There is a striking difference between ethnicities in the success rate of finding a suitable organ donor. After one year on the transplant list, 28% of people from minority ethnic groups as opposed to 41% people of white ethnicity, had been successfully matched and transplanted in 2019/20 in the UK (2020/21 data was affected by COVID-19).
This alarming fact poses questions about inequality within transplantation services. However, the problem is far more multifaceted than it first appears. In the UK, there are far fewer registered donors from black and South Asian communities, amplified by a greater proportional need. It’s scientifically established that blood and organs can be racially and ethnically specific and in a country such as the UK, that is ethnically diverse, this contributes directly to the disparity in waiting times.
This last point is a difficult one to get your head around, so we ask Dr Nadia Terrazzini, Principal Lecturer in Clinical Immunology at the University of Brighton, to help us dig a little deeper into some of the immunological factors that determine transplant success and to tell us why ethnic concordance is often important in finding a match.
Q1: Most people are familiar with the different blood groups and how ABO compatibility is crucial in successful transfusion, but could you give an overview of any other potential incompatibility problems in relation to solid organ transplantation please?
ABO blood compatibility is indeed a critical factor both in transfusion and in transplantation. Organ transplants need to be matched by blood group, because a blood group mismatch causes immediate and irreversible humoral reaction, called hyperacute rejection. This is mediated by proteins in your blood, called antibodies, which can recognise and react to small bits of sugar embedded in the surface of the blood cells.
But even when blood groups are matched, we can have the rejection of a transplanted organ as a cellular reaction mediated by the T-cell response. T-cells are white blood cells that are part of the adaptive immune system and protect us from foreign particles (antigens) that are recognised as “non-self”. All nucleated cells express proteins on their surface, known as the Major Histocompatibility Complex (MHC) or, more specifically in humans, the Human Leukocyte Antigens (HLA). These HLA allow us to react to infections as they present exogenous and potentially dangerous antigenic peptides that T-cells recognise to initiate an immune response. T cells are able to recognise our own HLA (this is called ‘self-restriction’), so we normally do not activate a response to our own cells and tissues (i.e. we are ‘tolerant’).
HLA are the most polymorphically expressed proteins of the whole genome. It means that there are vast numbers of variants of HLA expressed by different people. We all express individual forms of HLA and the likelihood of having identical HLA to another person is extremely low. This diversity of expression gives us a great genetic survival advantage, in that we can all react differently to micro-organisms, such as viruses or bacteria. Without this variability of HLA expression, if a virus was able to kill one individual, it would be killing all of us. So HLA help to save us from extinction!
The problem arises when, due to this considerable diversity of expression between individuals, the recipient’s T-cells recognise the HLA on the transplanted organ as “non-self”. When tissues from an organ transplantation are identified as “non-self”, the immune system is triggered in the same way it is when a dangerous micro-organism is detected, and ultimately, destruction of the transplant is initiated.
Q2: How does ethnicity play a role in these differences?
Unless you are an identical twin, it is very likely that you are quite different genetically from the next person, and this of course is the case for the HLA found on the surface of your cells too. We all express two different sets of HLA variants, as alternative forms of genes called alleles. We inherit these genes from our parents as a set (called the haplotype), one set from each parent and we express them both (i.e. they are codominant). The inheritance of either forms of these alleles from each parent is completely random. This means that one sibling might express a different HLA haplotype to another and the odds of having an identical match is 1 in 4 (or 25%). But still, the chances of having complete matching of HLA within your family are far greater than when compared to the general population.
Outside of your immediate family, the next group of people with potential HLA similarities are from within your own ethnic group, where there are fewer genetic differences. This is because up to a point, allele frequencies stay within populations with demographic history, meaning closer HLA matches. You can imagine that with so many potential variants of HLA, it seems almost impossible that a match will ever be made, but you just need to search for the closest match by way of a point scoring system. It’s doubtful that the donated organ will be an identical HLA match, but this is where immunosuppressants come in, that help dampen the immune response.
The barriers behind the unavailability of organs for some demographics are not just socioeconomic or cultural; they are also immunological. A patient’s ethnicity on the organ waiting list is never directly considered. Still, if the availability of organs from minority ethnic groups is low and the donor organ pool is mostly white, the point-system matching the HLA ultimately means there are more available matches for people of white ethnicity in the UK. It is fundamental that people understand and are aware of the importance of organ availability and that there needs to be an increase in donations from minority ethnic groups.
Q3: Is there a difference in terms of immunological factors between a living as opposed to a deceased (cadaveric) organ transplantation?
There have been promising advances in cadaveric transplant donations, namely the liver or portions of the liver, like the lobes. However, living donations have a much higher survival rate than the cadaveric, mainly due to the increased inflammatory markers usually seen in the latter. This normal inflammatory process damages the organ, making it more susceptible to rejection, where the donor’s immune system attacks the graft leading to rejection. Interestingly, this rejection can happen years later and is commonly referred to as delayed rejection. Overall, a living organ donation is preferable.
Q4: Even with successful immunological checks and common HLA factors, some recipients still reject transplant organs – why is that?
There are different stages of rejection that are classified as hyperacute, acute or chronic. Hyperacute and acute rejection happens immediately or within weeks after the organ is transplanted, but chronic rejection can occur months or even years later. Even with the best matched HLA compatibility, there are other polymorphic proteins that are genetically unique to an individual that may initiate an immune response and ultimate rejection. It has been shown in controlled experimental environments using genetically identical test subjects, that rejection is still possible. Organisms are extremely adept at identifying self from non-self, and again, the correct balance of immunosuppressant drugs is vital to the viability of a transplanted organ. Whilst immunosuppressants help to mitigate the immune system’s attack, they also expose the body to a range of infections and diminish its vigilance against cancer.
Q5: Are artificial organs the way forward in transplantation?
Artificial organs are another great frontier to explore, bringing hope for the future. New technologies use stem cells and draw upon 3D printing to create an organ scaffold. The use of pluripotent stem cells to differentiate into any cell in the body means that potentially any target tissue can be manufactured. This possibility can free recipients from relying on organ donations and the worries of rejection. We know the benefits of working with stem cells and how promising the future looks. The therapeutic use of stem cells is already a reality for the treatment of many blood disorders. Further years of study around stem cells can also help to advance the area of new treatments in transplantation.
Q6: What practical advice would you give to students that want to focus their career path towards Immunology?
Be curious, be interested, keep reading, keep asking questions, be inspired by networks and societies outside of your academic studies. Immunology is not something just found in a book, on the side, it’s all around us. If COVID has taught us anything, it’s that immunology is at the core not just of our survival, but how we live as communities. There are so many connections between science, communication and what we do for each other. With a proper immunological knowledge we can protect communities, from improving organ donation to vaccination rates. And the more we learn, the more we can facilitate the development of new strategies in clinical immunology.
