POLICY BRIEFING Transplant Immunology September 2017 The British Society of Immunology is the largest Introduction immunology society in Europe. Our mission is to promote excellence in immunological research, scholarship and Transplantation is the process of moving cells, tissues, or clinical practice in order to improve human and animal organs, from one site to another, either within the same health. We represent the interests of more than 3,000 person or between a donor and a recipient. If an organ immunologists working in academia, clinical medicine, system fails, or becomes damaged as a consequence of and industry. We have strong international links and disease or injury, it can be replaced with a healthy organ collaborate with our European, American and Asian or tissue from a donor. partner societies in order to achieve our aims. Organ transplantation is a major operation and is only Key points: offered when all other treatment options have failed. Consequently, it is often a life-saving intervention. In • Transplantation is the process of moving cells, 2015/16, 4,601 patient lives were saved or improved in i tissues or organs from one site to another for the the UK by an organ transplant. Kidney transplants are purpose of replacing or repairing damaged or the most common organ transplanted on the NHS in diseased organs and tissues. It saves thousands the UK (3,265 in 2015/16), followed by the liver (925), and i of lives each year. However, the immune system pancreas (230). In addition, a total of 383 combined heart poses a significant barrier to successful organ and lung transplants were performed, while in 2015/16. transplantation when tissues/organs are trans- However, whole organs are not the only type of transplant. ferred from one individual to another. The cornea, for example, is the most transplanted single tissue, with 5,734 procedures carried out in 2015/16.i • Rejection is caused by the immune system Hematopoietic stem cell transplantation (HSCT), often identifying the transplant as foreign, triggering a called blood and marrow transplantation (BMT), is another response that will ultimately destroy the trans- common tissue transplantation procedure. Used to treat planted organ or tissue. Long term survival of the a broad spectrum of diseases, though most commonly transplant can be maintained by manipulating the for blood or bone marrow cancers such as leukaemia immune system to reduce the risk of rejection. and lymphoma, around 3,600 HSCT transplants were undertaken in 2012. • Donor and recipient are carefully matched prior to transplantation to minimise the risk of rejection. The immune system plays a critical role in They are matched based on their blood group, transplantation. The complex mechanisms of immunity, tissue typing, and how the recipient’s blood serum which under normal circumstances work to identify reacts to donor cells. foreign microbes and direct the immune system to destroy them, pose a significant barrier to successful • Immunosuppressive drugs are used to prevent transplantation. Rejection of a transplant occurs in and to treat transplant rejection by dampening the instances where the immune system identifies the overall immune response. However, immunosup- transplant as foreign, triggering a response that will pressive drugs are non-specific and leave patients ultimately destroy the transplanted organ or tissue. more susceptible to disease as well as being associated with numerous unwanted side effects. The intensity of the immune response against the organ or tissue, also commonly referred to as the graft, will • Further research on the immunological mecha- depend on the type of graft being transplanted and the nisms of rejection will help improve cross match- genetic disparity between the donor and recipient. To ing, diagnosis and treatment, as well as facilitat- reduce the possibility of rejection, the donor and recipient ing the discovery of novel strategies for preventing are carefully matched for immune compatibility prior to transplant rejection. transplantation. However, the small pool of eligible donors can make it difficult to find a donor-recipient match and there will always be a degree of rejection against the graft. A critical undersupply of donated organs means that waiting lists for transplants are extremely long. Patients needing a kidney transplantation, for example, wait on British Society for Immunology Julia Deathridge 34 Red Lion Square Intern London, WC1R 4SG Telephone: 020 3019 5911 Email: [email protected] POLICY BRIEFING Transplant Immunology September 2017 average 944 days (more than two and a half years) for a damaged or destroyed blood cells. Haematopoietic life-saving transplant.ii stem cell transplants are used to treat certain types of cancer e.g. leukaemia, and blood diseases where the There were 6,943 patients registered for organ transplant bone marrow has become damaged preventing the in the UK as of March 2015.i Unfortunately, 479 of production of healthy blood cells. These stem cells these patients died during 2015/16 whilst waiting for a can be harvested either directly from bone marrow transplant due the small pool of transplantable organs.i or from the cord blood (blood from the placenta and These figures underline the value of every organ and umbilical cord) from consenting mothers following highlight the importance of a successful transplantation childbirth. and maintaining long-term transplant survival. Manipulation of the immune system can support long- term survival of the graft ensuring that every transplant is The immunology of transplant rejection as successful as possible. Distinguising between self and non-self There are several types of transplantation involving tissues and organs: When the immune system encounters a foreign organism, it mounts an attack against it to protect the body from • Autograft –Transplantation of cells, tissues or organs infection. To prevent an attack on our own cells and between sites within the same individual e.g. skin tissues (autoimmunity), the immune system must be graft. able to differentiate between our own healthy tissues and foreign invaders. • Allograft – Transplantation of organs or tissues from a donor to a non-genetically identical individual of the Foreign invaders are presented to the immune system in same species. Allografts are the most common type the form of small molecules called antigens. Identification of transplant. of these non-self antigens will trigger an immune response and will stimulate the production of antigen- • Xenograft – Transplantation of an organ or tissue specific antibodies that mark infected cells for destruction between two different species. ‘Pig valves’, for by the immune system and help amplify the immune example, are commonly used to repair or replace response. a defective heart valve in humans. In 2015/16, 6,069 xenograft valve replacements were carried out in The Human Leukocyte Antigen (HLA) complex is a England by the NHS.iii Xenotransplantation of whole group of genes that encode the proteins responsible for organs is not currently viable, although it is an area of identifying foreign agents to the immune system. These huge scientific interest as a potential solution for the proteins are found on the surface of all cells and act as existing critical undersupply of adequate organs. ‘self-markers’ telling the immune system not to trigger a response. Each person will have their own specific set of • ABO incompatible – ABO refers to blood group, which HLA proteins, based upon their unique genetic make-up, can vary between individuals. For most transplant that the immune system will have learned not to react to. types, matching of blood group between donor and Any cell not displaying these specific HLA proteins will be recipient is a key strategy in reducing rejection risk. identified as ‘non-self’ by the immune system and will be However, blood group compatibility is not always treated as a foreign invader. required for transplantations. For example, in the case of very young children with immature immune Mechanism of rejection systems, ABO incompatible transplants can be carried out with less risk of transplant rejection. Graft rejection occurs when the recipient’s immune system attacks the donated graft and begins destroying • Stem cell transplant – Stem cells are cells that have the transplanted tissue or organ. The immune response the capacity to develop into a range of different types is usually triggered by the presence of the donor’s own of cells in the body. Blood stem cells (haematopoietic unique set of HLA proteins, which the recipient’s immune stem cells) can develop into all the different cells system will identify as foreign. found in the blood and are donated to replace British Society for Immunology Julia Deathridge 34 Red Lion Square Intern London, WC1R 4SG Telephone: 020 3019 5911 Email: [email protected] POLICY BRIEFING Transplant Immunology September 2017 The degree of similarity between the HLA genes of the Chronic rejection donor and recipient is known as histocompatibility; the more genetically compatible the donor and the recipient, Repeated episodes of acute rejection can ultimately the more tolerant the recipient’s immune system should lead to chronic rejection of the graft and failure of the be of the graft. However, unless the donor and recipient transplant. Chronic rejection commonly manifests as are genetically identical (e.g. as in identical twins) there scarring of the tissue or organ which can occur months to will always be some degree of rejection. As well as non- years after acute rejection has subsided. At present, there self HLA proteins, other surface proteins on the donor is no cure for chronic rejection other than removal of the graft can also be identified as a foreign antigen and illicit graft. an immune response. Finding an eligible donor-recipient match In some cases, a patient may experience something known as ‘graft versus host reaction’ where mature Rejection can be minimised by carefully matching immune cells already present in the donor graft begin the donor and recipient for compatibility prior to attacking the healthy cells of the recipient.