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.

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.