Although organ transplantation has been taking place for over 50 years, there are a number of significant challenges, such as a shortage of donor organs, maintaining the quality of an organ in transit, and the risk of organ rejection both immediately after transplant and in the following years.
Scientists at King’s College London, part of King’s Health Partners Academic Health Sciences Centre, are working hard to solve these problems – through techniques known as protein therapeutics and cell therapy.
The work using protein therapeutics aims to reduce the risk of an organ being damaged in the hours and days following a transplant, by maintaining the quality of the donor organ prior to transplantation.
Currently, organs cannot survive outside the body for more than around 24 hours. In daily life when an infection or virus meets cells or fluids in the body, it activates a part of the immune system, known as the ‘complement’ system, which attacks and attempts to destroy the cells of the intruder organism.
The complement system is usually kept in check by ‘regulators’ which are found on the surface of the cells. Their presence prevents it from attacking the body’s own cells. However, when an organ is removed for transplantation, complement regulators are lost from the surface of cells due to the lack of blood flow and consequent lack of oxygen. Unregulated, the complement system begins to attack the organ’s own cells, severely damaging it. Once the transplant is complete, the effect can be amplified as the complement system supports the recipient’s own blood cells in its attack on the organ – resulting in organ rejection.
Working with the biotechnology industry, scientists at the MRC Centre for Transplantation have evolved a method for coating the inner surface of donor kidneys with a protective layer made from a substance which is a natural regulator of these proteins in humans.
Dr Richard Smith, Director of Protein Therapeutics at the MRC Centre for Transplantation said: ‘We have engineered a protein Mirococept to combat organ damage during transit outside the human body and immediately after transplantation. It is an artificial replacement for complement regulators. If enough Mirococept proteins reach the organ’s cell membranes, it can prevent the complement cascade from starting and increases the number of donor organs suitable for transplantation.’
It is hoped this research will help alleviate the clear imbalance between supply and demand of donor organs for transplantation. According to NHS Blood and Transplant, at 31 March 2010, there were 7,183 patients waiting for a kidney transplant in the UK, and 2,694 kidney transplant operations were performed during the year 2009-10.
Dr Richard Smith and his team have also introduced the ‘tail’ in Mirococept which is specifically designed to latch on to cell walls. He continued: ‘When we are preparing an organ for transplant we wash it in a solution, and the risk is that the protein will be washed off the organ. The ‘tail’ we have developed snags onto the cell surface and holds it there. Imagine the difference between throwing a bucket of water at a wall and throwing a bucket of paint, the water will run off but the paint will stick. This technique, known as tethering, not only enables the protein Mirococept to reach particular types of cells, but also gives it a much better chance of staying there.’
Mirococept has already been tested in a pilot scale clinical study of 16 kidney transplant patients and this showed that the tethering technique was clinically feasible and safe. The next step is large-scale clinical trials to test whether this method has clinical benefits for patients undergoing organ transplants.
The other exciting area of research is cell therapy – a type of potential treatment scientists hope will improve the longevity of a transplant.
Currently, transplant recipients have to stick to a strict regimen of potent drugs that pacify the immune system and hopefully prevent rejection of the donated organ. However, because these drugs suppress the immune system, they may also bring serious health complications, such as infections and some types of cancer.
Scientists at King’s are looking at other ways of prolonging the life of a transplant, which involves using a type of white blood cell – regulatory T cells found in healthy individuals – as a treatment to prevent an individual’s immune system from becoming over active and rejecting the organ.
Professor Giovanna Lombardi, Professor of Human Transplant Immunology at the MRC Centre for Transplantation, said: ‘Animal studies have already shown that these cells can effectively prevent a transplant being rejected. We are currently identifying ways to ‘grow’ these cells from the blood of healthy individuals in the laboratory without them losing their ability to suppress other immune cells and are carrying out a study of the number and quality of regulatory T cells from patients on the waiting list for a kidney transplant. We are optimistic that we will be able to carry out the first clinical trials in transplant patients in the next few years.’
It is expected that any clinical trials would involve the isolation and expansion of these cells. The cells would be taken from a patient, multiplied in the laboratory into the numbers of cells needed, and reintroduced into the patients themselves. In any clinical trial, these cells would be generated in Good Manufacturing Practice (GMP) compliant facilities in development at Guy’s Hospital.
The new research developments were presented at the British Science Festival in Birmingham.
Notes to editors
1. Smith RAG, Koffman G, Chowdhury P, Smith KCG, Watson CJ, Nicholson ML, Zhou WD, Sacks SH. Membrane-localising complement inhibitors – clinical progress. Molecular Immunology, 44 (16), 3915-3915, 2007
Patel H, Smith RAG, Sacks SH, Zhou WD Therapeutic strategy with a membrane-localizing complement regulator to increase the number of usable donor organs after prolonged cold storage. Journal of the American Society of Nephrology, 17 (4), 1102 – 1111, 2006
2. Tsang J Y-S, Tanriver Y, Jiang S, Xue S-A, Ratnasothy R, Chen D, Stauss HJ, Byct RP, Lombardi G, Lechler R (2008). Conferring indirect allospecificity on CD4+CD25+ regulatory cells by T cell receptor gene transfer favours transplantation tolerance. J Clin Invest 118 3619-3628.
A video explaining this research is available at http://areavenall.ds6218.dedicated.turbodns.co.uk/videos/extending-the-life-of-a-transplant/extending-the-life-of-a-transplant.wmv. Information contained in this video is embargoed until 12.30 BST 15 September 2010.
King’s College London
King’s College London is one of the top 25 universities in the world (Times Higher Education 2009) and the fourth oldest in England. A research-led university based in the heart of London, King’s has nearly 23,000 students (of whom more than 8,600 are graduate students) from nearly 140 countries, and some 5,500 employees. King’s is in the second phase of a £1 billion redevelopment programme which is transforming its estate.
King’s has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities; over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450 million.
King’s has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe; no university has more Medical Research Council Centres.
King’s College London and Guy’s and St Thomas’, King’s College Hospital and South London and Maudsley NHS Foundation Trusts are part of King’s Health Partners. King’s Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world’s leading research-led universities and three of London’s most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: www.kingshealthpartners.org.