Transplantation is the process that involves the transfer of organs, tissues, or cells from one site to another. Transplantation typically takes place across individuals with the aim of repairing or replacing damaged organs or tissues. Owing to the rapid advancements in modern medical science, thousands of lives are saved each year by successful transplants.
Transplantation. Image Credit: David Tadevosian/Shutterstock.com
The recipient and the donor are matched on several parameters, such as the blood group, tissue typing, etc. However, it must be mentioned that there are some challenges in this process with the immune system being the most formidable barrier. The immune system has elaborate mechanisms in place to reject foreign agents.
If the immune system deems the transplant to be foreign, it will trigger responses that eventually lead to the destruction of the transplanted organ or tissue. It is, therefore, important to understand the mechanisms at play behind rejection as that will aid in correct diagnosis, delivery of appropriate treatment, and reduction of the risk of rejection. This knowledge will also enable scientists to develop new drugs and treatments to blunt the harmful immune response, which, in turn, would ensure that the transplanted organs survive longer.
A Brief History
In 1941, British immunologist Peter Medawar studied skin grafting because the problems of successful skin grafting had become important, owing to severely injured soldiers returning home during the Second World War. In 1944, he showed that the skin allograft rejection was essentially a graft versus host response.
In 1954, Joseph E. Murray performed the first successful identical twin transplant of a human kidney, in Boston. The success continued with the first successful liver transplant being carried out by Thomas E. Starzl and the first successful heart transplant by Christian Barnard, in 1967. E. Donnall Thomas is credited with the first successful bone marrow transplant, in 1968.
Typically, immunosuppressive drugs can minimize the risk of transplant rejection. Schwatrz and Dameshek were instrumental in this regard as in 1959 they demonstrated, in rats, that 6-mercaptopurine was immunosuppressive. Many new immunosuppressive agents have been developed since and this has really improved the survival rate of transplanted organs.
Different Types of Transplants
The degree of genetic parity or disparity between the host and the donor determines the success of a graft. A xenograft is the transplant of an organ or tissue between different species and, unsurprisingly, this is where maximum disparity exists and rapid rejection occurs. On the other end of the spectrum are autografts where grafts from one part of the body are used on another part of the same individual. These grafts do not elicit rejection.
Isografts are transplants between genetically identical individuals, while allograft refers to the transplant of organs or tissues between members of the same species but different genetically. Allografts are the most common types of transplants. Histocompatibility between the host and the donor determines the rate of rejection in allografts. ABO refers to the blood group and is one of the key matching factors for transplants, to minimize the risk of rejection.
Mechanism and Stages of Immune Rejection
When the immune system deems a transplant to be foreign, it mounts an attack to protect the body. The immune system sees the invader as an antigen, which leads to the production of antigen-specific antibodies.
The proteins responsible for identifying antigens are encoded by a group of genes, i.e., the Human Leukocyte Antigen (HLA). The HLA is individual-specific and depends on the genetic make-up. The donor’s HLA (or other surface proteins) on the transplant will be deemed as foreign by the host’s immune system, leading to rejection.
There are different stages of clinical rejection. Hyperacute rejection occurs within minutes or hours of the operation. This is often caused by the presence of recipients’ antibodies (perhaps from previous blood transfusions) that match the donor’s antigens. The reaction of antibodies and antigens causes blood clots and leads to immediate rejection.
Acute rejection is less severe and occurs within half a year of transplantation, with the first three months being the riskiest phase. In this case, antibodies do not pre-exist but are formed at a later stage post detection of non-self-antigens in the graft. Early detection and the use of immunosuppressant drugs can reduce the risk of rejection. Multiple acute rejections can lead to chronic rejection and transplant failure.
Immunosuppressive Drugs
These drugs dampen the immune response and help in mitigating the rejection risk. These drugs are often administered in two phases – a high initial induction dose and a lower later maintenance dose. The dosage varies depending on the type of graft. Side effects may lead to the use of alternative drugs as well. Historically, steroids have been used as immunosuppressants but they have significant side effects (e.g., high blood pressure, impaired renal function, diabetes mellitus, etc.). By far, the most important drawback of these drugs is immunodeficiency.
Owing to the non-specific nature of these drugs, they leave the patients vulnerable to other infections. A fine balance needs to be struck between reducing immune response to reduce rejection risk and preserve enough immunity to combat other infections.
The Future of Transplant Therapies
Continuous research is expected to result in the development of novel drugs with minimum side effects that will eventually eliminate the rejection risk. Stem cells could also play a huge role in transplant therapy in the future. The pluripotent stem cell has the ability to mature into any cell and, therefore, its potential can be exploited to grow organs and tissues.
Stem cell therapy can, hence, reduce the rejection risk significantly and reduce the strain on organ supply. It must, however, be noted that research in this field is time-consuming and unlikely to fully mature in the next decade. In the near future, drugs remain at the forefront of transplant medicine research.
Despite huge advancements in immunological research, immune rejection remains a formidable challenge. Extensive research is required to devise new strategies to mitigate the risk of rejection and ensure the long-term survival of the transplant.
Further Reading