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transplantation

transplantation Routine success with transplantation of human organs was not obtained until the mid 1960s, in spite of its ancient appeal. Prior to this, skin and endocrine gland grafting had often been attempted from one human to another, but the reports on the outcome were confusing and the observations uncritical.

The groundwork for the new science of transplantation immunology was laid by Medawar and other British biologists in the 1940s. They showed that rejection of tissue transferred from one person or animal to another was invariable, except for grafts between identical twins, or a few special cases (e.g. cornea). In the 1950s they further showed that this tissue rejection was a response of the immune system, rather than a biochemical or physiological ‘misfit’. But since an antibody could not be identified, a new form of immunity was sought and found. Suspicion fell on the small lymphocytes. These, with their relatively huge nucleus and minimal cytoplasm, had always been suspected of some important role in the body, but since they had shown no capability to multiply nor to act as phagocytes, they had not been taken seriously. Soon, however, these lymphocytes were found in fact to be capable of division and enlargement when suitably provoked by foreign cells or particular proteins. So this previously neglected cell type became recognized as the key player in the exquisite differentiation of foreign material from the ‘self’, particularly of cells only slightly different from the body's own cells. The recognition of this mechanism explained the rejection of grafts. Although understandably seen as existing to frustrate transplant surgeons, this ‘cell-mediated’ immune mechanism clearly had a wider, fundamental role, as yet not fully understood.

Human grafts

In the 1950s, surgeons in Boston, led by Joseph Murray, established that a kidney graft, from one healthy human twin to the other who had terminal chronic kidney failure, could reverse all the features of the disease, even though the donor kidney had no nerve supply and was placed in an unnatural position in the patient's pelvis. About this time, Medawar showed that the immune response in adult mice to experimental grafts could be abolished by prior injection of the donor cells at birth — tolerance had been induced.

The first attempts at reducing the human immune response to kidney grafts employed crude total body irradiation to depress the bone marrow and lymphocyte activity. These attempts largely failed. By 1960 the strategy was to use the newer anti-cancer drugs (notably 6-mercaptopurine and related substances, derived from the military poison gas nitrogen mustard). In cancer patients such drugs were known to suppress the immune response. One such agent, azathioprine, was shown by the British surgeon Roy Calne to have a promising effect on cell-mediated immunity against grafts, without serious side-effects of general toxicity or liability to infection. In Paris and Boston, the first medium-term kidney graft survivals were obtained using this drug alone. A major advance followed when Starzl in Denver found that steroid hormones, previously shown to have no effect on graft survival if given alone, combined with azathioprine to give powerful immunosuppression.

Rapid progress

This unpredicted innovation led to a drug regimen which was to be the core treatment for the next 20 years, establishing kidney transplantation as an acceptable form of treatment. Indeed, from 1963 onwards there was a period of optimism that routine organ grafting of all kinds would soon follow. This was encouraged by the concurrent rapid progress in immunology. The key role of circulating lymphocytes was now known, but the similar cells in the thymus gland were apparently inactive; the absence of any demonstrated effect of removing the adult thymus seemed to relegate it to the status of an evolutionary vestige, in spite of its size and prominence in early life. The puzzle was solved in the UK in 1960 by Jacques Miller's serendipitous discovery that immediate removal of the thymus in new-born mice caused profound and lasting absence of cell-mediated immunity, allowing permanent acceptance of a skin graft — but also liability to some types of infection. Clearly the thymus was vital in the maturation of some circulating lymphocytes. Soon, markers were developed for lymphocytes that neatly classified them into T-cells (thymus-derived), responsible for cell-mediated immunity, and B-cells (bone marrow-derived), responsible (after maturation into plasma cells) for antibody production.

Around this time also, tissue typing methods emerged for identification of antigens on body cells, similar to red blood cell grouping but more complex. This gave the hope that any human organs donated could be matched closely to a potential recipient. Better methods for organ storage and the construction of perfusion machines allowed preservation and even long-distance transport of kidneys to patients with a good match. In this growth period of human transplantation, with the hopes that a final solution was at hand, even monkey kidneys were transplanted to human patients — and some of them were not rejected immediately.

Kidney failure

Meanwhile, from 1960 onwards, patients with renal failure were successfully treated with long-term dialysis on the artificial kidney. This back-up was crucial before and after transplantation. At this time kidneys were taken a little while after the donor's heart had stopped and death had been pronounced. These kidneys were slightly damaged by the intervening lack of oxygen and did not usually work immediately, but since kidney tissue shows powers of revival and can pick up later, the artificial kidney could be used during this shut-down time. However, when the first human liver transplants were attempted in the optimistic mid 1960s, the result was disastrous, not only because of the formidable new surgical challenge, but also because the liver was more sensitive to lack of oxygen after the death of the donor. Since there was no artificial liver or heart equivalent to the artificial kidney, if these transplanted organs did not function immediately, death was inevitable. This created pressure for donor organs to be as fresh as possible, and some cautious initiatives were taken, notably cooling the donor at the time of death, to reduce the oxygen requirement of the organs.

Coincidentally with this need within the service of transplantation, the success of resuscitation and artificial ventilation for critically-ill patients in intensive care had thrown up the problem of patients who survived with irreparable brain damage, who had otherwise good physiological function but could no longer breathe for themselves. In these circumstances it was pointless to continue artificial ventilation. The first formal discussion of possible criteria for diagnosis of irreversible coma was by the Harvard Committee of 1968, and the pioneer Boston transplant surgeons unwisely involved themselves in their discussions. Shortly afterwards in that same year, Christian Barnard carried out the first human heart transplant. He was praised at first for his daring innovation, but others, experienced in transplantation or otherwise, followed his lead with poor results, which were publicly revealed. There was professional criticism of such adventures worldwide, and increasing hostility from the public and media over many aspects, notably the tasteless publicity attaching to the patient and donor. The public were also uneasy when, for the first time, the details of the diagnosis of brain death and ‘heart-beating’ organ donation were revealed. It seemed to some that these reasonable criteria for death had been introduced to help transplant surgeons, whereas they were required primarily in order to avoid pointless persistence with artificial ventilation.

Hesitant times

The consequences of that ‘year of the heart’ were a loss of confidence inside and outside the small world of organ transplantation, a virtual moratorium on human organ grafting apart from kidneys, and a rise in ethical debates on biomedical matters, with the emergence of a cadre of biomedical ethicists. Worthy government committees embargoed the transport of donors, and declared that death should be decided by ‘traditional means’, but they did encourage kidney transplantation with supportive publicity and donor card drives, attempting to incorporate organ donation into a respectable routine. This was not unconnected with the emergence of kidney transplantation as a more cost-effective treatment for chronic renal failure than regular dialysis.

In the late 1960s, one new agent, anti-lymphocyte serum (ALS), was prepared and had spectacular success in experimental grafting. This encouraged the restart of human liver transplantation by two pioneers, Starzl in Denver and Calne in Cambridge, and evaluation of heart transplantation was funded at a centre under Shumway in Stanford. Such transplants were widely regarded as experiments without hope — a last resort for the most hopeless of patients — but the results of all organ grafting improved slowly, with or without the new ALS and its successors playing a supporting role in immunosuppression. The 1970s were a time of numerous small improvements in the surgical detail of kidney transplantation and post-operative management. The still rapidly-increasing understanding of immunology made little impact on clinical transplantation at this time. Better tissue typing methods appeared, but they did not fulfil the earlier promise (except in bone marrow transplantation).

Innovation resumes

By 1976 it was thought appropriate to formalize the criteria for brain death. These were duly agreed, and issued by medical bodies and governments, separating the matter carefully from the needs of transplantation. In Britain, fully ten years after Barnard, one heart transplant unit was cautiously approved, funded and controlled. Other nations took similar steps. Though there were critics, their objections centred largely on the cost of high technology medicine in a world of simple need. With tasteless publicity avoided, the new heart transplant units soon reported good results.

After the cautious growth of the mid 1970s, organ transplantation moved forward rapidly again with the introduction, in 1978, of a new immunosuppressive agent. This innovation came neither from basic immunology, nor from cancer chemotherapy, but from the routine mass-testing of soil samples in the search for microorganisms producing antibiotics or substances with anti-cancer or immunosuppressive effects. A Norwegian fungus was found to make, in its struggle for survival, a useful product later called cyclosporine A (CsA), which had a powerful, safe, inhibitory action on lymphocytes, and which showed promise in animal transplantation. Reluctantly the company concerned prepared CsA for sale, but only as a prestige product, since the transplantation market was judged too small at that time for profitable investment. CsA proved to be a tricky agent to use, and animal testing had failed to reveal its toxicity for human kidneys, but once the art — rather than the science — of its use was mastered, it changed the history of transplantation. Steroids were still necessary as a partner for the new drug, and the new regimen was so powerful that it overrode the need for precise tissue typing. Results of kidney transplantation improved with its use, and rejection crises were rarer and less dramatic. But the main effect was to make liver and heart transplantation possible and widely accepted, and these became routine medical practice world-wide. In America, liver grafting became the single most expensive standard procedure in the world of surgery. Other pharmaceutical companies noticed the new, expanding potential market, and in the 1990s a steady stream of new products emerged; again they were obtained by synthetic chemists' changes to anti-cancer drugs, and rivals to cyclosporine came from other fungi from Easter Island and Japan. This success in countering rejection, as well as further experience in day-to-day management, meant better graft survival with fewer complications and deaths. Those patients considered eligible for organ transplants increased, and the upper and lower age limits moved steadily apart. Patients with major additional abnormalities, notably diabetes or serious vascular disease, were no longer automatically excluded.

But this success carried with it a crisis in the supply of organs in the 1990s. While candidates for kidney transplant could survive and grow older on dialysis while waiting for an organ, suitable liver and heart patients soon died. This shortage also led to concerns from professionals and patients' organizations about the traditional allocation of scarce organs based on tissue typing matching alone, since this now had only a minor role in the cyclosporine age. New ethical questions were aired. Were those with rare blood and tissue types now unfairly excluded? Was it fair to let older or sicker patients wait as long as younger, fitter ones? Should organs be given to those known to be feckless and likely to default from their medication and follow-up? Was it acceptable to offer cadaver organs to those from ethnic minorities and religious groups opposed to becoming cadaveric donors themselves, but who nevertheless would accept organs if living in countries with well-developed donation and sharing schemes?

As the service of transplantation also expanded out from its origins in the Western, developed nations, it moved from a base in Western academic medicine to become a service available in countries with different cultural assumptions. A remarkable variety of patterns of development was seen. In well-off nations, transplantation and dialysis spread quickly as a routine, but even there divergent views on organ donation were seen — some, such as Norway, used large numbers of living, related donors, and some, such as Eire, used none. Some countries, like Japan, had deep cultural hostility to interfering with the body after death, and no cadaveric donations occurred. Previously poor nations, such as those with new wealth from oil, at first sent even their poor citizens abroad in the 1970s, with their families, for living donor transplantation; then in the 1980s their governments set up transplant units at home, usually with expatriate surgical staff who often trained local professionals and handed over to them in the 1990s. Lastly, in very poor nations with limited facilities and no cadaveric donation, the vast majority of patients with chronic renal failure remained untreated and died, usually unaware of the diagnosis, and certainly having no expectation of cure. In these nations the wealthy or the élite could purchase treatment in private clinics and could easily induce poor people to part with a kidney, for money.

New shortages

In spite of every effort, the attempts to increase cadaveric donors in the developed world were not successful and new initiatives to deal with this shortage were numerous. These included the acceptance of less-than-perfect organs, the increasing use of living, related kidney donors, and even the surgical removal of parts of the liver and pancreas or a lobe of the lung from living donors, with encouragement of emotionally-involved genetically unrelated donors, such as spouses, to come forward. Whilst payment for kidneys from unrelated donors in other lands was officially deplored in the countries in which the science and surgery of transplantation had developed, this practice occurred; if the greed of intermediary brokers could be dealt with, the arrangement was locally accepted as reasonable.

The organ shortage meant a new look at the use of xenograft organs — from other species. It had always been assumed that monkeys, with their closeness to man, would be the first source of such organs, but by the 1990s monkeys had powerful human friends, their use in medical research was stringently controlled, and many species were declared to be protected. Pursuit of this ‘concordant’ source seemed less necessary when another scientific discipline began to impinge on transplantation and even began to supplant immunology from its traditional role as the tissue grafter's essential laboratory partner. Genetic engineering began to provide a range of new techniques which could alter the nature of donor tissue and reduce the violent antibody and cell-mediated attack on xenograft tissue. Selected genes could be inactivated in the donor; gene insertion could add new proteins that would neutralize the reaction to antibody; cloned animals could be raised by transfer of cell nuclei from adult animals to embryos, after suitably engineering the nuclei. All this meant that the use of species ‘discordant’ with man could be contemplated. The animal turned to was the easily bred, non-violent pig, an animal possessing conveniently human-sized organs, and one already used for food and lacking unpleasant diseases — except one possible retrovirus. After studies had shown no passage of this organism to humans, regulatory bodies gave a careful blessing to the development of xenotransplantation.

Organ transplantation has come far in one generation and those involved continue as before to travel hopefully, with the usual mix of help from both basic science and industry, as well as good luck and serendipity.

David Hamilton

Bibliography

Ginns, L. C.,, Cosimi, A. B.,, and and Morris, P. J. (1999). Transplantation. Blackwell, Oxford.
Starzl, T. E. (1992). The puzzle people. University of Pittsburgh Press.


See also brain death; dialysis; immune system; life support; organ donation; phagocytes; stem cells; thymus.

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transplantation, medical

medical transplantation, surgical procedure by which a tissue or organ is removed and replaced by a corresponding part, usually from another part of the body or from another individual. A life-saving medical technique, transplantation also is an important tool in experimental biology; it is used to investigate endocrine gland functions, to study the interactions of cells in developing embryos, and to culture malignant tissue in cancer research.

Types of Transplanted Tissues and Organs

Transplantation to replace such diseased or defective tissue as corneas and hearts necessarily requires a dead donor; paired organs such as kidneys, or large or regenerating organs or tissues such as skin, bowel, lung, liver, or blood, can be donated by live donors (see blood transfusion). Skin autografts, employing skin from the patient's own body, are used to replace lost skin; autograft transplants are also done with bowel, bone, cartilage and other connective tissue, and ovarian tissue. Replacement skin for autografts is now also grown in laboratories. Autograft bladders, tracheas (windpipes), blood vessels, nostrils, and vaginas have also been grown from a patient's cells using various methods and been successfully implanted. Bone marrow transplants can come either from a donor or from stored host bone marrow. Controversial fetal tissue implants have been used for some neurodegenerative diseases and experimentally for fetus-to-fetus transplants in certain genetic disorders. In addition to transplanted human tissues and organs, artificial parts ranging from heart valves to hip sockets are routinely implanted. See also heart, artificial.

Immunological Rejection of Transplanted Tissue

In transplanting complex organs (but not small tissue grafts), the larger blood vessels of the organ are surgically connected to those of the recipient. Connective tissue cells gradually link together the graft and host tissue. The main obstacle to successful transplantation is the rejection of foreign tissue by the host (see immunity). Transplanted tissue from another individual (i.e., homograft, or allograft, tissue) contains antigens that stimulate an immune response from the host's lymphocytes. Homograft tissue is normally destroyed within a few weeks; the rejection mechanism is similar to that by which the body resists infection. The greater the number of foreign antigens on the donor organ, the more rapid and severe the rejection reactions.

Implantation of tissues grown from a patient's own cells (autograft transplants) will not provoke an immune reaction, which is one of the main reasons why the growing of tissues and organs in bioreactors for implantation is of interest to researchers. Organs donated from one identical twin to another are usually viable because such organs are antigenically identical, but even organs transplanted between individuals who are fairly closely matched antigenically, such as siblings, have a good chance of being rejected. An antigenic typing system based on human lymphocyte antigens (HLA typing), pioneered by Jean Dausset in Paris and Rose Payne at Stanford, has made it possible to identify histocompatibility and minimize rejection.

Today, most recipients of transplants are maintained on immunosuppressive drugs. The side-effects of such antirejection drugs, which can themselves be life threatening, include increased risk of infection, cancer, diabetes, and other conditions. In time, however, many patients develop a tolerance to the implanted organs, and some can eventually be weaned off the drugs.

Researchers continue to study various ways to fool the immune system into accepting foreign tissues or to take advantage of the immune response. A new technique for nerve transplant begins with the patient taking immunosuppressive drugs, but after the patient's damaged nerves begin to grow and connect along the transplant, the drugs are discontinued and the immune system is allowed to destroy the transplanted nerve.

Noncellular tissues or tissues where the donor cells are not important to the graft (e.g., bone and cartilage) can usually be successfully transplanted without rejection. In these transplants the grafts provide nonliving structural support within which the recipient's living cells gradually become established. Corneal transplants have a high success rate largely because there are so few blood vessels in the cornea that corneal antigens may never enter the host's system to stimulate an immune reaction. Bone-marrow transplants effectively bring their own immune system with them, often rejecting the new host, instead of the other way around, in a reaction known as graft-versus-host disease.

Artificial organs, such as artificial bone, can be implanted successfully because such organs (prostheses) do not produce antigenic substances. Artificial joints made of stainless steel have been developed; newer implants have used nonrusting titanium joints with the midsection of bone substitute composed of lightweight polyethylene.

Organ transplants from animals to humans are subject to hyperacute rejection, and transplantation of tissues from animals has been attempted for almost a century without much success. Some progress has been made, however, in circumventing the immune reaction. In one experimental approach, the tissues and organs of transgenic pigs, genetically engineered animals that have had human genes inserted, are combined with newly developed immunosuppressive drugs. In a potential step toward a different approach to developing swine that could be used as a source of organs, researchers have cloned pigs in which a gene that causes rejection by the human immune system has been genetically disrupted. The endangered species status of chimpanzees, genetically closest animals to humans, has eliminated their use as donors. Although transplants from animals to humans, called xenotransplants, might benefit the thousands of patients waiting for human organs, the possibility that they could spread some unknown animal virus into the human population has caused concern and delayed research experimentation.

History

Human tissue grafting was first performed in 1870 by a Swiss surgeon, Jacques Reverdin. In 1912 the French surgeon Alexis Carrel developed methods of joining blood vessels that made the transplantation of organs feasible. He advanced this technique further and stimulated the use of transplantation in experimental biology. He also developed fluids and the means of circulating them so that transplanted tissues could be kept alive outside a living body in artificial media. Theoretical work by Jean Dausset, George Davis Snell and Baruj Benacerraf on the genetic basis of histocompatibility paved the way for practical applications. In the 1940s, Sir Peter Brian Medawar and Sir Macfarlane Burnet described foreign tissue rejection and acquired immunological tolerance, opening the way for transplant operations. The first successful transplant of a human kidney (between identical twins) was made by Joseph E. Murray in 1954. The first human heart transplant was performed by the South African surgeon Christiaan Barnard in 1967; in 1968, Edward D. Thomas performed the first successful bone-marrow transplant between people who were not twins. In the following decades liver, kidney, heart, pancreas, bone-marrow, small intestines, and multiple organ transplants became more and more routine.

As transplantation has become more common and more successful, the demand for organs has risen dramatically. The development of heart transplantation has produced an ongoing reexamination of the traditional biological and legal definitions of death, because obtaining a healthy organ for transplantation depends in large part on the earliest possible establishment of the donor's death. More than 2,000 heart transplants per year were being performed in the United States by the late 1990s, with thousands of patients waiting for available hearts. In all, more than 64,000 people were waiting to receive new organs, including hearts, kidneys, livers, lungs, and pancreases. Many people carry organ donor cards, which indicate their wish to donate if they are killed in an accident, and many states require hospitals to request donation from the families of eligible donors. A side effect of the demand for donated organs has been the increasing use of lung and liver tissue, as well as kidneys, from live donors. In younger children receiving a liver transplant due to acute liver failure, part of the child's liver may be left in the body in hope that the organ will recover and immunosuppressive drugs will no longer need to be taken.

In the late 1990s surprising successes were achieved in transplanting body parts other than organs. Surgeons in France and the United States were able to transplant hands that became partly functional without rejection crises. In 2005 a French surgical team achieved a partial face transplant, replacing damage areas (nose, lips, and chin) of a woman's face with skin and underlying tissues from a dead donor. A nearly total face transplant was performed in the United States three years later, and a total face transplant was performed in France the year after that. Although receiving less attention, successful transplants of knees, the trachea (windpipe), and the larynx (voice box) have also been achieved. Such operations, called nonvital transplants, have become possible owing to improved surgical techniques, monitoring of rejection, and drug therapy. Still largely experimental, they must be approved by ethics committees before being undertaken, especially as the risk of taking immunosuppressive drugs may outweigh the benefits of the operation.

Bibliography

See studies by R. Simmons et al. (1987) and M. Dowie (1988). See also L. Gutkind, Many Sleepless Nights: The World of Organ Transplantation (1988) and publications of the United Network for Organ Sharing.

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Transplantation

Transplantation

Modern medicine continues to offer many miracles that lengthen the life spans of humans, as well as greatly increase the quality of life that they enjoy. If one were to draw up a "top ten" list of technical feats, surely the ability to successfully transplant an entire organ from one human to another would be high on the list. Transplantation can be defined as the transfer of cells, tissues, or organs from one site in an individual to another, or between two individuals. In the latter case, the individual who provides the transplant organ is termed a donor, and the individual receiving the transplant is known as the recipient. The science of transplant biology has, in fact, become a victim of its own success, in that the demand for organs exceeds the supply of donors.

Types of Transplants

There are four basic types of transplants, which reflect the genetic relationship of the recipient to the donor. The autograft is the transfer of tissue from one location of an individual's body to another location that is in need of healthy tissue; in other words, the recipient is also the donor. Common examples of autografts are skin transplants in burn patients and bypass surgery in patients suffering from coronary heart disease. The syngraft is a transplantation procedure carried out between two genetically identical individuals. These types of transplants, like autografts, are always successful, unless there have been technical problems during the surgery. The first successful human kidney transplant was a syngraft, carried out in 1954 between identical twins.

An allograft is the transfer of tissue or an organ between nonidentical members of the same species. This is the predominant form of transplantation today, and allografts have dominated transplant research for many years. Finally, the xenograft represents the most disparate of genetic relationships, because it is the transfer of tissue or organs between members of different species. Many think that xenografts are the answer for solving the shortage of transplant tissue and organs that we are currently experiencing. Both allo-grafts and xenografts have the disadvantage that the recipient's immune system is designed to recognize and reject foreign tissue.

The Genetic Basis of Transplant Rejection

Research that began in the 1940s gave geneticists the first hints that a portion of the mammalian genome contained a cassette of genes that governed the acceptance or rejection of transplanted tissues. This grouping of genes was labeled the major histocompatibility complex (MHC). Subsequently, it has been found that the MHC also contains genes that are involved in governing antibody responses as well. MHC molecules are identical between identical twins, but are otherwise different for every individual. Thus they allow the body to distinguish "self " from "nonself " on the molecular level.

The immunogenicity (ability to induce an immune response) of major transplantation antigens is so strong that differences between the antigens of the donor and recipient is enough to trigger an acute rejection response. To the extent that it is possible, therefore, the recipient and donor are matched for MHC type, to minimize acute rejection.

However, there are cases in which the donor and recipient are very well matched, and yet rejection of the graft still occurs. This is due to other genes found in various places in the genome, known as minor histocompatibility genes, that encode for other weaker transplantation antigens, or foreign peptides, that can cause a chronic rejection response. Currently, researchers have not been able to determine the extent or location of all of these genes. Results obtained from the mapping of genes in the human genome will aid in overcoming this problem.

The Mechanisms of Transplant Rejection

The immune system's attack on foreign tissue is mediated by lymphocytes, phagocytic cells, and various other white blood cells. Various subgroups of lymphocytes have different responsibilities. Once stimulated, the B-lymphocytes (derived from bone marrow) will develop into a cell that produces antibodies (soluble proteins that specifically seek out invaders). Antibodies may cause hemorrhaging by attaching to the lining of blood vessels in the transplant and then activating a naturally occurring series of potent enzymes known as the complement system.

The T-lymphocyte (derived from the thymus) can develop either into a T-helper cell, which serves a regulatory function, or a T-cytotoxic (killer) cell. Activated T-helper cells induce T-cytotoxic cells to destroy a foreign graft by attacking those cells in the transplant that display incompatible antigens.

The task of the transplant treatment team is to somehow derail this natural process of reacting to foreign tissue long enough for the graft to "heal in" and survive without at the same time putting the patient at risk for increased infectious disease. To control this type of response, various immunosuppressive drugs, such as cyclosporine, have been developed. Great strides have been made in controlling rejection of transplated tissue and organs by these methods.

The Supply Crisis in Transplantation

The predominant issue in transplantation biology is now one of increasing the supply of organs for patients in need of them. This is not only a technical problem, but in some cases, raises ethical issues as well. For instance, there have been cases of parents with a sick child purposely conceiving a second child for the main purpose of being a bone marrow donor for their ailing offspring. There has also been the rise of a black market in body parts, particularly emanating from China, in which various organs from executed prisoners are offered for sale.

Researchers have come up with numerous new options to improve on the availability of organs needed for transplantaion. For instance, chemicals can be used to stimulate a patient's own stem cells (cells that can develop into almost any type of tissue, depending upon the local influences it encounters) to migrate from the bone marrow to the diseased organ, develop into the right type of cell, and regenerate the organ. A more controversial application of stem cell research involves the use of embryonic stem cells. One version of this strategy is to remove DNA from the patient's own skin cells, inject it into a donated human egg from which the nucleus has been removed, and then allow that egg to develop into an early-stage embryo. The embryo can then be harvested for embronic stem cells that can be influenced into growing into the organ of choice. Another major strategy is to collect embryonic stem cells from aborted fetuses or from umbilical cord blood. This whole topic has become a very highly debated issue due to the involvement of human embryos, as has the entire burgeoning field of stem cell-applied medical treatment.

Adapted from Roitt, 2001.

One of the most promising, and controversial, sources for new organs for humans are xenotransplants from other species, particularly baboons and pigs. Many individuals are very strongly opposed to raising animals for the sole purpose of harvesting their organs for humans, viewing it as inhumane. Another area of controversy, particularly concerning baboon donors, is the possibility of spreading unknown diseases into the human population. There are already established precedents for viral diseases jumping from primates to humans, such as the AIDS virus (HIV), Ebola virus, and the hantavirus. Consequently, there is a fear that xenotransplantaion could unleash a new plague upon humans. More and more xenotransplant research is moving toward the use of pigs, since it is very much less likely that a pig virus could infect a human. The development of pathogen -free colonies of pigs would also greatly reduce the likelihood of such an occurrence.

The real advantage to using pigs is that they are easily bred, mature quickly, and their organs are of a comparable size to that of humans. In addition, pigs are amenable to genetic engineering, whereby the genes that encode transplantation antigens that would be recognized by a human recipient could be removed so that the resulting organs would not be recognized as foreign in the human. In addition, pigs have now been cloned, so that once such an antigen-free animal has been constructed, we could have a continuous source of immunologically nonstimulating organs available for transplantation into human patients.

see also Agricultural Biotechnology; Cloning Organisms; Embryonic Stem Cells; Immune System Genetics.

Richard D. Karp

Bibliography

Colen, B. D. "Organ Concert." Time Magazine (Fall 1996): 70-74.

Goldsby, R. A., T. J. Kindt, and B. A. Osborne. Kuby Immunology, 4th ed. New York: W. H. Freeman, 2000.

Lanza, R. P., D. K. Cooper, and W. L. Chick. "Xenotransplantation." Scientific American 277, no. 7 (1997): 54-59.

Miklos, A. G., and D. J. Mooney. "Growing New Organs." Scientific American 280, no. 4 (1999): 60-65.

Roitt, Ivan M., Jonathan Brostoff, and David K. Male. Immunology. St. Louis: Mosby, 2001.

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Transplant, Surgical

Transplant, surgical

A surgical transplant involves removing organs or tissues from one person and replacing them with corresponding ones from another part of that person's body or from another person. The idea of surgical transplantation dates back several centuries, but it has become a practical medical approach only in the last few decades of the twentieth century. The main reason is that the body naturally rejects foreign tissue placed inside it. Only since the mid-twentieth century have doctors begun to learn more about the body's immune system and how to suppress it's natural rejection response.

The history of transplants

The idea of transplanting animal or human parts dates back for many centuries. In the sixteenth century, a transplantation technique was developed for replacing noses lost during battle or due to syphilis (an infectious disease contracted through sexual contact). The technique involved using skin from the upper inner arm and then grafting (transplanting) and shaping it onto the nose area.

During the nineteenth century, advances in surgery (like the development of antiseptic surgery to prevent infection and anesthetics to the lessen pain) increased the success rates of most surgical procedures. However, transplantation of organs failed as surgeons had no knowledge of how to "reconnect" the organ to the new body. Transplant surgery did not move ahead until doctors developed techniques for reconnecting blood vessels in the early twentieth century.

Words to Know

Graft: Bone, skin, or other tissue that is taken from one place on the body (or, in some cases, from another body) and then transplanted to another place, where it begins to grow again.

Immune system: The body's natural defense system that guards against foreign invaders and that includes lymphocytes.

Immunosuppressant: Something used to reduce the immune system's ability to function, like certain drugs or radiation.

Lymphocytes: A type of white blood cell that is involved in the body's immune response.

Radiation therapy: Use of radioactive substances to kill cancer cells in the human body.

Studies in rejection

The next major advance in transplantation did not occur for more than 40 years. Although kidney transplants were attempted, the recipient's body always rejected the organ. Researchers experimenting with transplants began to suspect that the body's rejection of the implanted organ was an immune system response to foreign tissue. During World War II (193945), British biologist Peter Medawar (19151987) became interested in skin graft problems while working with severely burned soldiers. He soon proved that the rejection was due to the immune system, which attacked the foreign tissues or organs as foreign invaders, much the same way it works to ward of viruses and other disease.

The first successful human kidney transplant took place at Loyola University in Chicago, Illinois, in 1950. In the years following, however, most transplants resulted in rejection (only those between identical twins were successful). As a result, scientists began to focus on controlling the immune system so it would accept the transplant.

Advances lead to successes

By the early 1960s, doctors discovered how to match donor and recipient tissue more closely. They also began to use a combination of radiation (to destroy certain cells) and drugs to suppress the immune system, in effect shutting it down to prevent rejection. These antirejection drugs are called immunosuppressants. As a result of this therapy, the first successful human pancreas transplant took place in 1966. The following year, Thomas Starzl (1926 ) of the University of Colorado performed the first successful liver transplant. (Because of its complicated blood supply, the liver remains difficult to transplant.)

In 1967, Christiaan Barnard (1922 ), a South African surgeon, received worldwide notoriety for achieving the first successful heart transplant. Barnard took the heart of a young woman and implanted it in Louis Washansky, a 55-year-old grocer. Washansky survived only 18 days. Barnard's second patient, dentist Philip Blaiberg, lived for 17 months.

The next major advance came in 1972 with the discovery of cyclosporine, an extremely effective immunosuppressant. This drug has proven to be the most effective medicine used to combat the body's own immune system. It has increased survival rates for transplant patients, especially in heart and liver operations.

Because transplantation of both lungs succeeds better than transplanting a single lung, and because most patients with lung disease also have serious heart deterioration, heart-lung transplants are sometimes performed. The first successful operation of this type was carried out in 1981 at Stanford University Medical Center by Bruce Reitz (1944 ) and Norman Shumway (1923 ).

In September 1998, in a landmark operation, a team of microsurgeons from four countries spent fourteen hours delicately attaching the forearm and hand from a dead Frenchman to Clint Hallam. The only other reported hand transplant before this took place in Ecuador in 1964, but it had failed because potent immunosuppressant drugs had not yet been developed. The Hallam transplant, however, was doomed from the beginning. Before the operation, Hallam had told doctors he had lost his hand in an industrial accident. The truth was that it had been severed in an accident in a prison in his native New Zealand. After the operation, Hallam agreed to adhere to a physical therapy program to train his new hand and to a regimen of immunosuppressant drugs. But he did neither. Finally, in February 2001, because Hallam's body was rejecting the transplant, a doctor who had helped attach the hand amputated it.

The lesson doctors learned from this transplant, though, were not lost. Between the end of 1998 and the beginning of 2001, nine other people received new hands in six countries. All were reported doing well. Three of those patients even received right and left hands in double transplants.

Current state of transplantation

Doctors have successfully transplanted hearts, kidneys, livers, lungs and other tissues for many years, but problems still remain. Many grafts do not survive permanently. Graft-versus-host rejection, in which lymphocytes in the transplanted tissue attack the foreign host tissue, is difficult

to control. (Lymphocytes are white blood cells, the body's main infection-fighting agents.) Cyclosporine is very expensive and has serious side effects, including possible kidney damage, elevated blood pressure, seizures, and other nervous system disorders.

Research on how to selectively control the immune system continues. Another problem facing the field of transplantation is the extreme shortage of available donors. Although transplantation is now a relatively common operation with thousands of surgical transplants performed in medical centers throughout the world each year, many people who need a transplant do not receive one. Nearly 20,000 people die in the United States each year who would have been suitable organ donors. But only about 3,000 of these organs are ever donated and harvested.

[See also Antibody and antigen; Immune system; Surgery ]

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Transplant, Surgical

Transplant, surgical

Stories of transplanted tissue and body parts go far back in myth and legend. It is said that in the sixth century, the Christian patron saints of medicine, Cosmos and Damian, performed a transplant. They replaced the cancerous leg of a white man with the healthy leg of a recently deceased black man.

Skin Grafts

In India, skin grafts were done as far back as the sixth century b.c. to replace noses that had been amputated as a penalty for adultery. The Indian process of skin grafting was introduced to Western medicine by Italian surgeon Gaspare Tagliacozzi in the sixteenth century. He attached a skin flap from a patient's forearn to the patient's nose. Several weeks later, he released the arm from the now-repaired nose. Tagliacozzi used the patient's own skin because he felt that foreign body tissue would be rejected. Thus he correctly anticipated what is still the major problem with successful transplantation: rejection of foreign body tissue.

Skin grafting was reintroduced in the nineteenth century. In 1869 French surgeon Jacques Louis Reverdin found that successful grafts required thinner tissue. In 1881 Scottish surgeon William MacEwen reported success with bone allografts (transplants from one person to another) in children. Despite these reported successes, most attempts at transplantation failed. Inadequate surgical techniques or rejection by the recipient caused most failures.

Carrel's Techniques

In 1902 French surgeon Alexis Carrel developed a method of sewing together small blood vessels using tiny needles and fine thread. Carrel and Dr. Charles Guthrie of the University of Chicago performed a series of organ transplants on animals. While the transplants were at first successful and the organs functioned, they ultimately failed. Other experimenters had similar results.

Rejection

Researchers who were experimenting with transplants suspected that the body's immune system was rejecting the implanted organs. They believed that it was the foreign tissue that was the problem.

British biologist Peter Medawar became interested in skin graft problems while working with severely burned soldiers during World War II (1939-1945). Medawar found that when a patient received a skin graft for a second time from the same donor, the second graft was rejected twice as quickly as the first had been. To Medawar, this clearly indicated an immune response. Further experiments revealed that grafts between twins were not rejected.

In 1954 Medawar went on to prove that immune tolerance was acquired during an embryo's development. Injection of foreign substances into embryonic or newborn mice would produce permanent tolerance to those substances later in life. In other words, the mouse's body would forever recognize such a substance as "self," instead of responding to it as a foreign invader in need of destruction by the immune system.

Kidney Transplants

Surgeons continued to experiment with transplants. They focused their efforts on the kidney because of its relatively simple blood supply system. In 1933 Russian surgeon Yuri Voronoy performed the first human kidney transplant in Kiev, Ukraine. This kidney transplant, like those performed in cities throughout the world all failed. One patient, a 26-year-old Boston doctor, lived for six months with his new organ.

A Boston team finally achieved success in 1954. A 24-year-old man was dying of kidney disease. He was referred, along with his twin brother, to the Boston team. The transplant from twin to twin succeeded. The door was now open. The Boston surgical team performed 23 successful identical-twin kidney transplants between 1954 and 1966. However, transplants between non-twins still resulted in rejection.

Attempts to suppress the immune response by radiating (exposing to X-ray) the recipient's body and the donated organ were unsuccessful. In the early 1960s two major breakthroughs finally addressed the rejection problem. Beginning in 1962, it became possible to closely match donor and recipient tissue. This technique markedly decreased the likelihood of rejection in transplantation.

Immunosuppressant therapy was greatly improved by the discovery of cyclosporin in 1972. The widespread use of cyclosporin ushered in the era of widespread organ transplantation. Again, Starzl showed cyclosporin era of widespread organ transplantation. Again, Starzl showed cyclosporin to be more effective when used with steroids.

Transplantation Today

The liver remains difficult to transplant because of its complicated blood supply. The first successful liver transplant was performed by Starzl at the University of Colorado in 1967. Cyclosporin greatly improved the outcome of such transplants. The first human pancreas transplantation was performed by Drs. Richard Lillehei and William Kelly of the University of Minnesota in 1966.

Physicians found that transplantation of both lungs succeeds better than transplanting a single lung. Because most patients with end-stage lung disease also have serious heart deterioration, heart-lung (both lungs) transplants are sometimes performed. The success of this operation is aided by cyclosporin. The first successful heart-lung transplant was carried out in 1981 at Stanford University Medical Center by Drs. Bruce Reitz and Norman Shumway.

Other body parts are now transplanted, but problems remain. Many grafts do not survive permanently. Cyclosporin is very expensive and has serious side effects. Still, a 1992 government report found that organ transplants in the United States were largely successful. Favorable outcome rates vary according to the organ transplanted.

[See also Barnard, Christiaan ; Kidney transplant ]

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transplantation

transplantation (trans-plahn-tay-shŏn) n. the implantation of an organ or tissue from one part of the body to another, as in skin or bone grafting, or from one person to another, as in kidney or heart transplants. Transplanting organs or tissues between individuals is a difficult procedure because of the natural rejection processes in the recipient of the graft. Special treatment (e.g. with immunosuppressant drugs) is needed to prevent graft rejection.

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transplantation

transplantation See graft.

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