Immunology of Transplant Rejection

2021-02-24 12:00 AM

Rejection is caused largely by differences in HLA alleles between donor and recipient. Immunosuppressive agents are used for preventing and mitigating rejection.


The immune system plays a critical role in transplantation. The complex mechanisms of immunity, which under normal circumstances work to identify foreign microbes and direct the immune system to destroy them, pose a significant barrier to successful transplantation. Rejection of a transplant occurs in instances where the immune system identifies the transplant as foreign, triggering a response that will ultimately destroy the transplanted organ or tissue.

The immunology of transplant rejection

Distinguishing between self and non-self

When the immune system encounters a foreign organism, it mounts an attack against it to protect the body from infection. To prevent an attack on our own cells and tissues (autoimmunity), the immune system must be able to differentiate between our own healthy tissues and foreign invaders.

Foreign invaders are presented to the immune system in the form of small molecules called antigens. Identification of these non-self antigens will trigger an immune response and will stimulate the production of antigen-specific antibodies that mark infected cells for destruction by the immune system and help amplify the immune response. The Human Leukocyte Antigen (HLA) complex is a group of genes that encode the proteins responsible for identifying foreign agents to the immune system. These proteins are found on the surface of all cells and act as ‘self-markers’ telling the immune system not to trigger a response.

Each person will have their own specific set of HLA proteins, based upon their unique genetic make-up, that the immune system will have learned not to react to. Any cell not displaying these specific HLA proteins will be identified as ‘non-self’ by the immune system and will be treated as a foreign invader. 

Mechanism of rejection

Graft rejection occurs when the recipient’s immune system attacks the donated graft and begins destroying the transplanted tissue or organ. The immune response is usually triggered by the presence of the donor’s own unique set of HLA proteins, which the recipient’s immune system will identify as foreign.

The degree of similarity between the HLA genes of the donor and recipient is known as histocompatibility; the more genetically compatible the donor and the recipient, the more tolerant the recipient’s immune system should be of the graft. However, unless the donor and recipient are genetically identical (e.g. as in identical twins) there will always be some degree of rejection. As well as nonself HLA proteins, other surface proteins on the donor graft can also be identified as a foreign antigen and illicit an immune response.

In some cases, a patient may experience something known as ‘graft versus host reaction’ where mature immune cells already present in the donor graft begin attacking the healthy cells of the recipient. Graft versus host reaction, where the donor graft is described as being “immune-competent” (i.e. capable of producing an immune response) is a particular risk with stem cell transplants (bone marrow transplant) and can also occur following blood transfusions. 

Clinical stages of rejection

Rejection is caused largely by differences in HLA alleles between donor and recipient. Immunosuppressive agents are used for preventing and mitigating rejection.

Hyperacute rejection occurs within minutes to hours due to preformed antibodies in the recipient. Lymphocyte cross-matching has almost eliminated this problem.

Acute rejection occurs in the first 6 months and may be cellular (CD8+ T lymphocytes kill graft cells) or antibody-mediated.

Chronic rejection occurs after months or years and may be cell-mediated or antibody-mediated. The vasculature components are targeted, and the histopathologic changes depend on the organ involved.

Finding an eligible donor-recipient match

Rejection can be minimized by carefully matching the donor and recipient for compatibility prior to transplantation. The better matched the donor and recipient are the more successful the transplantation is likely to be. Compatibility between donor and recipient is assessed using a combination of tests, including:

ABO blood group compatibility – The donor and recipient are tested for compatible blood groups. This is the first test to be carried out as the transplant will be rapidly rejected if the blood groups do not match. In some transplants, for example, young children and also bone marrow transplants, ABO compatibility is not a necessity.

Tissue typing – A blood sample is taken from the recipient to identify the HLA antigens present on the surface of their cells to help find a histone-compatible donor. The more alike the HLA types of the donor and recipient are the more likely a transplant will be successful. Family members, in particular siblings, are often the best HLA matches due to their genetic similarity.

Cross-matching – Blood samples are taken from both the recipient and donor, and the cells of the donor are mixed with the blood serum of the recipient. If the recipient’s antibodies attack the donor cells, they are considered a positive match and transplantation will not be suitable due to the increased risk of hyper-acute rejection.

Panel reactive antibody test – The blood serum of patients awaiting transplantation is tested for reactive antibodies against a random panel of cells. Previous exposure to foreign tissue, by blood transfusion, pregnancy, or prior transplantations, is likely to increase the number of HLA antibodies in the blood. The more HLA antibodies present, the higher the panel reactive antibody (PRA) level denoted to the patient, and the greater the chance of graft rejection. If PRA levels are high, it may be more difficult to find a match and a higher dosage of immunosuppressive drugs may be required.

Serology screening – For patients undergoing stem cell transplantation they and their donor will undergo pre-transplant serology screening. This is undertaken to detect the immune status of both the donor and a potential recipient against a number of clinically significant infectious organisms, including viruses like HIV, Cytomegalovirus (CMV), and Epstein-Barr Virus (EBV), thus determining the potential for re-infection or reactivation of the infection upon immunosuppression. Individuals are often matched according to the CMV and EBV status.