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The Science Behind Transplantation

Although the human body is generally quite robust, there are times when - for reasons related to physical trauma or disease - some parts of the body do not function as they should. One of the more drastic solutions to this is transplantation, which is the process of moving cells, tissues, or organs from one site to another.


What types of transplantation are there?


There are several different types of transplantation depending on (1) where the cells, tissues, or organs are coming from and (2) who is receiving the transplant or graft (shown in Figure 1).


Transplantation of material between different parts of the body in the same individual is known as an autograft, in which a common example of this would be skin grafting, where the skin is taken from one part of the body and placed over an area where the skin is missing or damaged (e.g. as a result of burns or surgical removal of cancerous skin). On the opposite end of the spectrum, it is possible to perform transplants between different species (xenografts) in a few cases. For example, heart valves from certain animals such as pigs or cows can sometimes be used as replacements for human valves.


However, when we talk about transplantation in a clinical context, we are typically referring to transplantation between different individuals of the same species. In rare cases, the individuals are genetically identical and the transplantation procedure performed is called an isograft. Though in most cases, transplants are between non-identical individuals and are referred to as allografts.

Figure 1: A diagram showing how the types of transplantation differ depending on the source of the graft and the recipient.


The first successful solid organ transplant achieved between humans was a kidney transplant between identical twin brothers in 1954 performed by Joseph Edward Murray, who eventually won a Nobel Prize for his work on organ transplantation. This milestone was crucial in showing that organ transplantation was possible, and paved the way for thousands of other successful transplants.


Today, over 100,000 solid organ transplants are performed globally each year, with kidney transplants being the most common transplants carried out. However, do bear in mind that many other parts of the body can be transplanted, such as the liver, the corneas, and even stem cells.


Graft rejection


Despite its game-changing clinical applications, one of the biggest problems we currently face with transplantation is rejection. This is basically when the recipient’s immune system attacks the transplanted tissue or organ in an attempt to destroy it.


Essentially, the process of rejection happens because the immune system is trained to attack “foreign objects” inside the body. They accomplish this by recognising molecular structures on the surface of foreign substances, which are called antigens. While being able to identify foreign material is helpful for fighting off harmful pathogens, the immune system has no way of recognising that the transplant is supposed to be helpful and thus attacks it in the same way instead.


The concept of transplant rejection has been demonstrated on mouse models with experimental skin transplants, where different inbred mouse strains either accept or reject the transplant depending on the similarity of the mouse it came from (See Figure 2).

Figure 2: A diagram showing the patterns of transplant acceptance and rejection between different animals-specifically a white mouse strain (A), a brown mouse strain (B), a hybrid between these first two strains (A/B), and a guinea pig. While a skin transplant from one white mouse to another white mouse (which in this model are inbred to the extent they are genetically identical) is successful, a transplant from a brown mouse to a white mouse is rejected due to identification of foreign material. Meanwhile, a transplant from a white mouse strain to a hybrid mouse strain is accepted because the hybrid mouse’s immune system identifies the genetic material from the white strain as being part of its own genetic makeup. In contrast, the transplant does not work in reverse, which is because the white mouse’s immune system can identify part of the transplant as foreign for it is composed partly of differing genetic material. Finally, the guinea pig transplant is rejected by the mouse’s immune system because the genetic material is totally foreign due to being from a different species. This figure is courtesy of Immunopaedia.org.


It is also possible for this phenomenon to work in reverse - that is, for the transplant to attack the recipient - if the donated transplant contains immunocompetent cells (i.e. cells which are capable of producing an immune response) as is the case in bone marrow or stem cell transplants. This is known as graft-versus-host disease (GvHD) and is caused by immune cells from the graft perceiving the rest of the body as foreign and producing an immune response against the rest of the host. At its most severe, this response can be life-threatening.


The key antigens that the immune system recognises in transplant rejection and GvHD are human leukocyte antigens (HLAs), which are encoded by a series of genes known as the major histocompatibility complex (MHC). All HLAs (which can also be referred to as MHC molecules) correspond to one of three MHC classes, but only HLAs corresponding to the first two are relevant here since HLAs relating to class III are not involved in graft rejection.


In essence, MHC class I HLAs are expressed on all types of nucleated cells (i.e. not red blood cells since they do not have a nucleus), while MHC class II HLAs are expressed only on immune cells. If the HLAs expressed on transplanted material do not match the HLAs expressed on host cells, then the immune system is able to distinguish between the self and the foreign tissue (this phenomenon is known as allorecognition), and an immune response is induced.


What types of rejection are there?


Transplant rejection can be split into three clinical categories depending on when it occurs:

  1. Hyperacute rejection: Occurs within hours (or even minutes) following transplantation

  2. Acute rejection: Occurs in the days and weeks following transplantation

  3. Chronic rejection: Occurs months or years following transplantation


Hyperacute rejection

Hyperacute rejection is normally caused by the presence of Y-shaped molecules known as antibodies. These antibodies are typically specific for either HLAs or blood group antigens present in the donor material.


When these antibodies bind to donor antigens, they stimulate the immune system to attack the lining of the blood vessels in the graft (the vascular endothelium). In response to this injury, platelets (a type of blood cell) are activated and start to aggregate at the site, which results in the formation of blood clots (thrombosis) in the blood vessels of the graft. These blood clots cut off blood supply to the graft, leading to necrosis (i.e. the death of the graft tissue).


The only way to stop hyperacute rejection is to remove the allograft. However, this kind of graft rejection is the rarest of the three types. In fact, it encompasses less than 1% of transplant rejection cases because of the extensive tests that are now performed on the donor graft and the recipient to rule out the presence of such antibodies (discussed in more detail in the next section).


Acute rejection

Acute transplant rejection generally involves a type of white blood cell known as T cells, which are capable of recognising intact class I and class II HLAs displayed on the surface of special donor cells known as antigen-0presenting cells.


There are a few different types of T cells with different roles in the immune system, but the main two types involved in graft rejection are cytotoxic T cells, which kill cells directly, and helper T cells, which assist in the activation of other immune cells.


Receptors on the surface of T cells (known as T cell receptors or TCRs) interact directly with these HLAs, which is known as direct allorecognition. However, allorecognition is also possible with smaller components of a donor HLA via indirect allorecognition, which is when antigen-presenting cells from the recipient engulf donor HLAs and internally process them before presenting small fragments of the donor HLAs on their surface which the TCRs can also recognise.

Figure 3: Diagram showing the difference between direct and indirect allorecognition. In direct allorecognition, the HLA (or MHC molecule) is presented by a donor antigen-presenting cell. Whereas in indirect allorecognition, only a small fragment of donor material interacts with the T cell and is presented by a recipient antigen-presenting cell instead. This figure was taken from Ingulli (2010)’s Mechanism of cellular rejection in transplantation.


This allorecognition leads to the activation and proliferation of T cells. Consequently, these activated T cells may either attack the graft directly (in the case of cytotoxic T cells), or send out signals that attract other immune cells to the site of the graft (in the case of helper T cells), further increasing the number of immune cells attacking the graft. This type of acute transplant rejection is known as acute cellular rejection or T cell-mediated rejection.


Meanwhile, it is also possible in some cases for an individual to develop antibodies to donor HLA molecules over time, which leads to what is known as acute humoral rejection. Its mechanism is similar to hyperacute rejection as outlined above, but is less severe and occurs over a longer period of time.


Chronic rejection

The mechanisms behind chronic transplant rejection are not as well understood in comparison to hyperacute and acute rejection, but it is thought to be caused by a combination of immunological mechanisms (similar to those outlined above) and non-immunological mechanisms.


Chronic rejection is typically characterised by the formation of scar tissue (fibrosis), the thickening and hardening of the walls of graft arteries (arteriosclerosis), and a gradual loss of function over time. Although chronic rejection can affect any organ type, it is particularly common in lung transplants, which means that the survival period following transplantation tends to be shorter than in recipients of other transplanted organs.


Preventing transplant rejection


Although an identical twin would be the ideal donor since they would be most genetically similar to the recipient and have the same MHC molecules, the rarity of this as an option (since identical or monozygotic twins account for just 0.4% of births globally) means that clinicians have to resort to other methods to find the best possible match.


Fortunately, there are a couple of things that can be done to reduce the chances of transplant rejection.


HLA typing

There are several screening tests that are used to assess the suitability of a match between a recipient and a potential donor. One common test is to establish blood types in order to ensure that donor and recipient blood groups are compatible. Following this, a blood test known as “tissue typing” or “HLA typing” is carried out to determine how many of the donor and recipient HLA molecules match one another and if it is enough for a successful transplant.


The British Society for Histocompatibility and Immunogenetics (BSHI) recommends testing five specific HLA markers (HLA-A, HLA-B, HLA-C, HLA-DR & HLA-DQ), and since individuals can express two kinds of each marker if they inherit different alleles for the MHC molecule from each parent, this means there are ten markers to be matched. A “10/10” match is optimal, but one mismatch is also acceptable, and multiple mismatches are not recommended.


With that in mind, it can take time to find an appropriate match because of the massive diversity in individual MHC combinations, but close family members of an individual in need of a transplant (such as parents or siblings) are more likely to have enough matching HLA molecules, which makes them the next best option after an identical twin. However, it is also possible for the donated organ or tissue to come from an unrelated individual if there is enough HLA similarity between the individuals.


Cross-matching

Another test carried out is cross-matching, which is where the recipient is tested to ensure that they do not have existing antibodies against the donor’s HLA antigens in order to prevent hyperacute rejection.


Immunosuppression

However, regardless of the extent of measures taken to minimise the degree of rejection, there is always still some risk of rejection. Consequently, the recipients of immune transplants will have to spend the rest of their lives taking medication that reduces the effectiveness of their immune systems (known as immunosuppressants).


Although immunosuppressants are useful for this purpose, they are unable to reduce the immune response that is initiated specifically against the transplant. Instead, they dampen down the whole immune system, which means that people taking them are more likely to get opportunistic infections. Opportunistic infections are caused by pathogens that would not normally cause disease in healthy individuals, but are able to take hold in those taking immunosuppressants because their immune systems have been compromised. Examples of pathogens that are commonly responsible for opportunistic infections in transplant patients include cytomegalovirus and Listeria monocytogenes.


Another drawback of immunosuppression is that the immune system’s normal defences against the development of cancer are also dampened, leading to an increased risk of developing certain cancers such as Kaposi’s sarcoma, a type of cancer that affects connective tissues.


As a result, immunosuppression in the context of transplantation needs to strike a good balance between sufficient control of the immune system to prevent it attacking the transplanted organ, thereby leaving the recipient with enough function so that they can still fight off infection to some extent.


The future of transplantation


Although transplantation is a highly valuable tool in healthcare, it is not possible to immediately provide this to all the individuals in need of them since chronic rejection can still persist despite the development of donor matching procedures and immunosuppressants.


Besides that, there are simply not enough organs available. As a matter of fact, there are currently around 6,000 individuals on the waiting list for a transplant in the UK.


To increase the number of organs available for donation, some countries such as France, the Czech Republic, and Singapore use an opt-out system where consent for organ donation after death is assumed unless an individual specifies otherwise.


In addition to this legislation, there is also a wide variety of cutting-edge research into transplantation being carried out which aims to address the shortage of transplants in different ways.


For example, it may be possible in the future to use material from genetically modified pigs as transplants. Indeed, this has already been tested in China, where researchers have transplanted pancreatic islet cells (which are capable of producing insulin) from gene-edited pigs into people with diabetes. Furthermore, other research focuses on how to increase the tolerance of the host to transplanted organs. For instance, one researcher outlined how a special type of T cell known as a regulatory T cell (which is involved in suppressing immune responses) could be modified to suppress the immune response specifically against the transplant.


At the end of the day, if some of these exciting new potential developments in the field of transplantation can eventually be put into practice, this would mean that we are able to give even more people who are experiencing what could otherwise be life-ending organ failure a second chance.


Author


Emma McCarthy

MSc Health Data Science

University of Manchester


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