Transplantation Immunology

The process of shifting cells, tissues, or organs from one location to another, either within the same person or between a donor and a recipient, is known as transplantation. An organ system can be substituted with a healthy organ or tissue from a donor if it malfunctions or becomes damaged as a result of a medical condition. Organ transplantation is a significant procedure that is only considered after all other therapeutic options have been failed. As a result, it is typically a life-saving procedure. Organ transplants saved or improved the lives of patients in the United Kingdom. The most frequent organ transplanted on the national health service in the UK is the kidney, which is followed by the liver and the pancreas. Numbers of paired heart and lung transplants were also carried out. However, complete organ transplants are not the only choice. With many surgeries performed, the cornea is the most donated single organ.  Another frequent tissue transplantation method is hematopoietic stem cell transplantation, often known as blood and marrow transplantation. many hematopoietic stem cell transplantations were performed to treat a wide range of disorders, the most frequent of which were blood or bone marrow malignancies such as leukemia and lymphoma.

In transplantation, the immune system is extremely important. Immunity's diverse systems, which normally operate to recognize foreign germs and lead the immune system to eliminate them, are a substantial barrier to efficient transplantation. Rejection of a transplant occurs when the immune system recognizes the organ or tissue as foreign, generating a reaction that destroys the transplanted organ or tissue.

The severity of the immune reaction against the transplanted organ or tissue, also known as the graft, is determined by the type of transplant and the genetic discrepancy between the donor and receiver. Prior to transplantation, the donor and recipient are carefully matched for immunological compatibility to minimize the risk of rejection. However, due to the limited number of qualified donors, finding donor-recipient compatibility can be challenging, and there will always be some rejection of the graft. Due to a significant shortage of donated organs, transplant waiting lists are exceedingly long. For instance, patients in need of a kidney transplant must wait for an average of 1000 days (approximately three years) for a life-saving transplant.  As of March 2015, there were many organ transplant candidates in the United Kingdom. Sadly, due to the limited supply of transplantable organs, a lot of these patients died while waiting for a transplant.  These data emphasize the worth of each organ and the significance of a successful transplant as well as long-term transplant survival. Modulation of the immune system can help the graft survive for as long as possible, assuring that every transplantation is successful.

 

Transplantation Types

There are several types of transplantation of the organs including:

  • Autograft. Transplantation of tissues or organs from one site to another in the same person, such as a skin graft.
  • Allograft. Transplantation of anatomical structures from a donor to a non-genetically similar person of the same genus. The most prevalent type of transplant is allografts.
  • Xenograft. The transplantation of a tissue or organ from one species to a different one. Pig valves, for example, are frequently utilized in humans to repair and replace a damaged heart valve. The national health service performed many xenografts valve repairs. Whole-organ xenograft transplantation is presently not feasible, despite the fact that it is a highly debated scientific topic as a reasonable alternative to the urgent shortage of appropriate organs.
  • ABO incompatible. ABO refers to a blood group that varies from person to person. The matching of blood groups between donor and recipient is a crucial method for lowering the risk of rejection in most transplantation modalities. For transplants, however, blood group matching is not usually essential. ABO-incompatible transplantation, for example, can be performed with minimal risk of transplant rejection in very young children with underdeveloped immune function.
  • Stem cell transplantation. Stem cells are cells in the body that have the ability to differentiate into a variety of different types of cells. Blood stem cells, also known as hematopoietic stem cells, are used to replace injured or aged blood cells since they may transform into all of the various cells found in the blood. Hematopoietic stem cell transplantation is used to treat cancers such as leukemia, as well as blood disorders in which the bone marrow has been destroyed, inhibiting the formation of normal blood cells. These stem cells can be extracted from consenting mothers' bone marrow or blood from the placenta and umbilical cord of the baby.

 

Transplantation Rejection Immunology

Differentiation Between our own and foreign Cells

When the immune system comes into contact with a foreign entity, it launches an attack in order to keep the body safe from diseases. The immune system must be able to distinguish between our normal tissues and external attackers in order to avert an attack on our cells and tissues (autoimmunity).

Antigens are tiny particles that are displayed to the immune system in the shape of foreign enemies. The discovery of these foreign molecules will elicit an immune reaction and encourage the development of antigen-specific antibodies, which will identify invading pathogens for elimination by the immune system and aid in the augmentation of the immune response. The Human Leukocyte Antigen complex is a collection of genes responsible for coding proteins that help the immune system recognize foreign invaders. These proteins are located on the surface of all cells and serve as self-markers, indicating to the immune system that it should not respond.

Depending on individual genetic background, each person will have their own set of human Leukocyte Antigen proteins that the immune system will have trained not to respond to. The immune system will identify any cell that does not express these specific human Leukocyte Antigen proteins as non-self and address it as a foreign threat.

 

Mechanism of Graft Rejection

Graft rejection occurs when the recipient's immune response assaults the given tissue or organ and proceeds to eliminate it. The presence of the donor's own specific set of human Leukocyte Antigen proteins, which the recipient's immune system recognizes as foreign, frequently triggers the immunological reaction.

Histocompatibility refers to the degree of resemblance between the donor and recipients' human Leukocyte Antigen genes; the more genetically similar the donor and recipient are, the more tolerant the recipient's immune system should be of the transplant. There will always be some level of rejection unless the donor and receiver are genetically identical (e.g., twins). Other surface molecules on the donor graft can be detected as a foreign antigen and provoke an immune response, in addition to foreign human Leukocyte Antigen proteins.

 

Stages of Transplant Rejection

Hyperacute Rejection Phase

This happens minutes or hours after transplantation and is triggered by the development of preexisting antibodies in the recipient that match the donor's foreign antigens, initiating an immunological reaction to the graft. Prior blood transfusions, transplants, or multiple pregnancies could have resulted in the development of these antibodies. Antibodies interact with cells in the graft's blood vessels, forming blood clots that block oxygen from flowing to the graft, resulting in a prompt rejection of the graft.

 

Acute Rejection Phase

Within the first six months following surgery, this happens. All transplants, with the exception of identical twins, will result in some extent of acute rejection. Recipients are most vulnerable during the first three months, but rejection can happen at any time. The development of antibodies in response to the discovery of foreign antigens in the donated graft causes acute rejection. Acute rejection can be managed by inhibiting the immune response if detected early enough, and irreversible destruction to the graft can be prevented in certain situations.

 

Chronic Rejection Phase

Repeated events of acute rejection can eventually result in chronic graft rejection and transplantation failure. Chronic rejection is marked by scarring of the tissue or organ, which might take months or years to appear after acute rejection has gone. There is currently no treatment for chronic rejection other than graft resection.

 

Donor-recipient Matching

Prior to transplantation, the donor and recipient should be thoroughly matched for compatibility to reduce rejection. The greater the donor and recipient match, the more probably the transplant will be effective. A variety of tests are used to determine donor-recipient compatibility, including:

  • ABO blood group compatibility. Both the donor and the recipient are tested to see if their blood typing is compatible. This is the first screening to be performed because if the blood typing does not match, the transplant will be rejected quickly. ABO compatibility is not required in some transplantations, such as those performed on children and bone marrow transplants. 
  • Tissue typing. A blood sample is drawn from the recipient in order to detect the human leukocyte antigen antigens located on the surface of their cells, which will aid in the screening for a histone compatible donor. The more similar the donor and recipients' human leukocyte antigen types are, the more likely the transplant will be successful. Due to their genetic similarities, family members, particularly siblings, are frequently the best Human leukocyte antigen matches.
  • Cross-matching. Blood samples are collected from both the recipient and the donor, and the donor's cells are combined with the recipient's serum samples. If the recipient's antibodies target the donor cells, it's deemed a positive match, and transplantation isn't recommended because of the higher chance of hyperacute rejection.
  • Panel reactive antibody test. Reactionary antibodies against a random sample of cells are examined in the blood serum of patients undergoing transplantation. The quantity of human leukocyte antigen antibodies in the blood is likely to boost after prior exposure to foreign tissue, such as through blood transfusions, pregnancy, or past transplants. The bigger the number of human leukocyte antigen antibodies present, the greater the patient's panel reactive antibody level, and the greater the risk of transplant rejection. It may be more difficult to locate a match if panel reactive antibody levels are elevated, and a higher dose of immunosuppressive medications may be indicated.
  • Serology screening. Patients and donors receiving stem cell transplantation will be subjected to pre-transplant serology testing. This is done to determine the immune function of both the donor and the possible future recipient against a variety of clinically important disease-causing organisms, such as HIV, Cytomegalovirus, and Epstein-Barr Virus in order to rule out the possibility of re-infection or reactivation of the infection after immunosuppressive drugs. People are frequently matched based on Cytomegalovirus and Epstein-Barr Virus status.

 

Immunosuppressive Medications

Patients are given immunosuppressive medicines to weaken the immune reaction in order to reduce the likelihood of transplant rejection. Immunosuppressive medications are given in two stages: an initial induction stage with a high dose and a later maintenance stage with a smaller dose.

Based on the type of transplant and the medication regimen selected, the medication combination and dose will vary. If a patient has an acute rejection event, the drug combination may need to be changed, and the dose may need to be increased. Alternative medications may be administered as a result of adverse effects. In the past, the most often prescribed immunosuppressant medication was steroids. However, because of the negative side effects, their use is being limited.

All recent immunosuppressive medications have drawbacks. Immunodeficiency is one of these medications' significant drawbacks. Due to the non-specific nature of these immunosuppressive medications, they will weaken general immune system function, leaving patients vulnerable to infectious agents. Furthermore, many of these treatments are linked to negative side effects like elevated blood pressure, reduced renal function, diabetes mellitus, and increased cancer risk, to mention a few. Patients must take a significant number of immunosuppressants every day for the remainder of their lives, which has a significant influence on their health and mode of living. A delicate balance must be maintained between reducing immune system function to minimize rejection, avoiding medication toxicity, and preserving adequate immunological function to fight disease.

 

Immunophilin-binding Medications

Cyclosporine and tacrolimus are two immunophilin-binding medications that are currently available. These drugs are calcineurin inhibitors, and they work by reducing the generation of cytokines, notably IL-2, which suppresses T cell activation. They are linked to several other toxicities, many of which are dose-dependent. Both medications can cause nephrotoxicity. Cyclosporine causes higher hirsutism, gingival enlargement, hypertension, and hypercholesterolemia than tacrolimus. It's also crucial to be aware of possible drug interactions.

The soil fungus Streptomyces tsukubaensis produces tacrolimus, a macrolide lactone antibiotic. It has the same mode of action as cyclosporine but attaches to a distinct cellular protein. With tacrolimus, neurotoxicity, baldness, and posttransplant diabetes mellitus are more common than with cyclosporine.

The change of brand to generic tacrolimus is common, although it necessitates careful monitoring of tacrolimus concentrations.

 

Mammalian target of rapamycin (mTOR) inhibitors

Sirolimus is a macrocyclic antibiotic generated via Streptomyces hygroscopicus fermentation. It binds to FKBP-12 and likely affects the function of the mTOR inhibitor, which inhibits IL-2–mediated signaling pathways and causes G1-S cycle arrest in T and B Lymphocytes. Sirolimus can cause leukopenia, low platelets, anemia, high cholesterol, and hypertriglyceridemia, among other side effects. Mucositis, delayed wound closure, lymphocele development, pneumonitis, and protracted delayed graft function have all been linked to it.

 

Antiproliferative Medications

The most frequently used medications in this class are azathioprine and mycophenolate mofetil. Various antiproliferative drugs have been tried, including cyclophosphamide and, more recently, leflunomide.

Antiproliferative drugs stop DNA replication and stop B and T lymphocytes from proliferating. Mycophenolate mofetil is a chemical synthetic version of the natural fermentation product mycophenolic acid that inhibits inosine monophosphate dehydrogenase in a noncompetitive, reversible manner. Purine biosynthesis is hampered by this. Nausea, diarrhea, leukopenia, and thrombocytopenia are all side effects of mycophenolate mofetil. Mycophenolate mofetil has been linked to invasive cytomegalovirus infection in the past. Mycophenolate mofetil administration has been linked to improved or stable kidney function, many years after transplantation.

 

Antibodies

The FDA has approved two IL-2 receptor antagonist antibodies for kidney transplantation inducement. Anti-lymphocyte globulins, such as muromonab-CD3, and polyclonal antibodies, anti-thymocyte globulins generated from horse or rabbit origins, have been licensed for the management of rejection. In some healthcare institutions, they have also been used as induction medications. Because of decreased use and the introduction of additional successful treatments, daclizumab was taken off the market in the United States.

Antibodies bind to lymphocyte-specific antigens, causing thymus-derived lymphocytes to be depleted and disrupting cell-mediated and humoral immune function. Lymphocytes are depleted by complement-mediated lysis in the vascular compartment or opsonization and consequent macrophage uptake. Fever, shivering, thrombocytopenia, leukopenia, and headache are common side effects after the first few doses.

Belatacept is a protein complex that inhibits T-cell stimulation by blocking co-stimulation. It has been approved by the FDA and the European Medicines Agency for use in the management of acute rejection of renal transplantation in adults when combined with corticosteroids and immunosuppressive drugs.

Belatacept was also linked to a minor but significant increase in the likelihood of lymphoproliferative disease after transplantation. Patients who have not been subjected to the Epstein-Barr virus have a higher chance of developing the post-transplant lymphoproliferative disease. Patients who have never been exposed to the Epstein-Barr virus will have a harder time generating an efficient immune reaction if they get infected after transplant.

 

Corticosteroids

Corticosteroids have long been a staple of immunosuppression and are still widely used today. Newer treatments, on the other hand, strive to limit the use of corticosteroids in order to avoid the negative side effects that come with them. Corticosteroids are still useful in the treatment of acute rejection events.

 

Future Transplantation Treatments

Other new medications, in addition to current immunosuppressive agents with better selectivity and fewer side effects, could one day drastically minimize or eliminate the likelihood of rejection.

Beyond their present use in managing blood diseases, stem cells may have a significant effect on transplantation in the future. Multipotent stem cells have the potential to differentiate into any cell in the body, which can be used to build tissues and organs. Furthermore, the fact that other cell types can be made to have stem cell capabilities indicates that the cells required to make the tissue could come straight from the recipient, avoiding rejection.

Another potential strategy is to use 3D printing to create organ scaffolding and then grow stem cells around them to biologically recreate the tissue being transplanted. Bio-manufacturing of tissues and organs would alleviate the load on the restricted donor organs while also reducing the likelihood of transplant rejection if the patient's stem cells were employed.

Improvements in stem cell transplant, on the other hand, are unlikely to have a significant impact on organ transplants in the next years, according to the UK national strategy for organ transplants. As a result, enhancing existing treatments and discovering new immunosuppressive regimens remain on top of transplant medicine research.

Improving donor-recipient compatibility testing could minimize the chance of transplant rejection and improve the transplant's lifespan. The immune response of the recipient will be more tolerant of the transplanted organ or tissue if the donor and recipient are well matched. Furthermore, a better knowledge of the discrepancy between the donor and recipient may serve to better advise post-transplantation treatment techniques and avoid recurrence bouts of acute rejection.

Significant advancements in transplant practice have resulted from immunological studies. Immune rejection, on the other hand, is still the most severe obstacle to efficient transplantation. Continued research is needed to develop strategies to reduce the risk of rejection, optimize diagnosis, and ensure the transplant's long-term viability, all of which would have a considerable influence on the already-scarce donor organs.

 

Conclusion

Over the last three decades, advancements in transplantation immunology have enabled the immediate increase of organ and tissue transplantation in medicine. Even when human leukocyte antigen incompatibility exists, modern immunosuppressive drugs have enabled the regulation of solid organ and tissue rejection as well as graft-versus-host syndrome. Hematopoietic stem cell transplantation is not only a viable therapy option for hematological diseases, including primary immunodeficiencies, but it is also the therapy of choice in many situations. Novel immunosuppressors with less toxic effects and more selectivity to reduce graft rejection while conserving general immunity and therefore permitting improved infection management will likely be developed in the future in the field of transplantation immunology. Gene therapy has shown promise in treating severe primary immunodeficiencies; nevertheless, there are several issues with this strategy that must be addressed quickly, the most serious of which is insertional mutagenesis, which has been observed with the gene vectors employed so far in this.