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Principles of transplantation immunology 

Principles of transplantation immunology

Chapter:
Principles of transplantation immunology
Author(s):

Ross S. Francis

, and Kathryn J. Wood

DOI:
10.1093/med/9780199204854.003.0505_update_001

Update:

Chapter reviewed in November 2011 and minor updates made.

Updated on 31 May 2012. The previous version of this content can be found here.
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date: 24 April 2017

Since the first successful transplant of a kidney between identical twins in 1955, transplantation has progressed from being an experimental procedure to a routine clinical therapy offering immense benefits for patients with organ failure, but the survival of transplanted organs remains limited by the body’s immune responses, and many of the complications of transplantation result from the crude nature of our attempts to suppress these.

The immune system has evolved to protect the individual from invasion by pathogenic microorganisms as well as mutation of the individual’s own cells that may be premalignant, hence stringent discrimination of ‘self’ from ‘nonself’ or ‘altered self’ is crucial.

The immune response to transplanted tissue

The immunological response that follows transplantation of tissue between genetically nonidentical individuals is complex. (1) Inflammatory signals generated at the site of transplantation as a result of local surgical trauma as well as injury from graft ischaemia and reperfusion activate cells of the innate immune system, promoting the presentation of alloantigens—particularly molecules of the major histocompatability complex (MHC)—to recipient T cells. (2) Activation and clonal expansion of alloreactive recipient T cells is a key event in allograft rejection, resulting in the production of populations of effector lymphocytes. (3) The resulting activated lymphocytes, together with other activated cells of the immune system such as macrophages and neutrophils, are able to migrate to the graft by following chemoattractant molecules that are also produced by the inflammatory response within the graft. (4) Many effector mechanisms contribute to graft destruction, including the delayed type hypersensitivity response, direct cytotoxicity and B cell alloantibody production.

Clinical features of allograft rejection

In clinical practice allograft rejection is frequently categorized depending on the timing in relation to the transplantation procedure, or the dominant arm of the immune system involved. (1) Hyperacute rejection—occurs if preformed complement-fixing antibodies against allogeneic MHC molecules or ABO antigens are present at the time of transplantation; modern crossmatch techniques have made this extremely rare, but in solid organ transplantation it is characterized by rapid widespread vascular thrombosis leading to infarction of the graft within minutes to hours. (2) Acute rejection—may be predominantly due to acute cellular rejection or acute antibody-mediated rejection; leads to a sudden deterioration in graft function over days to weeks; usually responds to treatment with intravenous corticosteroids, with or without increased baseline immunosuppression. (3) Chronic graft dysfunction (‘chronic rejection’)—may be partly due to chronic activation of the immune system; causes gradual deterioration in graft function occurring over weeks to months; there is no effective treatment.

Immunosuppressive therapy

Many different immunosuppressive regimens for solid organ transplantation are in clinical use. The agents employed include (1) glucocorticoids—act principally by binding to cytoplasmic glucocorticoid receptors, which then translocate to the nucleus and reduce the expression of many molecules important in the immune response; (2) antiproliferative agents—e.g. azathioprine, mycophenolate mofetil; interfere with DNA synthesis and prevent cell cycle progression, thus impairing the clonal expansion of alloreactive T cells; (3) calcineurin inhibitors—e.g. ciclosporin, tacrolimus; bind cytoplasmic immunophilins to form complexes that can inhibit the calcium-dependent phosphatase calcineurin, a rate-limiting enzyme in the T-cell receptor signal transduction pathway; (4) mammalian target of rapamycin (mTOR) inhibitors—e.g. sirolimus, everolimus; bind to the regulatory kinase mTOR, which has a critical role in cytokine receptor signal transduction; (5) depleting antibodies—e.g. anti-thymocyte globulin (ATG), alemtuzumab (a humanized monoclonal antibody directed against human CD52); cause profound lymphocyte depletion; (6) other biological agents—e.g. daclizumab and basiliximab, both of which are mouse–human chimeric monoclonal antibodies directed against CD25 (the high-affinity IL-2 receptor α‎-chain), and belatacept, a fusion protein linked to CTLA-4 (CD152) that blocks T cell costimulation and hence activation.

Clinical perspective and future prospects

Modern immunosuppressive therapy has improved 1-year graft survival to above 90%, but late graft loss and the adverse effects of chronic immunosuppression remain a significant problem. Challenges for the future include the development of better assays to monitor the immune response following transplantation and make it easier to individualize immunosuppressive therapy, improving the risk:benefit ratio, as well as facilitating trials of novel therapies that may lead to donor-specific hyporesponsiveness or even operational transplantation tolerance, which remains the holy grail of clinical transplantation and can be defined as the lack of a destructive immune response towards the graft without the requirement for indefinite nonspecific immunosuppressive therapy, while preserving immune responses to pathogens.

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