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Organ and Cell Transplantation

Description
Organ transplantation is the greatest therapeutic advancement of the second half of the 20th century. Of all medical specialties, the pioneers of transplantation make up the largest number of experts awarded with, or nominated for the Nobel Prize.  The development of transplantation has involved almost all medical specialties.  In the history of medicine, there is perhaps no other example of such extensive cooperation and exchange of knowledge and experience among basic scientists, surgeons and physicians in achieving a common goal.  The progress of transplantation has forced doctors to “rewrite” medical textbooks dealing with a great spectrum of post-transplantation issues, such as the physiology of transplanted organs, the recurrence of initial disease in the transplanted organs, and the complications arising from immunosuppressive drugs, infectious diseases, and cancer.

Who is at Risk?
Islet transplantation is the transplantation of isolated islets and into another person.  It is an experimental treatment for type 1 diabetes mellitus.  Once transplanted, the islets begin producing insulin, actively regulating the level of glucose in the blood.  While significant progress has been made in the islet transplantation field, many obstacles remain that currently preclude its widespread application.  Two of the most important limitations are currently inadequate means for preventing islet rejection, and the limited supply of islets for transplantation.  Current immunosuppressive regimens are capable of preventing islet failure for months to years, but the agents used in the treatments are expensive and may increase the risk for specific malignancies and opportunistic infections.  New immunomodulatory agents offer the greatest hope of revolutionizing the field.  New drug regimens capable of inducing tolerance to the transplanted islets would allow recipients to maintain their grafts without general immunosuppression and its associated toxicities.

Sources: Imperial College Press, “Transplant International”, “ New England Journal of Medicine”, “Diabetes Care”

Detecting the Genes that Contribute to Transplant Rejection
A group of physicians and scientists led by Scripps Research Associate Professor Daniel Salomon, M.D. has been awarded a federal research grant of more than $15 million over five years to apply cutting-edge genomic technologies to advance our understanding of kidney transplantation. Salomon and his colleagues have been monitoring several hundred patients who have had kidney transplant surgeries with technologies for gene expression profiling and proteomics, and several thousand transplant patients by complex trait genetics. One of the team’s overall goals is to answer one of the most pressing problems in kidney transplantation: why do some patients do well after a transplant while others do not? The research involves advancing our understanding of what causes acute and chronic kidney injury. Kidney dysfunction is common to many different disease states, including diabetes and hypertension, which can damage the tiny blood vessels within the kidneys. Several genetic and autoimmune diseases as well as bacterial and viral infections and environmental toxins can also cause damage to the kidneys. Severe damage can lead to kidney failure. With a kidney transplant operation, there is a danger of transplant rejection with the "allograft" or transplanted tissue taken from another person, arising from the fact that a donated kidney is foreign to the transplant patient’s body. Left alone, the person’s immune system will detect the foreign tissue, mount an immune response and attack it - acutely "rejecting" or killing the new tissue, leaving the patient no better off than before the transplant.

Wishing to avoid transplant rejection, doctors treat patients who have had kidney transplantations with a powerful class of drugs known as immunosuppressants, which weaken the immune response and mitigate the danger. With immunosuppressants, a transplanted kidney can survive and function well for years. However, immunosuppressants also have a dark side. Immunosuppressive drugs make transplant patients more likely to suffer heart disease, diabetes, infections and cancer. These drugs are also toxic, and they can slowly poison the very kidney they are protecting. They can also cause hypertension and hyperlipidemia, eventually leading to the failure of the new kidney transplant - a condition known as chronic allograft nephropathy. Because of all the drug toxicities, one of the major challenges in treatment following the transplant surgery is to determine the proper regimen of drugs for a patient. Salomon and his colleagues would like to use the discoveries of genomic science to build a new set of tools so that doctors can measure and predict how a patient will respond to immunosuppressive drugs. With such tools, transplant doctors could monitor patients regularly to make sure their treatment is always optimal and improve the safety of therapies for organ and cell transplantation. The genetics of the patient receiving the kidney determines the character of the immune response, but it’s the genetics of the donor that determines the impact of the transplantation. The researchers are hoping to come out with an understanding of what makes a good donor, and what is it about the donor organ that determines the long-term outcome of the transplant. Such a tool may also be useful for the development of a new generation of post-transplant drugs to treat patients or to protect the kidneys of patients with early kidney disease that still have good function.  The project is going into a prospective clinical validation trial later this year, and the researchers also hope to study liver and heart transplants with these approaches.  They are currently also studying the genomics of regeneration of human liver transplants after living donor and deceased donor transplants.

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