Immunobiology and immunopharmacology of organ allograft rejection

Much has been learned regarding immunobiological mechanisms responsible for the rejection of histoincompatible allografts. There has also been considerable progress in our understanding of mechanisms responsible for tolerance. The new knowledge gained regarding graft destructive alloimmunity process and the mechanisms of action of immunosuppressants have resulted in solid organ graft survival rates that are in excess of 80% at one year posttransplantation. The principles of tolerance mechanisms are yet to be successfully applied in the clinic. In this review, molecular and cellular mechanisms of action of clinically useful immunosuppressive drugs are reviewed from the perspective of regulation of the anti-allograft repertory.     

Monocytes in the rat: Phenotype and function during acute allograft rejection

Summary: Cells of the monocyte/macrophage system originate from the bone marrow, reach the organs via the blood, immigrate through post-capillary venules and further differentiate into organ-specific tissue macrophages. In rats and other species, activated monocytes/macrophages aggravate autoimmune reactions, rejection of non-vascularized allografts and chronic allograft rejection. It is very likely that they also contribute to acute allograft destruction. So far it has been impossible to distinguish the function of monocytes from that of macrophages, because cell phenotypes and their alterations upon activation are ill-defined. We have thus begun to characterize the ex vivo phenotype and function of rat monocytes in the normal state and during renal allograft rejection. Monocytes are recovered from both the central and the marginal blood pool by perfusing either the recipient's circulation or the allograft vasculature. Rat monocytes have a unique surface phenotype. During allograft rejection or after infusion of interferon-γ they up-regulate class II MHC molecules, CD161 (NKR-P1A), CD62L and CD8, while CD4 and CD43 are down-modulated. Activated perfusate monocytes exert increased in vitro cytotoxicity against tumour targets, which differs from that of NK cells. We speculate that activated monocytes contribute to kidney allograft destruction by directly damaging endothelial cells or by promoting intravascular coagulation.     

Apoptosis in the human liver during allograft rejection and end-stage liver disease

The contribution of apoptosis (programmed cell death) to cellular damage in human liver disease is unknown. Using the in situ DNA end labelling method (ISEL), evidence was sought of programmed cell death (PCD) in liver tissue from patients with various liver diseases. In particular, the study aimed to determine whether PCD is involved in either the loss of interlobular bile ducts (vanishing bile duct syndrome—VBDS) or the perivenular hepatocyte drop-out, both of which are characteristic of irreversible graft rejection. Large numbers of apoptotic hepatocytes were found in pervenular areas in tissues taken from patients with chronic graft rejection. Significant hepatocyte apoptosis, was not seen in long-term stable allografts, primary biliary cirrhosis, cholestasis, paracetamol-induced fulminant hepatic failure, or fulminant hepatic failure of indeterminate origin (non-A, non-B, non-C hepatitis). Bile ducts rarely stained positively, but mononuclear cells present in the post-transplant tissues were frequently positive, showing nuclear or cytoplasmic staining. The presence of cytoplasmic staining suggested that some mononuclear cells had ingested apoptotic DNA from other cellular sources. PCD may thus contribute to the perivenular hepatocyte loss in chronic rejection. The absence of ductular epithelial cell staining suggests that PCD is not involved significantly in the bile duct loss of VBDS. Furthermore, apoptosis of monomuclear cells implies that PCD may be involved in regulating the inflammatory cell infiltration of graft rejection.     

Immunohistochemical identification of renal lysozyme during allograft rejection in man

An immunoperoxidase staining method was used to identify lysozyme in biopsy or transplantectomy specimens of human renal allografts during reversible and irreversible rejection of the grafts. Proximal tubules in apparently functioning nephrons showed lysozyme staining. In irreversibly rejected grafts, infiltrating mononuclear phagocytes in and near peritubular and glomerular capillaries also stained intensely for lysozyme. In acute necrotizing arteritis, lysozyme-positive cells (mononuclear phagocytes) infiltrated the blood vessel wall. The presence of infiltrating lysozyme-positive cells in the transplant was consistent with poor graft survival. The variation in lysozyme staining of proximal tubular cells apparently was a reflection of the differences in the reabsorption capacity of the tubular cells, attributable to the tubular dysfunction of renal allografts. The infiltrating lysozyme-positive cells probably contribute to the increased urinary excretion of lysozyme during acute rejection.     

TLRs与同种异型移植排斥

Toll样受体(Toll-like receptors,TLRs)是一类在机体识别、清除入侵病原微生物免疫过程中起重要作用的受体.除此之外,新近的研究表明TLRs还参与同种异型移植过程中的排斥反应.本文就TLRs的这一进展进行了综述,内容包括TLRs的结构、功能和信号通路,TLRs与无菌性炎症,以及TLRs与皮肤、内脏移植排斥.     

Limiting dilution analysis of alloreactive T-cell status and distribution during allograft rejection

We have developed limiting dilution analysis techniques that discriminate between precursor T cells and T cells that have responded to prior contact with alloantigens. We used these techniques to monitor the behavior of functional T-lymphocyte subsets in sponge matrix allograft recipients. Thus, we were able to measure at the graft site and/or in the peripheral blood (1) all donor-reactive cytotoxic T lymphocytes, (2) the subset of donor-reactive cytotoxic T lymphocytes that has responded to graft alloantigens in vivo, (3) all donor-reactive helper T lymphocytes, and (4) the subset of donor-reactive helper T lymphocytes that has responded to graft alloantigens in vivo. In this communication, we describe some aspects of the in vivo T-cell response to allograft implantation that were revealed by this study.     

Immunology of renal allograft rejection

Allograft rejection remains the critical problem of renal transplantation. The immunologic mechanisms that underlie renal allograft rejection are heterogeneous and involve the humoral and cellular limbs of the immune response. Antibody-mediated hyperacute rejection is now rare owing to improved prospective cross-matching. Chronic rejection, characterized by intrarenal arterial fibrosis, is still poorly understood. Knowledge of the afferent and efferent processes involved in rejection has led to effective therapeutic and experimental strategies that employ monoclonal antibodies and other pharmacologic agents to reverse, or prevent, acute allograft rejection. In addition, allospecific tolerance has been achieved experimentally and clinically in a variety of manners. Preliminary studies on the mechanism of allograft tolerance induced by donor-specific blood transfusions before transplantation suggest a role for an immunoregulatory cell population that specifically down regulates cytotoxic lymphocyte responses to donor antigens in some recipients. A role for noninherited maternal antigens and anti-idiotypic antibodies in down regulating immune responses to allografts have also been reported by several studies. An improved understanding of allograft rejection and tolerance may identify approaches to prolong allograft survival without the morbidity and mortality associated with present-day immunosuppression.     

Induction of T-cell response to cryptic MHC determinants during allograft rejection

The presentation of MHC peptides by recipient and donor antigen presenting cells is an essential element in allorecognition and allograft rejection. MHC proteins contains two sets of determinants: the dominant determinants that are efficiently processed and presented to T cells, and the cryptic determinants that are not presented sufficiently enough to induce T-cell responses in vivo. In transplanted mice, initial T-cell response to MHC peptides is consistently limited to a single or a few immunodominant determinants on donor MHC molecule. However, in this article we show that under appropriate circumstances the hierarchy of determinants on MHC molecules can be disrupted. First, we observed that γIFN can trigger de novo presentation of cryptic self-MHC peptides by spleen cells. Moreover, we showed that allotransplantation is associated with induction of T-cell responses to formerly cryptic determinants on both syngeneic and allogeneic MHC molecules. Our results suggest that cross-reactivity and inflammation are responsible for the initiation of these auto- and alloimmune responses after transplantation.     

大鼠肝移植排斥反应期一氧化氮合酶的动力学变化

目的 探讨供体特异性输血（DST）预处理后大鼠同种肝移植物一氧化氮合酶（NOS）的动力学变化。方法 观察同基因肝移植（Ⅰ组），同种肝移植（Ⅱ组），DST预处理的同种肝移植（Ⅲ组）术后NOS的表型及亚硝酸盐/硝酸盐，细胞因子的动态变化。结果 Ⅱ组血中亚硝酸盐/硝酸盐，INF-α，TNF-α浓度明显增高，免疫组化显示，Ⅱ组移植物中macNOS^ 及ED1^ ,ED2^ 细胞数明显增多，Northern blot分析，Ⅲ组移植物中IL-10和TGF-BmRNA呈高水平表达；Ⅱ组移植物的iNOS和IL-12mRNA水平明显高于其他组。结论 DST预处理的移植物处于免疫无应答状态，NOS被抑制与TH2及TH3类细胞因子高表达有关。     

Cytokines in immunity and allograft rejection

Cytokines are highly potent regulatory molecules that are secreted by a variety of cells into the local microenvironment. These chemical messengers participate in the activation and regulation of immune function by a variety of mechanisms, including the stimulation and inhibition of cellular proliferation and differentiation. Cytokines also may have chemotactic activity. Six cytokine receptor families have been described, on the basis of their conserved structural features. Many cytokines are classified as proinflammatory cytokines, which promote both innate and adaptive immune responses. Solid-organ transplantation presents several unique challenges to the immune system, and cytokines play an important role in both antigen-dependent and antigen-independent immune recognition. The selective blockade of cytokine-mediated immune responses is a cornerstone of modern immunosuppressive therapy.     

IL-4 expression delays eosinophil-independent vasculopathy and fibrosis during allograft rejection in the mouse

Transplant vasculopathy in the mouse is thought to be dependent on IL-4 and mediated by IL-5 and eosinophils, whereas in the rat and human systems, IL-4 is associated with the absence of transplant vasculopathy and down-regulation of a Th1-type response. In this study we tested the possibility that the apparent difference in the role of IL-4 in transplant vasculopathy is related to protocol differences rather than to the species being studied. Using a protocol that closely resembles that used in rat and human studies, we developed a model of transplant vasculopathy in the mouse that is associated with Th1-type cytokines and independent of IL-5 and eosinophil infiltration. In this model IL-4 promotes a significant delay in vasculopathy in the graft (P = 0.04) and a decrease in the incidence of allograft rejection (P = 0.02). The data suggest that the role of IL-4 in transplant vasculopathy can be controlled by the protocol used to treat the transplant recipient.     

Suppressive dendritic cells as a tool for controlling allograft rejection in organ transplantation: promises and difficulties

The most important antigen-presenting cells are dendritic cells (DCs), which play a central role in the initiation of immunity and tolerance. Their immunoregulatory properties offer the potential of donor-specific control of graft rejection after organ transplantation. It has not been clarified which DC subpopulations mediate tolerance, and the use of natural DCs for therapeutic applications is therefore problematic. Suppressive DCs can be generated in vitro by treating the cells with biologic, pharmacologic, or genetic agents. Here we discuss approaches for generating inhibitory DCs and present DC-based animal models for control of allograft rejection. A prerequisite of suppressive DCs for therapeutic application in clinical transplantation is a reproducible method for their generation as well as the induction of irreversible suppressive function. Based on lessons learned from the use of DCs as tools in clinical vaccine trials in cancer, we discuss the unknown aspects and risks of DC therapy in transplantation.     

Cellular mechanisms of allograft rejection.

It is generally agreed that a multiplicity of mechanisms are involved in the rejection of various grafts across different histocompatibility barriers. Recent publications have concentrated less on the characterization of the cells involved in the rejection process and more on their initial activation and their infiltration into the graft.     

Role of IFN-gamma in allograft rejection

Interferon (IFN)-gamma is a cytokine produced mostly by activated T cells and NK cells that has complex effects on immune and nonimmune cells. IFN-gamma plays important roles in inflammation, usually in synergy with other cytokines, such as IL-1beta and TNF-alpha. The uniqueness of IFN-gamma lies in its ability to induce major histocompatibility complex (MHC) expression in many tissues, making it particularly relevant to transplantation. The results of graft rejection in the absence of IFN-gamma show that IFN-gamma modulates but is not essential for the allogeneic responses, suppressing generation of CTL. In vivo IFN-gamma has a protective role early in the response to vascularized organ allografts: transplants in mice have a tendency to develop necrosis when IFN-gamma is not available, apparently by failure of the microcirculation. The lack of IFN-gamma greatly reduces the induction of MHC in organ allografts, and it is possible that this is indirectly related to the protective effect of IFN-gamma. Nevertheless IFN-gamma also promotes graft vessel disease later in the course ofthe transplant. Thus IFN-gamma has diverse and potentially contradictory effects on organ allograft survival, acting both on the immune system and on the graft itself, the net effect depending on the graft type and the time post-transplant.     

The pathology of heart allograft rejection

The pathologist plays an important role in the care of cardiac transplant recipients. Day-to-day management of immunosuppression is largely dependent on the diagnosis and grading of acute rejection. While noninvasive methods have been tried experimentally, the endomyocardial biopsy remains the gold standard in monitoring the rejection status of the heart allograft. The diagnosis of rejection, however, is complicated by a variety of other histologic findings, which may be procedural or processing related, due to sampling, or specifically related to transplantation. Failed allografts, whether from autopsy or explantation, provide the opportunity to study short- and long-term changes in the transplanted heart. Allograft arteriopathy, or graft atherosclerosis, is the major limiting factor in long-term recipient survival. While the morphological features of graft arteriopathy have been well described, the mechanism and factors contributing to its development remain unclear.     

Variability of allograft rejection processes in

Cellular aspects of histocompatibility in allografts of the sponge have been studied. Three types of reactions were observed : 1) graft acceptance; 2) non-fusion, that is total absence of adherence between the sponges; 3) separative graft rejection, with strong adherence and fusion, followed by secretion of a dense collagen barrier between the sponges. These results clearly point out the variability of immune reactions in .     

Mechanisms of allograft rejection in the rat brain

Embryonic rat hippocampal primordia from class I and class II major histoincompatible donors were transplanted into the hippocampus of adult rat hosts. The allografts were rejected by a specific host immune response, which was identified by reference to events at a histocompatible hippocampal primordial graft (syngeneic to the host) of similar embryonic age placed simultaneously in the contralateral hippocampus of the same hosts. The present combined light immunohistochemical and electron microscopic study was undertaken to elucidate the mechanism of induction of the immune response by a graft of a tissue which does not constitutively express major histocompatibility antigens, to identify which cells are involved, and how they enter the brain and attack the graft, and to look for possible sources of variability in the outcome of such an attack. Our main findings are (1) that host and graft microglia play a prominent role from the earliest stages, and throughout the evolution of the histological changes, (2) that the later entry of host dendritic cells, lymphocytes, and lymphoblasts (with associated mitoses) into the perivascular cuffs of the graft vasculature ensures that the local immune response becomes self-propagating, (3) that the allografted neurons are killed by host cytotoxic lymphocytes only after a previous encirclement by host macrophage-derived microglial cells, and (4) that the observed variability (especially within different regions of a single allograft) is associated not with failure of immune induction, but with local failure of the graft tissues to express allotypic major histocompatibility antigens. Our observations confirm that once the host immune system has been primed, local factors leading to the induction of transplant major histocompatibility complex antigens make histoincompatible intracerebral transplants of embryonic into adult brain tissue vulnerable to vigorous and effective immune attack. The histological picture of the immune response observed in our intracerebral allografts resembles that described in intraventricular allografts of embryonic brain, in allografts of other organs and tissues such as skin, kidney, and heart, and also that seen in the response to brain autoantigens in multiple sclerosis and experimental allergic encephalomyelitis. However, the involvement of a special cell type, the perivascular microglial cell, in the early stages of immune induction in brain raises the possibility of designing future therapeutic approaches which might selectively block this step in conditions such as multiple sclerosis.     

冷冻保存异体软骨移植免疫排斥反应的研究状况

背景：目前多采用冷冻保存方法来降低异体软骨移植免疫排斥反应,但有关异体软骨的取材、冷冻保存方法、冷冻保存条件仍然需要深入的研究探讨。 目的：对于冷冻保存异体软骨移植后免疫排斥反应机制的研究进行回顾分析,并对不同保存方法的特点进行比较分析。 方法：由第一作者检索1990/2008 PubMed数据及万方数据库有关异体软骨移植后免疫排斥反应及冷冻保存方法对软骨移植影响等方面的相关文献。 结果与结论：异体软骨组织移植治疗关节软骨缺损治疗效果明显优于其他治疗方法。冷冻保存异体关节软骨保持了软骨组织的性状和生物学活性,而且可择期完成关节重建,并且有充裕的时间完成多项指标检测,防止供体携带细菌病毒和传染性疾病的传播,并且降低了软骨组织的抗原性,具有较大的临床应用价值。但冷冻保存的各个环节,如:低温保护剂的应用、降温和复温速度等方面还存在诸多问题,软骨移植后仍然会出现软骨吸收、退变等现象。随着冷冻生物学的不断进步,冷冻损伤机制的不断揭示,这些问题终将会解决,软骨组织冷冻保存技术会得到进一步的完善。