Transplant Immunology: The Origin of Organ Transplantation

Transplant Immunology: The Origin of Organ Transplantation

Abstract– Transplant immunology is the process of transferring different cells, organs and tissues from a donor to a recipient. When an organ is in the stages of failing, the organs system can be corrected by transplantation. Due to the complexities of the immune system, transplantation of any organ faces a multitude of challenges.  In the past, it was impossible for an individual to survive heart, liver or kidney failure. However, through the innovation of transplant immunology these conditions are now curable. Although the process is extensive and faces challenges post operation it still renders the most promising results in the field of transplantation immunology.

Index Terms-Donor and Recipient, Immunosuppressive drugs, Rejection

Introduction

Transplantation immunology is the process used to move different tissues, organs and cells from one site to another. This can be done between a donor and a recipient or this can be done within the same person. If an organ has suffered severe damage or is in the

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 Stages of failure as a result of disease or injury, it can be replaced with a healthy organ/cell/tissue from a donor. Organ transplantation is a major and extensive operation. Transplantation is only an option once all other resources have been exhausted. In 2015/16, 4,601 patient lives were saved or improved in the UK by an organ transplant.  Kidney transplants are the most common organ transplanted on the NHS in the UK (3,265 in 2015/16), followed by the liver (925), and pancreas (230)[2]. Although the most common, organ transplants aren’t the only type of transplant that is performed.  For example hematopoietic stem cell transplantation (HSCT), often called blood and marrow transplantation (BMT), is another common tissue transplantation procedure [2].  This type of transplantation is used to treat a multitude of diseases but it is commonly used to treat blood/bone marrow cancers such as leukemia and lymphoma. The immune system is a key factor in transplantation immunology. Because of the immune systems complexities, there is always some sort of difficulty because the body views the new tissue/organ as foreign and will tend to try and reject it to keep the immune system functioning properly.

1. history

Over the 20^th and into the 21^st century, transplantation immunology has established its presence in the medical world and has shown results, resulting in the benefit of thousands of patients. These therapies have enabled the transplantation of and improved the survival rates of transplanted patients. Due to the discovery of acquired immunological tolerance and experimental methods to produce tolerance by Billingham, Brent and Medawar raised the possibility of inducing in the recipient at the time of organ grafting a state of temporary immunological covering similar to the stage that occurs in fetal development [5].

figure 1- discovery of transplantation immunology Transplantation Immunology could not have advanced without the contributions and advances in general and thoracic surgery, medicine, and anesthesia, such as open-heart surgery, renal dialysis, antibiotics, and intensive care technology [6]. The introductions of cardiopulmonary resuscitation procedures were influential because they mandated redefinition of death in terms of irreversible brain damage rather than the cessation of heartbeat and respiration [6].  

2. transplantation rejection

Typically transplant rejection occurs when the immune system identifies the transplanted organ/tissue as foreign. Once identified as foreign the transplanted organ triggers a response within the immune system that will ultimately destroy it.

The intensity of the response of the immune system against the graft (organ/tissue being transplanted) depends on the type of graft being used [2]. Another key factor in identifying how the immune system will respond depends on the genetic disparity between the donor and recipient. To reduce the chance of rejection, donors and recipients are closely matched to ensure a nearly successful transplantation. Because there is such a limited amount of eligible donors, there is always difficulty finding a perfect match. So there will always be to a certain degree rejection.

Foreign antibodies are presented to the immune system in the form of small molecules which are called antigens. When non-self antigens are identified they 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 [1]. 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[1] [2].

Graft rejection happens when the patient receiving the transplants immune system attacks the graft donated by the donor. Once the immune system begins to attack the graft, it will begin the process of destroying the newly transplanted tissue or organ. The response of the immune system is triggered when the donor’s own unique set of HLA proteins is present.

The variance of similarity between the donors and the recipients HLA genes is known as histocompatibility. The more compatible the donor and the recipient genes are, the more tolerant of grafts the recipient’s immune system should be. If however the donor and recipient aren’t genetically identical there will always be a degree of rejection.

 Patients may experience something known as ‘graft versus host reaction’ where the mature immune cells already present in the donor graft begin to attack the viable cells of the recipient. This is mostly seen in stem cell transplants and may occur after someone has received a blood transfusion.

There are 3 clinical stages of rejection.

1. Hyper-acute rejection occurs within minutes or hours after the transplantation has taken place. This is caused because of preexisting antibodies of the recipient, that match the foreign antigens of the donor which triggers the immune system to respond against the transplant. These antibodies could have been generated as a result of prior blood transfusions, prior transplantations or multiple pregnancies. The antibodies react with cells in the blood vessels of the graft, causing blood clots to form, which prevent blood supply from reaching the graft resulting in immediate rejection of the transplant.
2. Acute rejection occurs within the first 6 months after the transplantation has taken place. There will be a degree of acute rejection in all transplantations, except between identical twins. Recipients of the transplant are most at risk within the first 3 months, but rejection can still occur at any stage. Acute rejection is caused when antibodies form following the detection of non-self antigens in the donated graft [2].
3. Chronic rejection occurs due to repeated episodes of acute rejection. Chronic rejection manifests because of the scarring of tissue/organ, which can occur months/years after acute rejection has subsided.

3. finding an eligible donor

Ensuring that the degree of rejection is as minimal as possible is by finding the closest matched donor. Compatibility is a must for a successful transplant. To find compatibility between donor and recipient is done using 5 tests: ABO blood group, Tissue typing, Cross-matching, Panel reactive antibody test and Serology screening.

1. Tissue typing is when a sample of blood is taken from the recipient to identify the HLA (human leukocyte) antigens that are present of the surface of their cells to aide in finding a histone compatible donor. Typically tissue typing is used in finding a donor amongst family members because of their genetic similarity.
2. ABO blood group compatibility is the first test administered between the donor and the recipient to ensure that the two have compatible blood groups.
3. Cross matching is when blood samples are taken from the recipient and donor. The cells of the donor are mixed with the blood serum of the recipient. If there is a positive match between the recipient and donor, transplantation will not be suitable due to increased risk of hyper-acute rejection.
4.  Serology screening testing is done when patients are undergoing stem cell transplantation. The recipient and donor will undergo pre-transplant screening. This test is conducted to detect the status of the immune system of both the donor and potential recipient against a number of clinically significant infectious organisms, including viruses such HIV, Cytomegalovirus (CMV), and Epstein-Barr Virus (EBV). This test determines the potential for re-infection or reactivation of the infection upon immunosuppression. Recipients and donors are often matched according to the CMV and EBV status. 
5. Panel reactive antibody test is when the blood serum of the patient awaiting transplantation is tested for reactive antibodies against a panel of cells. If there were any exposure to foreign tissue, by blood transfusion, pregnancy or prior transplantations, an increase the number of HLA antibodies will be present in the blood. The more HLA antibodies, the greater the panel reactive antibody (PRA) level denoted to the patient, and the greater the chance of the graft being rejected. If PRA levels are high, it may be more difficult to find a match and a higher dosage of immunosuppressive drugs will be required [2].

CONCLUSION

Immunological research has led to a multitude in advancements in transplant medicine. However, immune system rejections still possess a threat for successful transplantation of organs. Once there is a formidable barrier to allow the immune system to be receptive, patients will then have a full success rate. Steady research is needed to find ways of lowering the risk of rejection of transplanted patients. The goal of transplantation immunology is to the improve diagnosis and maintain long-term survival of the transplant. Constant innovation of compatibility testing between donor and recipient could reduce the risk rejection and increase the viability of the transplanted. The better matched the donor and recipient, the more tolerant immune system will be to the transplanted organ. Having a greater knowledge of genetic disparity between donor and recipient will help improve treatment strategies after transplantation and avoid episodes of transplant rejection.

References

[1]      2018) Immunology of Transplant Rejection. In: Sickle Cell Anemia Differential Diagnoses. https://emedicine.medscape.com/article/432209-overview#a1. Accessed 18 Nov 2018

[2]      Transplant Immunology. In: British Society for Immunology. https://www.immunology.org/policy-and-public-affairs/briefings-and-position-statements/transplant-immunology. Accessed 18 Nov 2018

[3]      Cardiac Transplant Program. In: The Pancreas and Its Functions | Columbia University Department of Surgery. http://columbiasurgery.org/news/2012/10/01/transplant-immunology-science-behind-organ-transplantation. Accessed 18 Nov 2018

[4]      Kumbala, Damodar and Rubin Zhang. “Essential concept of transplant immunology for clinical practice” World journal of transplantation vol. 3,4 (2013): 113-8.

[5]      Calne R (2006) Essay: History of transplantation. The Lancet. doi: 10.1016/s0140-6736(06)69928-5 

[6]      (Figure 1) Groth, C G et al. “Historic landmarks in clinical transplantation: conclusions from the consensus conference at the University of California, Los Angeles” World journal of surgery vol. 24,7 (2000): 834-43.