible bone marrow and tolerance to donor-type skin grafts were obtained using dimethylmyeleran (DMM) as a myeloablative agent and a non-depleting anti-CD8 monoclonal antibody (mAb) as the sole immunosuppressant. Surprisingly, bone marrow engraftment was facilitated by host CD4⁺ T cells, a subset normally considered unable to reject class I MHC-incompatible grafts. A combination of mAb to interleukins (IL)?4 and ?10 antagonized the “permissive” effects of host CD4⁺ T cells, indicating a possible role for Th2-type immunoregulation that can act on CD8⁺ T cells in this form of transplantation tolerance. The fate of graft-reactive T cells was monitored using anti-clonotypic antibodies. It was observed that bone marrow engraftment then led to peripheral deletion of mAb-blockaded, clonotype⁺ CD8⁺ T cells.     

Procoagulants in fetus rejection: the role of the OX-2 (CD200) tolerance signal.

The spontaneous loss of normal karyotype embryos may be initiated or prevented by the maternal immune system. In mice, loss between the time of implantation (day 4.5) and formation of a vascularized placenta (day 9.5) when the embryo is too large to survive by diffusion alone, is analogous to occult pregnancy failure in humans. They are called occult because usually the woman does not know she is pregnant. From studies in mice, these early losses have a different mechanism than abortion of a vascularized placenta (analogous to clinically evident human spontaneous miscarriage). The latter depend on the activation of the novel prothrombinase fgl2 on the fetal trophoblast and in maternal decidua by the T helper-1 (Th1) type cytokines TNF- alpha+gamma -interferon that arise from NK cells and NK gammadelta T cells; conversion of prothrombin to thrombin which in turn generates IL8 that activates polymorphonuclear leukocytes leads to embryonic death. These inflammatory processes are counteracted by Th2/3-type cytokines that arise in part from V gamma 1 delta 6 T cells reacting to, as yet, unidentified trophoblast antigens in the presence of the 'tolerance signaling molecule' OX-2. By contrast, peri-implantation losses (between implantation and formation of a vascularized placenta, analogous to occult losses in humans) appear to be dependent upon perforin(+)cells, complement activation, and products of alphabeta T and NK alphabeta T cells, but not on TNF- alpha or procoagulant activation. Similarities and differences between findings in the mouse and human, and the potential evolutionary significance of mechanisms affecting reproductive success are reviewed.     

A neural network approach to the biopsy diagnosis of early acute renal transplant rejection

AIMS: To develop and test a neural network to assist in the histological diagnosis of early acute renal allograft rejection. METHODS AND RESULTS: We used three sets of biopsies to train and test the network: 100 'routine' biopsies from Leicester; 21 selected difficult biopsies which had already been evaluated by most of the renal transplant pathologists in the UK, in a study of the Banff classification of allograft pathology and 25 cases which had been classified as 'borderline' according to the Banff classification in a review of transplant biopsies from Oxford. The correct diagnosis for each biopsy was defined by careful retrospective clinical review. Biopsies where this review did not provide a clear diagnosis were excluded. Each biopsy was graded for 12 histological features and the data was entered into a simple single layer perception network, designed using the MATLAB neural network toolbox. Results were compared with logistic regression using the same data, and with 'conventional' histological diagnosis. If the network was trained only with the 100 'routine' cases, its performance with either of the other sets was poor. However, if either of the 'difficult' sets was added to the training group, testing with the other 'difficult' group improved dramatically; 19 of the 21 'Banff' study cases were diagnosed correctly. This was achieved using observations made by a trainee pathologist. The result is better than was achieved by any of the many experienced pathologists who had previously seen these biopsies (maximum 18/21 correct), and is considerably better than that achieved by using logistic regression with the same data. CONCLUSION: A neural network can provide a considerable improvement in the diagnosis of early acute allograft rejection, though further development work will be needed before this becomes a routine diagnostic tool. The selection of cases used to train the network is crucial to the quality of its performance. There is scope to improve the system further by incorporating clinical information. Other related areas where this approach is likely to be of value are discussed.     

Regulatory role of Th-2 cytokines, IL-10 and IL-4, in cardiac allograft rejection

The host response to alloantigen results in T- and B-cell activation, upregulation of Class II MHC antigens, and cytokine production by Th-1 cells, resulting in generation of IL-2 and IFN gamma. Th-2 cell responses produce IL-4 and IL-10 which may shift the immune response from the Th-1 pathway to Th-2 responses, favoring Ig production. This could imply that Th-2-related cytokines protect allografts. In the following studies, employing cardiac heterotopic allografts in rats (Brown Norway into Lewis), we investigated regulatory roles of Th-2-related cytokines IL-4 and IL-10. Two strategies were used in animals receiving allografts: antibody-induced blocking of endogenous IL-4 or IL-10 and exogenous administration of either interleukin. Antibody to IL-4 failed to alter the rejection time, whereas anti-IL-10 greatly accelerated the rejection process. Northern blot analysis of RNA from allografted hearts revealed mRNA for both IL-4 and IL-10, while immunostaining showed strong staining for IL-10 and very weak staining for IL-4. Exogenous administration of either IL-4 or 10 caused prolongation of allograft rejection times. These findings suggest that in rat cardiac allografts intrinsic IL-10 functions to attenuate the rejection process.     

Emerging roles of endothelial cells in transplant rejection

Recent studies of endothelial cell biology have provided numerous original findings relevant to transplantation. The molecular mechanisms utilized by endothelial cells to regulate cell entry into the parenchyma are becoming more clearly defined. Emerging results have additionally elucidated how endothelial cells interact with and respond to T cells and antibodies specific for transplant antigens. Progress made in deciphering the cellular and molecular basis of endothelial cell-mediated inflammation has the potential to help with the identification of novel therapeutic targets for prolonging graft survival.