| antigen Antibody Organ allocation Rejection Immunosuppression 32 elias Organ transplantation ‘Nowadays it is possible to transplant a surprisingly large range of organs from one person to another. This has improved the lives of thousands of people throughout the world. However, organ transplantation is not without its problems. This article explains compatibility issues and how the risks of rejection of transplanted organs can be reduced. ransplantation is the removal of a whole lorgan, or part of an organ, from one body and its implantation into another body to replace the recipient's damaged or failing ‘organ with a working one. It can be split broadly {nto two areas — solid organ transplantation and bone marrow transplantation. Both can provide cure for various illnesses, but for the purposes of this article only solid organ transplantation compatibility will be discussed. Solid organs that can be transplanted include the kidneys, pancreas, liver, heart, lungs, skin, cornea and pancreatic islet cells. For organ transplantation to be successful there must be biological compatibility between the donor and recipient. If this is not the case, an immune response will be triggered in the recipient against the donor’ antigens, and the organ will be rejected BO blood group system “The ABO blood group system describes the antigens oon the surface of red blood cells, These antigens determine the individual's blood type. This can be group O, A, B or AB, depending on which genes ‘were inherited from the parents. Blood group A individuals have A antigens on the surface of their red blood cells; they will also have circulating antibodies directed against B antigens. Blood group B individuals have B antigens on the surface of their red blood cells and contain circulating anti-A, Biological Sciences ReviewAF Lave Wr A+ Figure 1 The ABO blood group system. antibodies. Individuals who are blood group AB have both A and B antigens expressed on the cell surface and have no circulating antibodies, whereas blood group 0 individuals have no antigens on the surface oftheir cells and contain anti-A and anti-B circulating antibodies (see Figure 1). Therefore before organ transplantation, the blood groups of both donor and recipient are determined to ensure compatibility (see Figure 2). Ideally the blood groups af the donor and recipient would be identical eg blood group O organ going to a blood ‘group © recipient), but this is not always possible. Im some cases there will be a difference between the donor and recipient blood type. For example, a blood group O donor can donate to a blood group A recipient, This is possible because a group O individual does not have either A or B antigens on the surface of their red blood cells, so no reaction will occur with the anti-B antibodies in the blood ‘group A recipient Human leucocyte antigen ‘The other antigenic system that must be compatible between donor and recipient isthe human leucocyte antigen (HLA) system. These antigens are protein complexes on the surface of all cells with nuclei The role of HLA molecule is to present foreign antigens ((e. during an infection) to the immune system, stimulating a response. Individuals express the combination of HLA antigens that are inherited from their parents. This is referred to as their HLA type. Research has shown that the fewer the number ‘of mismatches between clonor and recipient HLA, the less likely it is that the organ will be rejected post-transplantation. September 2012 Pre-transplantation testing Ia patient has been referred for transplantation, Jaboratory tests must be performed in order for them to be matched with the most suitable donor. First, a test is performed to determine the patient's HLA type. DNA jis extracted from the cells ina patient's blood sample, It is then combined with HLA.specific primers (small lengths of DNA that bind to specific types of HLA DNA) and subjected to the polymerase chain reaction, which creates multiple copies of the patient’s DNA (see Biotocica Scumces Review, Vol. 24, No. 2, pp. 20-21). The products of this reaction are then visualised using gel electrophoresis, which allows the scientist to determine the patient's HLA type. Second, the patient's serum — the part of the blood that contains all non-cellular material including antibodies — is screened to create an % _ Recipient Boge ee > J ><] \ 1) RE Figure 2 A80 blood group compatiilty for organ transplantationPositive Donor ce ) to 4 ) ral ‘A visualisation stain is aed 10 the reactor ‘The stains made of a mixture of chemicals that stains dead cells red Figure 3 The eros match test. 34 Antibody ‘Serum Patients serum Containing antibodies Patients serum is ‘mised with éoner cells and left to incubate I there are antibodies in the patient's serum ‘and they are donor specific, they wil bind Y donor cells { <_Somplement | Complement i addea ‘othe reaction and binds to patient antibodies bound to ng activate and cause ‘the death of the donor cells Patient's serum containing antibodies mixed with donor cells 4g ‘and left to incubate If there are no antibodies in the patient's serum drectea / “® ‘owards donor antigers, the surface of the they will not bind Complement — ) Complement is added, but ino antibodies are _/ bound to the donor cell then it cannot bind ‘af donor dicted ‘antibodies visualisation stain is added to the reaction ‘The stain is made of mixture of chemicals that stain lve cells, sreen antibody profile. The patients serum is mixed with ‘microbeads that have multiple HLAs on their surface A fluorescent tag is then added to the mixture, This tag will bind to any antibodies that have bound to the beads. The mixture is then run through an instrument that measures fluorescence to determine ‘whether any HLA antibodies are present and, ifthey are, the antigens they are directed against. Screening is essential because if the patient has pre-existing antibodies against the donor's HLA proteins, the transplanted organ may be rejected. Patients can develop these HLA-specific antibodies from erate Penton 3 three different events — termed sensitisation events, These events are pregnancy, blood transfusions and previous transplants. During a sensitisation event, the body's immune system ‘sees! an HLA that is non-self (je. the immune system has never been exposed 10 this before) and stimulates an immune response against it producing antibodies which can, remain in the patients body for a Tong time. The other major test performed before transplantation is ac match. This test involves mixing the patients serum with donor cells to see if theres any reaction (see Figure 3). If the patients serum contains antibodies against the HLA proteins expressed on the donor's cells, then the antibodies will bind to the donor cells, forming immune complexes. Complement is then added to the reaction. Complement is an immunological molecule that binds to antibodies and causes the cell to which the antibodies are bound to die, Therefore, if immune complexes have been formed, the complement will bind to the antibodies. This causes the donor cells to die — a positive reaction. However, if the patient’s serum does not contain antibodies against the donor's HILA proteins, then no antibodies will bind to the donor cells, complement cannot bind and cell death will not occur — a negative reaction. A stain is used to visualise the reaction — dead cells stain red, live cells stain green. If the result is postive, the transplant will not go ahead because the patient has amibodies directed against the donor and may reject the organ. Donors and organ allocation ‘Organ donors can be living or deceased. Living donors are generally family members or close friends of the patient who are willing to donate an organ to help save, or improve the quality of, the patient life, However, notall living donations come from friends or family. Altrustic donors also donate ‘organs. Altrustic donors are people who are willing to donate an organ without knowing who is going to Biological Sciences Reviewreceive it. People are able to donate a kidney as they can function ‘with their one remaining kidney. Kidney transplantation has been performed more than any other form of organ transplant. In the UK, 2732 out of 3740 transplants performed in 2011 were kidney transplants, and living donation has become the largest source of kidney donors. Kidneys are not the only organs that can be donated from a living donor, other organs include lobes of the liver, lobes of the lung, portions of intestine and portions of the pancreas, Deceased donation can also be split into two categories — donation following brain death (DBD) or donation following circulatory death (DCD). DCD is where the donor's heart has stopped beating and blood has stopped circulating around the ‘organs of the body. Organs donated from a DCD donor tend to be used close to the retrieval centre (the hospital where the organs are removed from the donor) to reduce the time the organ is outside 2 body. This is important, as research has shown that the longer an organ remains without a blood supply, the less likely the organ will fanction optimally post-transplantation, DBD donors are clinically dead but kept alive by a ventilator These organs have a constant blood supply until they are removed, and so they can be transported from the retrieval centre to a hospital where a potential recipient will be waiting, Organs from DBD donors are allocated via a national scheme. Patients on the national transplant waiting list accumulate ‘points for a given donor based on various factors, including how long they have been on the list, age and HLA compatibility with the donor. The patient with the highest number of points is selected for transplantation. The consulting surgeon will then assess this patient to ensure they ate fit for transplantation; if s0 the transplant will proceed, Organ rejection and immunosuppression Organ rejection is still the biggest problem after transplantation. 1t is caused by the recipien’s immune system attacking the transplanted organ. ‘There are different types of rejection based on the time posttransplant it occurs and the clinical features displayed. Hyperacute ejection happens within minutesof transplantation owing 10 pre-existing HLA andjor ABO antibodies. However, because of pre-transplantation laboratory testing. hyperacute rejection is now extremely rare. (If hyperacute rejection were to ‘cut, the organ would be removed from the patient immediately.) Accelerated acute rejection happens a few days to a week post-transplant. It occurs when a recipient has previously been sensitised and s0 a rapid immunotogical response is stimulated, which requires certain types of immunosuppressive drugs to combat. Acute rejection is seen within the first 6 months posttransplant and is thought to occur to some extent in all transplant recipients. Acute rejection occurs due to certain HLA mismatches between, the donor and recipient. Acute rejection is managed with immunosuppressive drugs tailored to each transplant recipient based on the symptoms shown and the immune cel present in the transplanted tissue atthe time of the biopsy. Chronic rejection may happen after 6 months post-transplant. It ‘occurs asa result of both immunological and non-immunological mechanisms. immunologically, chronic rejection is a result of September 2012 pees ente| Biopsy A procedure winere a sample of tissue is obtained using 2 surgical procedure, which can then be examined under a microscope to provide information needed to dlagnose, monitor or treat a condition Immunosuppression Lowering or suppressing the activity of the immune system. National transplant list A ist containing an order of patients ‘who requie a transplant and which organ they require, Polymerase chain reaction A technique used to amplify a region ‘of DNA, creating multiple copies. constant acute rejection episodes and an overwhelming antibody response directed toward the grafted tissue, Non-immunological factors that contribute to chronic rejection range fom infection of thetransplanted organ to complications associated withthe surgical procedure. Chronic rejection is managed with immunosuppressive drugs tailored to each transplant recipient. However, despite immunosuppressive drugs, chronic rejection remains the single largest problem in achieving long-term survival posttransplant. Despite the technique’ employed to ensure the best posible match between the donor and recipient, rejection can occut. As @ result, transplan recipients take immunosuppressve drugs for the restof their life to reduce the chance ofan immunological response mounted towards the transplanted tissue. Essentially, effective immunosuppression prolongs the life ofthe transplanted organ However, immunosuppressve drugs also have a negative effect as they leave the recipient with a depleted immune response, making, transplantation patients mote susceptible to infections Supply and demand ‘Throughout the world there is a great demand for organ donation. Some countries have far better donation rates than others (see Figure 4 on p.36). Spain is the lead country in rates of organ donation as it (as well as some other countries) has ‘opt out” legislation in place. Opt out is essentially presumed consent — all people are donors unless they actively opt out of organ donation, Other factors that increase the donation rate are a larger number of transplant centres per million population, a higher percentage of the population enrolled in university education, and a higher percentage of Roman Catholics (as this religion, in particular, supports organ donation) ‘The number of patients on the UK transplant list greatly exceeds the number of potential donors and transplants (see Figure 5 on p.36). Currently, efforts are being made to improve the donor iteeaeretuty British Transplantation Society website: wurm.bts.org.uk [NHS website for organ donation. You can join the organ donation register her, I also contains useful information and facts and figures about organ donation inthe UK: wwrw.organdonation.nhs.uk/ukt NHS Blood and Transplant Authority worw.nhsbt.nhs.uk 35[Bl Presumed consent 5 DB Informed consent | | 2a 21 Soe 20 15 148 u 145 Tat 132 132 | 10 | © Portes St go aghgi? 23 i gabab3 s = = zB 3 & s Country Redan fom won. uktransplant org.uk Figure International organ donation rates. Note that the countries with the highest donation rates all have presumed consent (opt out) legisation in place, Number 8000: 7597 7000 ~ TH Donors 0004 aes Es) oar es i Transplants * People on the traneplant ist 4000: a ase 2648 ane 2105 aa 2000 1000} 7 na 03 823 a 0. : 2000- " 2001- " 2002-2003" 2008- " 2005- 2006- | 2007- 2008 2009 2001 © '2002« 2003» 2008 ©2008 «= 2006. «= 2007 «2008-2009 2010 Year Taken fom Actity Report 2070-11, UK Transplant wwakcransplnt.orgu Figure 5 The number of transplants, donors and size of transplant waiting list in the UK over the past 10 years. The number of ‘transplants is greater than the number of donors because one donor is able to donate several organs. 36 Biological Scinces Reviewpool in order to match the demand. Ethnically, the UK is one of the most diverse countries in Europe, which also impacts on the organ transplant list Approximately one in four patients waiting for a Kidney are Black or Asian because they are more susceptible to conditions that can lead 10 kidney failure such as diabetes and high blood pressure AAs a result of higher demand and a shortage of ‘organ donors, Black and Asian people have to wait approximately twice as long for a kidney transplant as the rest of the UK population. This is, because Black and Asian people have uncommon HLA types, making it harder to find a suitable donor. Recently there was a push to increase the number of Black and Asian donors, but whether this thas made an impact remains to be seen. Since the first organ transplant in 1954, the rate of transplantation has groven exponentially. Since the 1950s, there has been massive improvement in both pre-and posttransplant care. Scentificimprovements determining donor and recipient compatibility and the advent of superior immunosuppressive drugs have increased the life expectancy of both the ¢rateful recipient and the transplanted organ. Organ transplantation has improved the lives of thousands ‘of people worldwide but despite the growth in transplant awareness, there tll avast difference in 6 PHILIP ALLAN Getting the most from lots more linked to the articles in each issue. # Register your detals, with a user name and * si Unlimited access for staff and = Annual subs Septomber 2012 Use the free online resources Register today for free revision exercises, weblinks, podcasts and + Goto www philipallan.co.uk/magazinesonline sssword of your choice + Log in with your code and keyword from the back cover ofthis iss Subscribe to the online archives Subscriptions to the online archives of back issues are available forall our ‘A-level magazines. Go to www.philipallan.co.uk/magazines for: © 100s of articles from digital versions of back issues accessible and comprehensive search students, with weblinks yo ‘tons for everyone to share, from as little as £64! the number of donors and potential recipients Efforts are being made to rectify this imbalance, but without a radical change in donor recruitment the disparity between the number of recipients and potential donors looks set to remain, Points for discussion = Can you think of any ways to increase the donor pool? = How should an ‘opt out’ scheme work? = What are the ethical complications of organ transplantation? Re ee a eee eon ae Transplantation Laboratory based in Manchester Royal Infirmary, arch focuses on the minor genetic disparities between donor and recipients undergoing stem cell transplantation and how they correlate with the onset creo repo * For an organ transplant tobe successful there must be biological compatibility between the donor and recipient. * There are two major antigenic systems that must be compatible for solid organ transplantation to be successful — ABO and HLA, * Despite the biological compatibility between the donor and recipient, organ rejection can occur and can vary in severity ‘Inthe UK, there isa large disparity between the number of potential organ donors and recipients. To reduce the gap, more people need ta be made aware ofthe benefits of organ donation. magazinesonline your magazine? DD wymagazines acd to your VLE PEG eet 37