Transplant rejection

Transplant rejection occurs when a transplanted organ or tissue is not accepted by the body of the transplant recipient. This is explained by the concept that the immune system of the recipient attacks the transplanted organ or tissue. This is expected to happen, because the immune system's purpose is to distinguish foreign material within the body and attempt to destroy it, just as it attempts to destroy infecting organisms such as bacteria and viruses. When possible, transplant rejection can be reduced through serotyping to determine the most appropriate donor-recipient match and through the use of immunosuppressant drugs.

Hyperacute rejection
Hyperacute rejection is a complement-mediated response in recipients with pre-existing antibodies to the donor (for example, ABO blood type antibodies). Hyperacute rejection occurs within minutes after the transplant and must be immediately removed to prevent a severe systemic inflammatory response. Rapid agglutination of the blood occurs. This is a particular risk in kidney transplants, and so a prospective cytotoxic crossmatch is performed prior to kidney transplantation to ensure that antibodies to the donor are not present. Hyperacute rejection is analogous to a blood transfusion reaction as it is a humoral-mediated immune response. For other organs, hyperacute rejection is prevented by transplanting only ABO-compatible grafts. Hyperacute rejection is not significant in liver allografts and cellular transplants because these tissues have remarkable regenerative abilities. Hyperacute rejection is the outcome of xenotransplanted organ in non-immunosuppressed recipients.

Acute rejection
Acute rejection may begin as early as one week after transplantation (as opposed to hyperacute rejection, which is immediate). The risk of acute rejection is highest in the first three months after transplantation. However, acute rejection can also occur months to years after transplantation. A single episode of acute rejection is not a cause for concern if recognized and treated promptly, and rarely leads to organ failure. But recurrent episodes are associated with chronic rejection (see below).

Acute rejection occurs to some degree in all transplants (except those between identical twins) unless the immune response is altered through the use of immunosuppressive drugs. It is caused by mismatched HLA, which are present on all cells of the body. There are a large number of different alleles of each HLA, so a perfect match between all HLA in the donor tissue and the recipient's body is extremely rare.

Tissues such as the kidney or the liver which are highly vascularized (rich in blood vessels), are often the earliest victims of acute rejection. In fact, episodes of acute rejection occur in around 10-30% of all kidney transplants, and 50 to 60% of liver transplants. Damage to the endothelial lining of blood vessels is an early predictor of irreversible acute transplant rejection.

The reason that acute rejection usually begins one week after transplantation is the delay in activation of the involved T-cells. Often transplanted organs are acquired from a cadaveric source (e.g. trauma victim) and as a result of ischemia and/or trauma are already in a state of inflammation. The inflammatory response results in donor-derived dendritic cells migrating to the secondary lymphoid tissues (e.g. lymph node) of the recipient. There they present self-antigen derived from the donated organ to recipient T-cells. T-cells that interact with allogeneic HLA complexes have the potential to become activated and develop an immune response against the 1.) self-peptide, 2.) the allogeneic HLA molecule itself, or 3.) a combination of both. These T-cells must differentiate before the alloreaction begins and the tissue is rejected. The alloreactive T-cells cause cells in the transplanted tissue to lyse, or produce cytokines that cause necrosis of the transplanted tissue. This process can take days, or even weeks to manifest.

The first successful organ transplant, performed in 1954 by Dr. Joseph Murray, was successful because the donor and recipient were identical twins, and therefore no T-cell-mediated responses could be generated against the transplanted organ.

The diagnosis of acute rejection relies on clinical data, including patient signs and symptoms, laboratory testing and ultimately a tissue biopsy. The biopsy is interpreted by a pathologist who notes changes in the tissue that suggest rejection. Generally the pathologist looks for three main histological features. First, the presence of T-cells infiltrating the transplanted tissue; these may be accompanied by a heterogeneous collection of other cell types including eosinophils, plasma cells and neutrophils. (The proportions of these cell types may be helpful in diagnosing the exact type of rejection.) Secondly, evidence of structural injury to the transplanted tissue; the characteristics of this injury will depend on the type of tissue being transplanted. Lastly, injury to the blood vessels in the transplanted tissue.

Recent technological advancements have led to genetic expression testing in the form of a blood test. These tests, such as AlloMap Molecular Expression Testing have a high negative predictive value help manage the ACR rejection in transplant patients. These genetic expression tests are specific to the transplanted organ type.

Chronic rejection
The term "chronic rejection" was initially a term used to describe a long-term loss of function in transplanted organs, associated with fibrosis of the internal blood vessels of the transplanted tissue. But this pathology is now termed chronic allograft vasculopathy. The term chronic rejection is reserved for cases of transplant rejection where the rejection is due to a poorly understood chronic inflammatory and immune response against the transplanted tissue.

Chronic rejection of the lungs
Chronic rejection after lung transplantation is the leading cause of long-term morbidity in lung transplant patients. The median survival of lung-transplant patients is approximately 4.7 years—about half that of other major transplanted organ recipients. Histopathologically, the condition is known as bronchiolitis obliterans. Clinically, patients present with progressive airflow obstruction often associated with dyspnea and coughing. Ultimately these patients succumb to pulmonary insufficiency or secondary infection. Bronchiolitis obliterans syndrome (BOS) is used to describe patients with airflow obstruction that cannot be ascribed to any other specific cause. This diagnosis is confirmed by a persistent drop (three or more weeks) in forced expiratory volume (FEV1) of at least 20%. Unfortunately, BOS is common in patients after lung transplant and presents in at least 50% of patients by 5 years and over 80% by ten years post-transplant.

The progression of disease is unpredictable and heterogeneous. In some cases, patients may develop a sudden drop in lung function which then stabilizes for years. In other instances, the progression is rapid leading to death within a few months. Although the onset of chronic lung rejection is unknown, risk factors include prior acute cellular rejection episodes, gastroesophageal reflux disease, infection (viral and bacterial), age of transplant recipient, HLA mis-matching, lymphocytic bronchiolitis and graft dysfunction (e.g. airway ischemia).

Rejection is a recipient response to a foreign antigen with the antigen being the transplanted organ or allograft. Histologically, lymphocytic infiltrates are first noted and this is followed by epithelial cell injury (at least within the lungs). The associated inflammatory reaction results in recruitment and proliferation of fibroblasts and myofibroblasts which leads to airway lesions and scarring. The condition is often patchy and heterogeneous and thus a bronchial biopsy in early disease may miss the formation of the granulation tissue that ultimately can lead to obliteration of airways.

Rejection mechanisms
Rejection is an adaptive immune response and is mediated through both T cell mediated and humoral immune (antibodies) mechanisms. The number of mismatched alleles determines the speed and magnitude of the rejection response. Different mechanisms tend to act against different grafts.

CMI=Cell mediated immunity

Treatment of rejection
Chronic transplant rejection is irreversible and cannot be treated effectively. Treatments with inhaled ciclosporin are being investigated as a means to delay or prevent chronic rejection of the lungs. At present the only definitive treatment is re-transplantation, if patients can be re-allocated and if donors are available.

Acute transplant rejection can be treated using chemotherapeutic drugs designed to suppress the immune system (see list below). Acute rejection is normally treated initially with a short course of high-dose corticosteroids, which is usually sufficient. If this is not enough, the course can be repeated or a triple therapy regimen can be used, consisting of a corticosteroid plus a calcineurin inhibitor and an anti-proliferative agent. Antibodies against specific components of the immune system can be added to this regimen, especially for high-risk patients. mTOR inhibitors can be used in selected patients, where calcineurin inhibitors or steroids are contraindicated. Acute rejection refractory to these treatments may require blood transfusions to remove antibodies against the transplant.

If a bone marrow transplant can be performed, the transplant recipient's immune system can be replaced with the donor's immune system, thus enabling the recipient's body to accept the new organ without risk of rejection. This requires that the bone marrow, which produces the immune cells, be from the same person as the organ donation (or an identical twin or a clone). There is a risk of graft versus host disease (GVHD) in which the lymphoid cells co-injected with the bone marrow transplant recognize the host tissues as foreign and attack and destroy them accordingly.

Immunosuppressive drugs used to treat transplant rejection

 * Calcineurin inhibitors
 * Ciclosporin
 * Tacrolimus
 * mTOR inhibitors
 * Sirolimus
 * Everolimus
 * Anti-proliferatives
 * Azathioprine
 * Mycophenolic acid
 * Corticosteroids
 * Prednisolone
 * Hydrocortisone
 * Antibodies
 * Monoclonal anti-IL-2Rα receptor antibodies
 * Basiliximab
 * Daclizumab
 * Polyclonal anti-T-cell antibodies
 * Anti-thymocyte globulin (ATG)
 * Anti-lymphocyte globulin (ALG)
 * Monoclonal anti-CD20 antibodies
 * Rituximab

The monoclonal anti-T cell antibody OKT3 was formerly used in the prevention of rejection, and is occasionally used in treatment of severe acute rejection, but has fallen out of common use due to the severe cytokine release syndrome and late post-transplant lymphoproliferative disorder, which are both commonly associated with use of OKT3; in the United Kingdom it is available on a named-patient use basis only.

Current diagnosis of organ rejection following transplantation relies on tissue biopsy, which is not ideal due to sampling limitations and risks associated with the invasive procedure. Cellular MRI of in vivo labeled immune cells offers a noninvasive approach to detect and monitor graft rejection after solid organ transplantation. Clinical application of a reliable and noninvasive technique to detect the early signs of graft rejection will improve not only the therapeutic treatment of transplant patients but also improve their quality of life. (Magnetic Resonance in Medicine (2011)