Allografts provoke a powerful immune response that results in rapid graft rejection unless immunosuppressive therapy is given. The pioneering studies of Medawar in the 1940s and 1950s firmly established that allograft rejection was due to an immune response and not a nonspecific inflammatory response. Later studies demonstrated that T-lymphocytes play an essential role in orchestrating the graft rejection response. The immunological effector mechanisms responsible for graft rejection are those that have evolved to provide protection from pathogens — in other words there are no unique immunological mechanisms causing graft rejection. Cytotoxic Tcells, delayed-type hypersensitivity and antibody-dependent effector mechanisms all play a role.
The allograft rejection response is directed against a group of cell-surface molecules called the ‘human leucocyte antigens’ (HLAs) which were first described by Dausset in 1958. HLAs are highly polymorphic (i.e. the amino acid sequence is very variable between individuals) and play a special role in immune recognition. Their normal physiological function is to display antigenic peptides derived from foreign pathogens so that they can be recognised by Tlymphocytes.
There are two types of HLA molecule — HLA class I and HLA class II. HLA class I molecules comprise a polymorphic alpha-chain which is associated with a smaller nonpolymorphic chain known as a beta2-microglobulin. HLA class II molecules comprise two polymorphic polypeptide chains designated alpha and beta The tertiary structure of HLA class I and HLA class II is similar. In both classes of HLA molecule, the extracellular domains form a cleft, the purpose of which is to hind and display foreign peptides for surveillance by T-lymphocytes . Each individual HLA molecule only binds one peptide at a time but can bind a wide range of different peptides. The two classes of HLA molecule differ with respect to the source of the peptides they bind. HLA class I molecules present antigenic peptides derived from within the cell, for example antigenic peptides derived from intracellular viruses. HLA class II molecules, in contrast, present peptides derived from the extracellular environment. In the context of organ transplantation it is important to note that the peptide-binding grooves of HLA molecules never lie empty. When they are not occupied by an antigenic peptide derived from an invading microorganism they are occupied by nonantigenic peptides derived from intracellular proteins, including peptides derived from HLA molecules themselves.
HLA class I antigens are present on all nucleated cells, while HLA class II antigens have a more restricted distribution and are expressed stongly on antigen-presenting cells such as dendritic cells, macrophages and B-lymphocytes. However, HLA class II expression is readily inducible on all cell types by cytokines such as interferon-gamma. HLA molecules expressed on donor tissues trigger a strong graft rejection response in the recipient by virtue of their special role in Tcell recognition and the fact that they are so polymorphic. It is rare for two unrelated individuals to have a completely identical set of HLA molecules. The high degree of HLA polymorphism between individuals is clearly unfortunate from the viewpoint of organ transplantation because it ensures immunological incompatibility between unrelated individuals. However, transplantation of organs is nonphysiological and it is reassuring to remember that the existence of extensive HLA polymorphism provides a survival advantage for the human species by maximising the chance that a given population will be able to recognise and mount an effective immune response to new pathogens.
T-lymphocytes recognise peptide antigens bound to HLA molecules through their T-cell receptor (TCR), and each Tcell expresses a unique TCR that binds to a particular HLA—peptide complex. During their development, T-cells that recognise self-derived peptides displayed by self HLA are normally deleted as they mature in the thymus gland, thereby eliminating self-reactive T-cells and avoiding autoimmunity.
The TCR is a heterodimer comprising an alpha- and beta-chain. It associates at the surface of the T-cell with the CD3 complex, which is involved in intracellular signalling after the TCR is activated by engaging antigen. Mature T-cells bear either CD4 or CD8 coreceptors and these bind to nonpolymorphic regions of class II and class I HLA, respectively, on antigen-presenting cells. Activation of a T-cell by an antigen-presenting cell requires the delivery of two distinct signals. The first signal (signal 1) is delivered after ligation of the T-cell receptor with an HLA—antigen complex. The second signal (signal 2) is delivered following the interaction of additional nonpolymorphic ligand—receptor molecules or co stimulatory molecules on the surface of the antigen-presenting cell and T-cell.
In the context of organ transplantation, allogeneic HLA molecules are exceptionally strong antigens because they are able to stimulate T-cells directly without the need to be broken down into short peptides and presented in the cleft of an HLA molecule. This pathway of antigen recognition is unique to transplantation and is called direct allorecognition. All of the commonly transplanted organs have large numbers of dendritic cells distributed throughout their parenchyma. These professional antigen-presenting cells are richly endowed with class I and class II antigens and possess all of the necessary costimulatory molecules to trigger activation of recipient T-cells. Allogeneic molecules can also be processed like other types of antigen and displayed as antigenic peptides associated with HLA molecules on recipient antigen-presenting cells — this is termed indirect allorecognition and makes an important contribution to graft rejection.
After encountering alloantigens, activated T-cells undergo a period of clonal expansion which is dependent on IL-2 and other T-cell growth factors. CD4 T-cells, through release of cytokines, play a central role in orchestrating the various effector mechanisms which are responsible for graft rejection. The cellular effectors of graft rejection include cytotoxic CD8 I-cells that recognise donor HLA class T antigens expressed by the graft and cause target cell death by releasing lytic molecules such as perform and granzyme. Graft-infiltrating CD4 T-cells that recognise donor HLA class II mediate direct target cell damage and are also able, by releasing cytokines such as interferon-gamma, to recruit and activate macrophages which act as nonspecific effector cells. Finally, CD4 T-cells provide essential T-cell help for B-lymphocytes that produce alloantibodies which bind to graft antigen and induce target-cell injury directly or through antibody-dependent cell-mediated cytotoxicity.
Types of allograft rejection
Allograft rejection can be divided into three distinct types on the basis of timescale and underlying pathophysiology:
• hyper acute rejection (occurs immediately);
• acute rejection (occurs in the first 6 months);
• chronic rejection (occurs months and years after transplantation).
Hyper acute rejection is avoidable and acute rejection, although common, can usually be reversed by immunosuppressive therapy. Chronic rejection occurs after all types of organ transplantation and, because it is largely resistant to currently available immunosuppressive therapy, is a major cause of graft failure. Allograft rejection manifests itself as functional failure of the transplant and is confirmed by histological examination. Biopsy material is obtained from renal and pancreas grafts by needle biopsy, and from hepatic grafts by percutaneous or transjugular liver biopsy. Cardiac grafts are biopsied by transjugular endomyocardial biopsy, and lung grafts by transbronchial biopsy. After small intestinal transplantation, mucosal biopsies are obtained from the graft stoma or more proximally by endoscopy. A standardised histological grading system, termed the Banff classification (named after the Canadian town where the initial scientific workshop was held) defines the presence and severity of allograft rejection after solid organ transplantation.
Hyperacute rejection is due to the presence in the recipient of preformed cytotoxic antibodies against HLA class I antigens expressed by the donor. These may arise from blood transfusion, a failed transplant or previous pregnancy. This type of rejection also occurs if an ABO blood group-incompatible organ graft is performed. After revascularisation of the graft, antibodies bind immediately to the vasculature, activate the complement system, and cause extensive intravascular thrombosis and graft destruction within minutes and hours. Kidney transplants are particularly vulnerable to hyperacute graft rejection, whereas heart and liver transplants are relatively resistant to this type of rejection. In clinical practice, hyperacute rejection can be avoided by performing a cross-match test on recipient serum to ensure that it does not contain antibodies directed against HLAs expressed by a prospective kidney donor. Even in the presence of a strongly positive cytotoxic cross-match test, liver transplants rarely undergo hyperacute rejection, although their long-term survival is inferior. It is not clear why the liver is so resistant to hyperacute rejection, but one factor may be that that it is less susceptible to ischaemia than the kidney by virtue of its dual blood supply: 60 per cent of the hepatic blood supply derives from the portal vein and 40 per cent from the hepatic artery.
Acute allograft rejection usually occurs during the first 6 months of transplantation but may occur later. It is mediated predominantly byT-lymphocytes, but alloantibody may also play an important role. Acute rejection is characterised by mononuclear cell infiltration of the graft. The mononuclear cell infiltrate is heterogeneous and includes cytotoxic T-cells, B-cells, natural killer (NK) cells and activated macrophages. Antibody deposition may also be present. All types of organ allograft are susceptible to this form of rejection and it occurs in 25—50 per cent of cases. Fortunately, the majority of acute rejection episodes can be reversed by appropriate immunosuppressive therapy.
Chronic allograft rejection occurs after the first 6 months, and is due to antibody- and cell-mediated effector mechanisms All types of transplant are susceptible to chronic rejection and it is the major cause of allograft failure. Interestingly, however, the liver appears more resistant than other solid organs to the destructive effects of chronic rejection. The pathophysiology of chronic allograft rejection is not completely understood. The underlying mechanisms are immunological, and both aIloantibodies and cellular effector mechanisms appear to contribute. However, it is now clear that alloantigen-independent factors also play a role in the pathogenesis. A number of risk factors for chronic rejection has been identified in the context of renal allograft rejection. These are:
• previous episodes of acute rejection;
• degree of HLA mismatch;
• long cold ischaemia time;
•cytomegalovirus (CMV) infection;
• raised blood lipids;
• inadequate immunosuppression (poor compliance).
The single most important risk factor for chronic rejection is acute rejection. After kidney transplantation, acute rejection with vascular inflammation and recurrent episodes of acute rejection are strongly predictive of subsequent graft failure from chronic rejection.
The histological picture of chronic rejection is dominated by vascular changes with arterial myointimal proliferation which results in ischaemia and fibrosis. In addition to vasculopathy, there are organ-specific features of chronic graft rejection. These are:
• kidney — glomerular sclerosis and tubular atrophy;
• pancreas — acinar loss and islet destruction;
• heart — accelerated coronary artery disease (cardiac allograft vasculopathy);
• liver — vanishing bile duct syndrome;
• lungs — obliterative bronchiolitis.
Chronic rejection causes functional deterioration in the graft resulting after months or years in graft failure. Unfortunately, currently available immunosuppressive therapy has had little effect in preventing chronic rejection.
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