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Immunobiology of graft rejection. The surgical transplantation of a graft from a non-identical donor of the same species elicits a response from the recipient's immune system. Termed an allogeneic response, this is a result of polymorphic proteins, particularly the MHC, that are different in the graft than those found in the recipient. The recipient immune system recognizes these differences as foreign which ultimately leads to the rejection of the graft. The specific immune mechanisms involved in the rejection of the graft can vary based on many factors, such as the genetic disparity between the donor and recipient and the organ transplanted.
Hyperacute rejection occurs immediately upon the perfusion of recipient's blood into the donor organ and is the result of preformed cytotoxic antibodies that target the vascular endothelium of the graft (Kissmeyer-Nielsen et al 1966). It is more commonly seen in xeno-transplantation but can also be rarely seen in allogeneic transplantation. Upon binding to donor antigens in the vasculature, these antibodies are capable of activating complement through the classical pathway. As a result, C1q, C2, and C4 components of the classical pathway are nearly always found in the endothelium of grafts with hyperacute rejection. Complement activation results in endothelial cell injury through endothelial dysfunction, retraction and sloughing. This promotes interstitial hemorrhage, edema, and neutrophil infiltration. Moreover, complement promotes platelet adhesion and activation, the amplification of the coagulation cascade, and the loss of thromboregulatory function in the vessel, which together leads to accelerated necrosis of graft tissue through fibrin deposition and the occlusion of graft vessels through thrombosis (Pierson IIII RN 2009).
The preformed antibodies, which are responsible for the initiation of the events that lead to hyperacute rejection, arise as a result of the prior sensitization of the host towards donor graft antigens. These antibodies can be formed both in allogeneic transplants, where donor and recipient are from the same species with genetic differences, and xenografts where the graft is from a different species and greater genetic disparity exists between the donor and recipient. In allogeneic conditions, prior sensitization to donor Ags can occur as a result of previous blood transfusions, pregnancies, or previous organ transplantations (Kissmeyer-Nielsen et al 1966).
This leads to the development of plasma cells and memory B cells capable of producing anti-donor antibodies that recognize. In particular, the presence of immunoglobulin (Ig) G that recognize donor class I and class II MHC prior to transplantation correlates with an increased risk of developing hyperacute rejection (Cecka et al 2005). Xenografts carry a more profound risk of hyperacute rejection since the prevalence of preformed anti-graft antibodies is greater as a result of the larger genetic discordance between the graft and donor. One percent of the circulating antibodies found in healthy individuals are believed to react with xenoantigens. The antibodies are predominantly IgG, but IgA and IgM antibodies are also present (Schaapherder AF et al 1994). These antibodies primarily target carbohydrate epitopes that are specific to donor graft antigens not found in the recipient, with antibodies developed against α-galactosyl having particular importance in the hyperacute rejection of porcine grafts in humans (Cooper DK et al 1993). It is believed these anti-α-galactosyl antibodies develop in humans as a response to intestinal flora, as the bacteria in the gut may provide a continuous source of α-galactosyl antigenic stimulation. Ultimately, it is the prior exposure to graft antigens that leads to the development of preformed antibodies responsible for the hyperacute rejection of the transplanted organ. The current clinical standard is to determine the patient's sensitization towards different HLA alleles in a panel reactive antibody (PRA) test.
Acute vascular rejection (acute humoral rejection)
Antibodies that develop after organ transplantation are responsible for the development of acute vascular rejection (AVR). These antibodies primarily target donor HLA class I, but can also target ABO blood Ags if blood types are not matched, graft endothelial cell Ags, and other polymorphic proteins called minor histocompatibility Ags (mH) that are expressed on the extracellular components of the graft (Venetz and Pascual 2007). These antigens are bound by B cell Receptors, activating B cells which then differentiate into IgM antibody producing plasma cells. Alloantigen activated T-helper (TH)-2 then provide further signals to B cells that promote the processes of somatic hypermutation (SHM) and class switch recombination (CSR) that produces higher affinity IgG antibodies. These signals provided by TH2 cells occur through the similar interaction between TCR and Ag presentation on B cell MHC class II, co-stimulation such as through the interaction of T cell bound Cluster of Differentiation (CD)-40 ligand (CD40L) with B cell bound CD40, and cytokine production (Feucht HE 2005 and Blanchard et al 1994).
TH2 cells could alternatively provide help to B cells in the absence of a similar TCR: MHC interaction with B cells. This occurs if both the TH2 cell and B cell are in close proximity such as when both are activated by the same graft APC. While B cells engage graft antigen on this APC, T cells can provide co-simulation and cytokines for this B cell as the T cell recognizes the MHC on the graft APC. This pathway appears to aid in B cell activation and IgM secretion, but not in promoting conversion to IgG antibody production (Steele DJ et al 1996). Since T cell help is required for the efficient production of alloantibodies, acute vascular rejection is often seen together with acute cellular rejection. In addition to this process, xenografts can elicit an effective B cell response without the need for T cell help.
The precise mechanisms by which donor-specific antibodies cause AVR are poorly understood. C4d, complement activation by product, has been found to correlate with AVR in renal and cardiac grafts and is utilized as a diagnostic indicator of AVR in biopsies (Venetz et al 2007 and Sis B et al 2010).
This strongly suggests a role for complement activation in AVR similar to that in hyperacute rejection. The initiation of the complement cascade could then lead to the pathophysiological and histological features of AVR, including capillary endothelial cell swelling, interstitial edema, interstitial hemorrhage, neutrophil infiltration, and formation of thrombi (Takemoto SK et al 2004),which together cause the loss of graft function.
The incidence of AVR is relatively low and effective treatments for its management or prevention are available. Estimates attribute 5% to 25% of graft losses to AVR in patients that had a negative crossmatch to donor MHC prior to transplantation (Sis B and Halloran PF 2010). Removal of donor-specific antibodies after their development is the most common and effective treatment to manage AVR.
Acute cellular rejection
The central role of T-cells in acute cellular rejection (ACR) has long been appreciated. Specifically, CD8+ cytotoxic T lymphocytes (CTLs) are the major effector cells responsible for graft loss in ACR. These cells become activated through recognition of foreign MHC class I molecules on donor APCs, and subsequently target and lyses donor graft cells expressing the same foreign MHC class I ( Kubota N et al 2006). Activated CTLs are capable of inducing the apoptosis of donor cells through several mechanisms, including through Fas-Fas ligand (FasL) interactions and perforin and granzyme B secretion (Graziotto R et al 2006). CD4+ T cells can differentiate into either TH1 or TH2 phenotype after activation through cognate interactions with MHC class II on APCs. TH2 cells interact with B cells and participate in the AVR response, whereas TH1 cells releases interleukin (IL)-2 that promotes CTL survival and proliferation, and also release IFNγ that increases CTL activity by increasing MHC class I expression on cells (Rocha PN et al 2003).
By promoting a proinflammatory state through the release of IFNγ and tissue necrosis factor (TNF)-α, TH1 cells affect the permeability of vessels, can initiate platelet aggregation, and promote a delayed-type hypersensitivity (DTH) reaction that relies on monocytes and macrophages. In the DTH response, monocytes mature into macrophages that can directly destroy graft tissue through a number of proteolytic enzymes and reactive oxygen species. Indirectly, macrophages can also promote graft destruction by acting as APCs to further activate T cells. They also release a wide variety of proinflammatory cytokines and growth factors including platelet-activating factor and fibroblastic growth factor that can lead to thrombi formation (Magil AB 2009). Specifically, self-MHC restriction occurs through positive selection in the thymus, where only T cells with the ability to react to peptides presented on self-MHC progress through development. Despite this restriction, it is estimated that up to 10% of a recipient's T cell repertoire can recognize foreign MHC (Sherman and Chattopadhyay 1993). This response, which is larger than those elicited by nominal Ags, is thought to be achieved through several proposed molecular mechanisms.
Late graft loss and chronic graft rejection
Late graft loss can take months, years, and even a decade or longer to develop in some organs. Among the most common causes of late graft loss is chronic allograft dysfunction, which is defined as the progressive decline in graft function occurring 3 months after transplantation (Tantravahi et al 2007),and it is estimated that this accounts for 44% of all kidney losses after one year post-transplantation (Tantravahi et al 2007). Chronic allograft dysfunction is usually accompanied with some common pathophysiological and histological features, such as replacement fibrosis that is often found within the grafts' parenchyma. Vascular pathology is also common in chronic rejection. Proliferative vascular lesions, caused by intimal hyperplasia and neointimal proliferation of smooth muscle cells, can progressively cause vascular stenosis. Similarly, atherosclerotic lesions can occur within graft vessels contributing to graft vasculopathy (Gourishankar and Halloran 2002). There are currently no effective strategies available to circumvent or treat chronic allograft dysfunction. Immunosuppressive agents that are effective at preventing acute rejection episodes fail to prevent it, and can possibly exacerbate this by mediating further graft damage.
Pathways of allorecognition
Direct allorecognition of foreign MHC on donor APC by recipient T cells is involved and is sufficient for rejection. This was shown in studies utilizing mice that lacked MHC class II expression on a strain that also lacked T and B cell development due to recombination-activating gene (RAG) deficiency. Processing of graft MHC was not possible since host APCs lacked MHC class II, and T-lymphocytes must have therefore recognized graft MHC directly. There are two models that could explain this direct recognition. The high determinant density model proposes that different MHC have different amino acids exposed at the peptide binding grove while also presenting self or foreign antigens. Therefore, certain recipient TCR clones will recognize peptides, of either self or foreign origins, as foreign because of the different amino acids that remain exposed on the binding groove of allogeneic MHC. In this model, a greater number of T cells will be activated because all allogeneic MHC would present this amino acid difference, and this high density would allow for the robust stimulation of T cells that recognize it (Afzali et al 2008). Conversely, the multiple binary complex models propose that different MHCs display a different set of self-peptides. Many different recipient T cells may react with the new peptides presented by allogeneic MHC resulting in a robust reaction (Afzali et al 2008).
Both models of direct allorecognition rely on molecular mimicry, such that the allogeneic MHC with a self or allo-peptide resembles a self-MHC molecule presenting a foreign antigen (Felix NJ et al 2007). It is also likely that that both models contribute to robust direct allorecognition.
Indirect allorecognition also contributes to graft rejection, although it is unlikely to produce as quick or robust response as direct allorecognition. Indirect recognition occurs after foreign MHC peptides are processed and presented on host MHC on host APC. This process is similar to the recognition of nominal antigens, and results in CD4+ responses because of presentation on self-MHC class II (Afzali et al 2008). The need for antigen processing makes the indirect recognition pathway slower than direct recognition. Moreover, fewer T cells would also respond in the indirect recognition pathway since a limited number of antigenic peptides can be derived from the polymorphic foreign MHC (Afzali et al 2008). Thus, it is generally regarded that the direct pathway dominates acute responses with indirect pathways contributing to longer term alloantigen presentation. However, indirect recognition alone is sufficient in causing acute rejection, and other groups indicate that in certain TCR transgenic models, indirect activation may be favoured (Brennan T V et al 2009).Therefore the relative contribution of direct versus indirect pathways has not been fully understood.
Other mechanisms of allorecognition have been described, although the relevance of these in vivo has not been established. In semi-direct allorecognition, host dendritic cells (DCs) are able to obtain intact allogeneic MHCs from donor APCs and endothelial cells through cell-cell contact or through the release and uptake of vesicles. Thus, host DCs would then be able to activate host T cells utilizing allogeneic MHC (Smyth et al 2006). In a different recognition pathway, non-hematopoietic graft cells have been reported to activate host T cells. While all previous mechanisms required host T cell activation through APCs, graft vascular endothelial cells in this model have been reported to activate recipient CD8+ T cells through direct allorecognition and by providing costimulation through B7-CD28 (Kreisel D et al 2002).
Rejection may be treated or prevented by immunosupresssion of the host and by minimizing the immunogenicity of the graft (by limiting MHC allelic difference). Most immunosupresssion is directed at T-cell responses and entails the use of the cytotoxic drugs, specific immunosuppressive agents, or anti-T cell antibodies. The most widely used immunosuppressive agent is cyclosporine A, which blocks T-cell cytokine synthesis. Immunosupression is often combined with anti-inflammatory drugs such as corticosteroids that inhibit cytokine synthesis by macrophage (Schwartz RS 2000). Recently, sirolimus (rapamycin) has gained greater use clinically to prevent T cell activation by inhibiting the mammalian target of rapamycin (mTOR). In T lymphocytes, mTOR activation occurs downstream of IL-2 ligation to IL-2R and constitutes the 3rd signal required for T cell activation (Sehgal SN 2003).
Another aspect that requires special consideration is graft-versus-host disease (GVHD). It occurs when donor T-cells respond to genetically defined proteins on host cells (HLA proteins mainly). Yet GVHD constitutes the major complication of allogeneic hematopoietic stem cell transplantation, and it remains lethal for those patients not responding to steroid therapy. Based on GVHD onset after surgery, two different subtypes have been defined. Acute GVHD, appearing prior to 100 days, is directly related to the degree of mismatch between HLAs. Donor T-cell and host APC play an essential role in the immunopathogenesis of GVHD. It is characterized by epithelial cell death in skin, intestinal tract and liver which may be fatal. Chronic GVHD, occurring more than 100 days after engraftment which is a major cause of morbidity and mortality in long-term survivors of allergenic hematopoietic stem cell transplantation (Ferrara et al 2009). It is characterized by fibrosis and atrophy of one or more of the same target organs as well as lungs and may be fatal.
Organ transplantation constitutes the treatment of choice to prolong life by replacement of damaged or non-functional organs. Tissue engraftment was a distant challenge in the seventies, but currently is a routinely procedure in the medical practice that has contributed to extent survival and quality of life within the general population. The success of organ transplantation is in very large part attributable to advance in immunosuppressive treatment. A theoretical solution to avoid the side effects of chronic immunosupression and also chronic rejection would be the induction of transplantation tolerance.