Transplantation: The Gift of Life

Contents:

• Introduction
• Stepping Stones to Successful Transplantation in the 20th Century
• Advances in Surgical Aspects of Transplantation
• Facing the Rejection Problem
• The Need
• The Next Step - Xenotransplantation

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Introduction

Transplantation of organs is one of the miracles of twentieth century medicine. Viewed as impossible in the 1950s, organ transplants have become today's life-giving therapy.

The aim of transplantation research is to have the immune system accept the presence of the transplanted organ, while retaining the ability to fight infection.

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Stepping Stones to Successful Transplantation in the 20^th Century:

• Alexis Carrell received the Nobel Prize in 1912 "in recognition of his work on vascular structure and the transplantation of blood vessels and organs." He was the first to demonstrate that animals tolerated grafts from their own tissues (autographs), but rejected those from unrelated animals.
• Medawar studied the rejection of skin grafts between strains of mice. He learned that successive attempts to graft skin from unrelated mice result in even more rapid rejection.
• Graft rejection can be prevented in mice and chickens if foreign cells from the future donor are introduced into the recipient when it is immunologically immature (i.e., in fetal or neonatal life). A skin graft would, for instance, survive if transplanted to an unborn mouse, but fail if given to an adult mouse (Medawar, MacFarlane, Burnet).
• Skin grafts between non-identical twin calves are not rejected because the calves share a common blood circulation in utero and are exposed to each other's blood cells before birth.
• MacFarlane, Burnet and Fenner (1949) deduced from experiments on animals that the body can distinguish "self" from "non-self." For this they received the Nobel Prize in 1960.
• Billingham and Medawar (1951) showed that corticosteroid hormones from the adrenal grand can delay skin graft rejection in animals such as rabbits. Dempster showed that steroids could ameliorate rejection of kidney transplants in dogs ("rescue therapy"). Thus it was shown that the previously-assumed insurmountable barrier to transplantation could be overcome. This knowledge was used to extend the useful duration of skin allografts in badly burned children, and also led to the recognition of graft-versus-host disease.

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Advances in Surgical Aspects of Transplantation:

• Surgical techniques for transplantation of kidneys were developed in dogs. Subsequent techniques were developed for transplantation of livers, hearts and lungs.
• Bone marrow transplantation was studied in rabbits, mice and dogs.
• The science of cryobiology (freezing) made possible the storage, first of rabbit skin, then of organs in general, for months at -79^o C.
• Barnard and his team practiced surgical techniques for three years on cadavers and anaesthetized live animals before they did the first human heart transplant in 1967.
• Lower and Shumway worked for many years on dogs to improve cardiac surgical techniques. Despite their technically-excellent surgery, human transplants failed because they could not control the rejection reaction. Shumway achieved permanent success in 1970.
• Thomas performed the first successful human bone marrow transplant in 1956.
• Murray and colleagues proved that kidney transplantation was possible. Caine showed that the drug Amarine (azathioprine) could prevent kidney transplant rejection in dogs. Murray and Thomas were awarded the Nobel Prize (1990) for their groundwork studies. This work was done largely on dogs. The Nobel citation said that the discoveries were "crucial for those tens of thousands of severely ill patients who can either be cured or given a decent life when other treatments are without success."

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Facing the Rejection Problem:

• Borel in Switzerland isolated cyclosporine from a fungus he found in Norway (1977). White in England found that cyclosporine much improved the acceptance of transplanted hearts in rats and pigs, and kidney transplants in dogs.
• Tissue typing for good matching of donor organ and recipient developed as immunological knowledge grew (histocompatibility and cytotoxic cross-matching). Snell pioneered studies of transplantation genetics in mice to identify the antigenic differences among strains of mice.
• International registries were established to enable rapid access to appropriate organs as they became available.
• The structure and function of the major histocompatibility complex genes was deduced by Dausset, Snell, and Benacerraf. Animals such as mice and rabbits were crucial for this work. These researchers were awarded the Nobel Prize in 1980.
• The recognition that there are numerous types of lymphocytes was made possible by the discovery of monoclonal antibodies. These antibodies are formed by fusing cancer cells with spleen cells of an experimental animal. These antibodies are the basis of one of the most effective forms of therapy for the rapid reversal of transplant rejection. Kohler and Milstein were awarded the 1984 Nobel Prize for their discovery of monoclonal antibodies.
• Since then, surgical techniques, medical management and new drugs (all tested on animals), as well as various drug combinations, have allowed successful single and double lung transplants, liver, kidney and pancreas transplants, multiple organ transplants, and small bowel transplants.

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The Need:

Many terminally ill uremic patients are young and otherwise healthy. Many young people suffer from cystic fibrosis and need double lung transplants. For those lucky enough to receive organ transplants, a return to a completely healthy state and normal life is achieved in 80 percent of kidney and heart transplants; 70 percent of liver transplants; and 90 percent or corneal transplants.

However, there is a shortage of organs for transplantation. As fewer appropriate organs become available (due to less drunken driving, seat belts, and better medical and surgical treatments of trauma), waiting lists for organs become longer and longer. Every year in Canada there are thousands of people on waiting lists for organ donations; only about 40 per cent of those waiting are able to receive organ transplants.

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The Next Step - Xenotransplantation:

The logical next step is cross-species transplantation. New knowledge and new drugs to enable effective control of tissue rejection open up the possibility that organs transplanted between closely-related species could function normally. Although optimal anti-rejection drug protocol is not yet known, research holds the hope that sometime in the future, patients who would die because a human organ is not available might be successfully transplanted.