medical transplantation

(biology) The artificial removal of part of an organism and its replacement in the body of the same or of a different individual. To remove a plant from one location and replant it in another place.

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 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.

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.

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.

—Richard D. Karp

The transfer of living organs and tissue from one part of the body to another or from one individual to another. Transplantation and grafting mean the same thing, though the term grafting is more commonly used to refer to the transfer of skin. See grafting (1).
Occasionally an organ is transplanted from one place to another within the body (autotransplants). Kidneys, for example, have been relocated to enable them to continue functioning after the ureters have been damaged. See also graft rejection.

• t. antigen — see histocompatibility antigen.
• bone marrow t. — has been used in the treatment of a variety of hematopoietic and immunological disorders, e.g. in dogs with aplastic anemia.
• corneal t. — full-depth and part-depth (lamellar) transplants are performed in animals when there is scarring of the cornea in the visual axis but the operation is difficult, the aftercare intensive and the failure rate high.
• t. immunology — the study of immune responses that distinguish between self and nonself and the rejection of transplanted tissue or organs.
• tendon t. — the procedure is not favored in horses where it was at one time used as a treatment for tendonitis. The success rate for return to racing performance is poor.