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In the 1940’s, pioneering immunologists such as Peter Medawar, Peter Gorer and George Snell working on animal models, developed the theories that underpin transplant immunology and the concepts of graft rejection.
Peter Medawar (born 26th February 1915- died 2nd October 1987) for his seminal work on Immunological tolerance in organ transplantation. He studied at Magdalen College in Oxford and carried out his seminal work in the University of Birmingham and University college of London where he was professor. His final role was as director of the National Institute for Medical Research, Mill Hill. Notable doctoral and post-doctoral students included Leslie B Brent and Rupert E Billingham respectively.
Peter Alfred Gorer (born 14th April 1907-11th May 1961) was a British immunologist, pathologist and geneticist and was the key developer of the discipline of Transplant Immunology. He was a graduate of Guy’s Hospital studied genetics at University College then worked at the Lister Institute in the late 1930s before returning to the pathology department at Guy’s. He is credited with describing the murine histocompatibility complex (H-2) and identifying antigen in the context of transplant tissue rejection. He was elected a fellow of the Royal Society in 1960.
Gorer collaborated with George Snell an American Geneticist from Boston Massachusetts. working on animal models, further developing the theories underpinning transplant immunology and the concepts of graft rejection.
Sir Peter Medawar (Nobel Laureate 1960) George Snell ((Nobel Laureate 1980) Peter Gorer (Royal Society 1960) Billingham, R., Brent, L. & Medawar P. ‘Actively Acquired Tolerance’ of Foreign Cells. Nature 172, 603–606 (1953).
Gorer, Peter Alfred, Sally Lyman, and George D. Snell. “Studies on the genetic and antigenic basis of tumour transplantation Linkage between a histocompatibility gene and ‘fused’ in mice.” Proceedings of the Royal Society of London. Series B-Biological Sciences 135.881 (1948): 499-505.
Peter Alfred Gorer, 1907-1961 | Biographical Memoirs of Fellows of the Royal Society
https://royalsocietypublishing.org/doi/10.1098/rsbm.1961.0008
Jean Dausset (Nobel Laureate 1980)
DAUSSET, J. “Iso-leuco-anticorps” [Iso-leuko-antibodies]. Acta haematologica vol. 20,1-4 (1958): 156-66. doi:10.1159/000205478
Since this pioneering work, we now understand the fundamental role that HLA plays in our ability to recognise self from non-self and why in transplant immunology, these polymorphic molecules are the major barrier to successful transplantation.
The speciality of Histocompatibility and Immunogenetics (H&I) arose to develop assays for HLA typing and HLA antibody identification in addition to crossmatching to determine the risk of transplantation between a particular recipient and donor. These assays are central to supporting patient work up for transplantation and facilitating effective use of donated organs.
In the UK there is a network of 24 H&I laboratories supporting both solid organ and haematopoietic stem cell transplantation. In kidney transplantation, patients are referred for transplant waiting list assessment and their HLA type and HLA antibody status is assessed. This information is required before a patient can be activated on the national transplant waiting list. Patients may develop HLA antibodies as a result of previous pregnancy, blood transfusion or transplant and establishing an accurate HLA antibody profile is essential to maximise a patients transplant opportunities. Scientists in the UK have played a significant role in developing the assays used throughout H&I laboratories to support kidney transplantation. Key developments in H&I services to support kidney transplantation are described below highlighting British contributions
A crossmatch is required to assess histocompatibility between a prospective donor and recipient.
The complement dependent lymphocytotoxicity (CDC) crossmatch assay
Dr Paul Terasaki is an American scientist but important to highlight as his development provided the platform for testing donor and recipient compatibility for most H &I laboratories around the world. Paul Terasaki and co-workers described the complement dependent lymphocytotoxicity (CDC) crossmatch assay. The aim of this assay was to replicate in the laboratory, what would happen if a transplant took place. Donor lymphocytes were incubated with recipient sera and if the recipient’s sera contained antibodies directed against donor HLA mismatches the CDC crossmatch assay would be POSITIVE. The introduction of this assay pre-transplant was fundamental in limiting the risk of hyperacute graft rejection due to donor specific HLA antibodies.
Flow cytometry crossmatch assay
In 1983 a flow cytometric crossmatch assay was described by Bernie Carpenter and co-workers at the Bigham and Women’s to further facilitate assessment of patient donor compatibility in kidney transplantation. The flow cytometry crossmatch had increased sensitivity over that of the CDC crossmatch. The UK H&I laboratories collaborated to understand the relevance of this new assay in clinical kidney transplantation.
DNA based HLA typing
HLA typing was initially performed using serological techniques, however these assays had major limitations due to the need for viable lymphocytes. The advent of molecular DNA based techniques revolutionized HLA typing.
HLA antibody identification
For many years the CDC assay was used for HLA antibody detection and identification. Patient sera was incubated with a panel of known HLA typed cells covering the majority of known HLA antigens allowing HLA antibodies to be determined. However, the advent Luminex® based solid phase assays in the 1990’s has revolutionised HLA antibody detection and identification. Commercial kits are available (One Lambda and Immucor) to allow the screening and accurate identification of HLA class I & II antibodies in a patient’s serum.
Luminex® based HLA antibody identification
With the advent of improved HLA antibody screening and identification, came the drive to improve organ allocation and utilisation. UK H&I scientists were in the forefront of initiatives to improve graft survival by reducing the need to undertake laboratory crossmatching pre-transplant.
The “Virtual” Crossmatch
Craig Taylor’s group in Cambridge published a 10-year experience of selective omission of the pre-transplant crossmatch in deceased donor transplantation. This study opened the door to the development of patient and donor compatibility assessment based on the donor HLA type and recipient HLA antibody history. Scientists across the UK H&I laboratories developed consensus guidelines recently published in 2021 to facilitate timely crossmatch result availability pre-transplant to limit Cold Ischaemia Time and improve graft outcomes.
HLA incompatible transplantation
Whilst the majority of work in UK H&I laboratories facilitates HLA compatible transplants, there are a small number of highly sensitized patients where the opportunity of an antibody compatible transplant is not realistic. In many cases these patients will still see a benefit if donor specific antibodies could be removed for a period to facilitate safe transplantation. Improvements in HLA antibody identification and monitoring have made it possible to develop HLA antibody incompatible transplant programmes.
Professor David Briggs
Kidneys from deceased donor organs have been allocated via NHS Blood and Transplant in a nationally coordinated manner based on recipient and donor factors. There have been four kidney offering schemes in the UK since the first Beneficial Matching scheme was established in 1989.
From: Watson, C.J.E., Johnson, R.J. & Mumford, L. Overview of the Evolution of the UK Kidney Allocation Schemes. Curr Transpl Rep 7, 140–144 (2020). https://doi.org/10.1007/s40472-020-00270-6
Professor Sue Fuggle
UK Living Kidney Sharing Scheme (UKLKSS)
This scheme has enabled over 1000 potential recipients with incompatible HLA or blood group live donor transplants receive live donor organs. The scheme has been a gamechanger as it eliminates the need for the burden of additional immunosuppression and proportionate attendant side effects. The scheme started in April 2007 and the 1000th pair in the UK was done the week commencing 11th March 2019.
The COVID-19 pandemic led to transplant units all over the UK and indeed the world at large as the impact of the virus was causing catastrophic morbidity and mortality to the highly vulnerable such as our renal transplant recipients. Perhaps the most significant breakthrough in getting over the pandemic has been the development of an effective vaccine.
It is therefore only right that we add Edward Jenner (17 May 1749 – 26 January 1823) the British Physician-Scientist who trained at St George’s Hospital, developed the world’s first vaccine leading to the eradication of smallpox throughout the world. The establishment of vaccines as a valid means of preventing infections has been a landmark in the prevention and control of diseases. In the UK the ready access to a reliable vaccine enabled our transplant programmes to re-open and for our renal failure patients to get back to receiving a transplant with a more acceptable risk benefit ratio enabling them the form of renal replacement therapy that provide the best potential quality of life.
Riedel S. Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent). 2005 Jan;18(1):21-5. doi: 10.1080/08998280.2005.11928028. PMID: 16200144; PMCID: PMC1200696.
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Joyce Popoola, with contributions from …
Last Updated on February 7, 2023 by neilturn