Transplant Immunology

Transplant immunology is the study of the immune response to organ transplants in surgery. There can be many complications that arise from transplants but a major factor is the immune system’s response to a foreign organ. 

Why does the immune system reject an organ?

Every person has a specific set of Human Leukocyte Antigens (HLA) which are proteins found on the surface of cells. HLA allows our immune system to detect ‘self’ cells and ensures they don’t attack our own cells. Sometimes this can go wrong which causes auto-immune diseases like rheumatoid arthritis. However, the transplant organ will actually have a foreign antigen so it is difficult to stop the immune system that usually helps us fight off viruses and other infections. 

Here you can see that the HLA antigens act as markers to alert the immune system of a foreign cell. There may also be other antigens and markers on the cell too that help the immune system recognise cells.

The immune system of a patient will respond to the presence of the HLA proteins from the donor. Doctors try to find a “match” or a donor with similar HLA proteins. The closer genetically a patient is to a donor, the greater chance of their body encoding for similar shaped HLA. This is known as their histocompatibility. 

Sometimes the donor organ can attack the patient as well. The donor organs immune cells will respond to foreign antigens in the recipient causing an immune response that damages healthy self tissue as well. 

Here you can see that stem cells from the donor tissue can specialise and mature into immune cells when they are transplanted into a patient. The immune cells will be programmed to recognise different HLA self antigens so when they encounter the patients cells, they will recognise them as foreign and attack them. As a result, the patient can be harmed during a transplantation.

Genetics 

When deciding who is the best match, genetics has to be taken in to account. The further down this list, the further away genetics will be which means there is a greater chance of rejection. However, genetic engineering is improving xenogeneic tissues which could improve transplantations and reduce risk of rejection.

  • Autologous = A patient’s own cells. This type of transplant can occur when a patient needs stem cells. Stem cells are unspecialised cells that can replace damaged tissues such as burns. Umbilical cord stem cells can be kept from the umbilical cord of a person when they were born and used when they need them later on. These cells will have the least risk of rejection as they came from one’s self. 
  • Syngeneic = coming from an identical twin. Identical twins will have the closest HLA proteins and will reduce the risk of rejection and complications of transplantation. 
  • Allogeneic = from an individual of the same species but they will be genetically different. A greater histocompatibility will decrease the difference in genetics. However, the HLA genes are very polymorphic which means they may differ drastically from one person to another even if they are related. 
  • Xenogeneic = from different species. Currently, xenotransplantation is being developed using genetic engineering where the organs and cells of pigs could be used in humans. This could solve the increasing shortage of donor organs and help thousands of people waiting for organ transplants. 

How does the immune system attack?

The immune system is a complex system in animals that requires the work of multiple immune cells such as: phagocytes, B-lymphocytes and T-lymphocytes. An Antigen Presenting Cell (APC) will recognise a foreign cell and will present the foreign antigens on its membrane. This will stimulate T cells to interact with the antigens on the APC and decide whether it is a foreign or self antigen. If foreign, the T cells (specifically known as T helper cells) will stimulate T killer cells (that destroy foreign cells) and B cells (that produce antibodies to combat foreign cells). Eventually, the donor tissue’s cells will die and rejected by the body. A similar process happens when a pathogen (virus or bacteria) enters the body but when that happens our immune system is protecting us.

This is a macrophage which is a type of phagocyte cell. The process seen here is phagocytosis where the macrophage will engulf a foreign cell into a phagosome. They will then use lysosomes to digest the foreign cell. The lysosomes are packets of enzymes that digest cell material. However, they do not digest the antigens on the cell. Instead, it combines the antigen with a Major Histocompatibility Complex (MHC) and presents the antigen on its cell membrane to become an APC.

On the right you can see the functions of APC’s. They stimulate T helper cells by acting as a signal: “Look at this antigen, I found it next to the liver”. The T helper cell will signal to other immune cells to fight the “infection” by stimulating more macrophages, B cells and T killer cells.

Solutions

How can we prevent rejection? As mentioned before, using identical twins is an easy way to ensure there is not an immune repose. However, many people do not have an identical twin which means this solution is not universal. Instead patients are given immunosuppressive drugs that reduce and weaken the activity of the immune system. Obviously, this will make people more susceptible to other secondary infections like viruses and bacterial infections. 

Scientists have been developing xenotransplantation which is spearheaded by a company called eGenesis. They have used CRISPR technology (a genetic engineering tool which snips out DNA and replaced it with other DNA) to create pigs that can be used for organ donation. Currently, scientists are studying cancer to understand how it evades the human immune system, then they can apply that system to transplantation to reduce the risk of rejection. Here is a video from a scientist at eGenesis explaining their research and its benefits:

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