Transplant, Surgical

The history of transplants

Transplantation and the immune system

Types of transplants

Donor organ and tissue networks

The future of transplantation

Ethical issues surrounding transplantation

Resources

A surgical transplant involves the removal of body parts, organs, or tissues from one person, either living or recently deceased, and implanting them into the body of another person. Transplants involve thoracic organs (heart and lung), abdominal organs (kidney, liver, pancreas, small intestine, and combinations of these organs), other organs (cornea, hand, skin-graft, and penis), and tissues, cells, and fluids (blood transfusions, blood vessels, bone,

bone marrow, Islets of Langerhans, heart valve, and skin). The first transplant within a human was a cornea transplant in 1905.

Although the idea of transplantation to cure disease dates back several centuries, transplantation has been considered a viable therapy for only a few decades. The relatively recent growth in transplantation stems primarily from expanding knowledge about the body’s immune system and the ability to suppress its natural response to attack foreign tissue. Another advance has been the ability to preserve organs out of the body for longer periods of time until they can be transplanted. Although most transplants involve the transference of tissues or organs between two humans, research is rapidly advancing toward using animal organs for transplantation into humans. Unfortunately donor organs are scarce, which has led to ethical questions concerning what patients would most benefit from receiving a transplant. For example, some believe that alcoholics suffering from cirrhosis of the liver should not receive a liver transplant that they may eventually destroy again because of alcohol abuse.

The history of transplants

The idea of transplanting animal or human parts dates back for many centuries. The mythical Chimera, animals made up of different animal parts, was believed to be the work of the gods. Perhaps the most famous chimera is the Sphinx in Egypt, which has the head of a man and the body of a lion.

The first viable transplantation occurred in the sixteenth century when a technique was developed for replacing noses lost during battle or due to syphilis. The technique involved using skin from the upper inner arm and then grafting and shaping it onto the nose area. In the eighteenth century, Scottish surgeon John Hunter (1728–1793) successfully transplanted a cock’s claw to the animal’s comb. Corneal transplants between two gazelles were also successfully performed in the latter part of the century.

During the nineteenth century, advances in surgery (like the development of antiseptic surgery to prevent infection and anesthetics to the lessen the pain) increased the success rates of most surgical procedures. However, transplantation of organs languished as surgeons had no knowledge of how to reconnect the organ to the new body. It was not until techniques for vascular anastomosis, or the ability to reconnect blood vessels, was developed near the twentieth century that transplant surgery began to move ahead. The first long-lasting renal transplant was performed in Germany in 1902, when a dog kidney was transplanted into another dog by using tube stents (a slender tube used to support the structural integrity of the artery during an operation) and ligatures (wires used to tie off the blood vessels) to make the vascular connections.

The next major advance in transplantation would not occur for more than 40 years. Although renal and kidney transplants were attempted, the transplant recipient’s body always rejected the organ. In 1944, Brazilian-born English scientist Sir Peter Medawar (1915–1987) showed 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. Although short-term successful renal transplants from donor to recipient were achieved in the early 1950s, these transplants usually were rejected by the patient’s immune system. As a result, scientists began to focus on manipulating the immune system so it would accept the transplant. In 1954, the first successful kidney transplant was performed by Joseph Murray in Boston, Massachusetts.

By the early 1960s radiation and drugs were being used to suppress the immune system, in effect, shutting it down to prevent rejection. As a result, that decade saw the first bone marrow transplant, and kidney/pancreas transplant. In 1967, Christiaan Barnard (1922– 2001), a South African cardiac surgeon, received world wide notoriety for achieving the first successful heart transplant.

The next major advance came in 1978 with the development of the extremely effective antirejection (also called immunosuppressant) drug cyclosporin. The first successful heart/lung transplant was performed by Bruce Reitz (in Stanford, California) in 1981; lung lobe transplant by Joel Cooper (in Toronto, Canada) in 1983; and whole lung transplant by Joel Cooper (in St. Louis, Missouri) in 1987. Continued research on how to selectively control the immune system has grown to the point that transplantation is now a relatively common operation with more than 35,000 surgical transplants performed in medical centers throughout the world each year. In 2005, the first successful partial face transplant was performed in France and, in 2006, the first successful penis transplant was performed in China.

Transplantation and the immune system

Once surgeons acquired the ability to sever and reconnect arteries, the ability to control the immune system has been the primary concern in transplant surgery. The immune system is a complex biological network intricately linked to cells found in the blood. Many individuals share similar antigens, (small molecular proteins found on the surface of tissues that can stimulate an immune response,) and one of the first goals is to match antigens between organ donors and the recipients. The idea is to increase the likelihood that the patient’s immune system will not attack because it recognizes a foreign antigen in the donor tissue.

Scientists have identified six primary types of antigens, called histocompatibility-locus antigens. Transplantation between people whose tissues and organs share all of these antigens generally is successful. For example, family members, particularly identical twins, usually have the same antigens. In fact, the first successful kidney transplant was performed in 1955 when a young man received one of the kidneys of his twin brother. As a result of such transplants, relatives are often the source of donor tissues for patients who need kidneys and bone marrow transplants because one kidney or some bone marrow can be donated without causing harm to the donor.

As the number of matching antigens between donor and recipient decreases, the need to suppress the immune system with drugs becomes increasingly important. Unfortunately, many of these drugs have side effects and can suppress the immune system to the point that the patient becomes susceptible to other infections and diseases, which can cause the transplant to be rejected and lead to the patient’s death. The advantage of cyclosporin is that it can be targeted somewhat to work in specific tissues and organs of the body, thus keeping the patient from becoming entirely immunocompromised, which can lead to death from any number of diseases and infections not directly related to the transplanted organ’s functioning.

The immune responses

Although there are probably many types of immune responses, scientists have only identified a few associated with organ rejection. Hyperacute rejection occurs when the patient’s body has already produced a large number of antibodies (proteins manufactured by the immune system to battle disease and infection) that immediately recognize the antigens from the donor organ. This type of rejection, which usually occurs because of incompatible blood types, is often instantaneous, sometimes causing the patient to die even before the surgery is completed.

Acute rejection usually takes several days to occur because the immune system’s white blood cells called lymphocytes, which are integral to its functioning because they initiate the production of antibodies, are lying dormant until the patient receives the organ. As the immune system initiates a response to the antigens in the donor organ, specific immune cells in the blood begin to attack. Acute rejection is combated by the use of immunosuppressive drugs. The longer the patient survives without a immune response attacking the organ, the greater the chances for keeping the immune system under control and for long-term survival.

However, chronic rejection can occur several months or years later. Although this type of rejection is rare, when it occurs, the donor organ slowly deteriorates despite all efforts at immunosuppression. Scientists do not fully understand why the immune response may kick in months or years after an organ has been successfully transplanted.

Types of transplants

There are many types of transplant surgeries, from specific cell and tissue transplants to entire organs. Cornea tissue transplants for the eye were one of the first successful transplants routinely performed. A thin transparent membrane found in front of the eye, the cornea can cause blindness or clouded vision if it is scarred by injury or infection. The transplant procedure involves cutting out part of the damaged cornea and replacing it with cornea from a donated eye. Cornea transplants are relatively simple procedures because they require no reconnection of blood supplying arteries, thus removing the danger of an adverse immune response. These procedures are successful 90% of the time.

The transplantation of bone tissue was first performed in the 1890s and involved replacing diseased or injured bone with pieces of bone from donors. The modern procedure involves using donor bone as a type of scaffolding built over metal nails that immobilizes and connects the patient’s remaining bone sections.

Unlike bones and the cornea, most other transplants are more difficult to achieve because they involve circulating blood and the immune system. Skin grafts for burn patients, for example, are often achieved using autografts (meaning from the self); in this case, segments of skin from other areas of the patient’s own body. A flap graft begins with the partial separation of skin from its original site until adequate blood circulation is achieved, then it is completely severed and grafted onto the transplant site. This technique has a high success rate for curing scars or deformities. A full thickness autograft entails removing small pieces of all the layers of skin for transplantation; these types of skin grafts are particularly suitable for the face to achieve the least amount of scarring. A split-thickness autograft removes tissue-thin layers of skin that heal easily when transplanted. The one drawback to this type of skin graft is that the transplanted tissue usually appears reddish, which makes them more noticeable. Some skin grafts come from the skin of human donors or other animals, like pigs, and are used when large areas must be covered. Unlike the cosmetic goals of other grafts, these grafts are used primarily to stop the patient from losing fluids through the burned area and to prevent infection. Research is also underway to grow skin for grafting from a few donated skin cells.

Bone marrow transplants are often used to treat patients with blood diseases, like leukemia. The transplant procedure involves taking the tissue from the center of bones through a needle, a technique called bone marrow aspiration. The marrow may be an auto graft taken from a patient while the disease is in remission and stored until they need the healthy blood cells. Bone marrow taken from other donors of the same species are called allografts. Unlike most immune responses in transplantation in which the donor’s body rejects the transplant, in bone marrow allografts it is often the transplanted marrow that reacts against the host. This is known as graft-versus-host disease.

Organ transplants

By far, organ transplantation has received the most attention in the popular press. People who would be severely debilitated or die because of failing organs are the recipients of organ transplants. The primary organ transplants are heart, liver, pancreas, lung, and kidney transplants. Under certain circumstances, a patient may receive more than one transplant, the most common multiple transplant procedure is the dual heart/lung transplant.

Kidney transplants are designed to treat patients whose kidneys are failing, making them unable to process body waste products. These transplants have approached a 90% success rate. If the transplant fails, the patient may be put on dialysis until a new donor kidney can be found. Dialysis uses a machine to artificially remove blood from the body, clean the waste products by filtering the blood, and then return the blood to the body.

Other transplantable organs include the liver, the heart, and the lungs. With the development of immunosuppressive drugs, liver transplants have been growing in their success rates, although many patients still die because of organ rejection or from infections. Heart and lung transplants are often performed simultaneously since they share an interrelated vascular system and survival rates are higher for lung transplant patients when they also receive a new heart.

Organ transplants are delicate and complex procedures that require a well trained staff and usually take several hours or much longer to perform. As the surgeon removes the organ, sutures (wire or some other material) are used to close or tie off arteries and other connections to the organ. The new organ is then placed in position and the painstaking task of reconnecting the organ begins. Although the techniques, like vascular anastomosis, for making these connections are well established, they can be difficult procedures. For example, many of the connections to the liver lie underneath the liver and out of the surgeons’ immediate view.

Organ preservation

Unlike tissues or cells, which can be maintained in functioning condition by placing them in life sustaining cultures (specially prepared nourishing fluids places in a dish or a bowl), organs that have been donated for transplantation require a more complex approach for their preservation. Perfusion is the process of using a pump or other mechanical device to circulate specific electrolyte solutions through the organ’s vascular system.

These solutions may support the organ’s metabolic (or chemical and physical) functioning. Some solutions are used, in effect, to freeze the organ. For instance, in cornea, skin, kidney, liver, heart, and pancreas transplants, some solutions are designed to cause hypothermia (subnormal body temperatures) in the organ. Organ tissues maintain their ability to function ten or more times longer when kept at a temperature of 32 to 39° F (0to4° C), and kidneys have been preserved for more than 50 hours using this approach.

Donor organ and tissue networks

Most organs and tissues used for transplantation come from nationwide networks designed to provide quick access to organs when they become available. For example, the United Network for Organ Sharing (UNOS) provides access to organs and tissues throughout North America. The more than 70 organ procurement agencies in the United States are crucial to the success of transplants since they facilitate access to and transportation of organs and tissues that remain viable for transplanting for only a limited amount of time after they are removed from the donor’s body.

The procurement begins when a hospital notifies a local organ bank that a seriously ill or dying patient (who is willing to donate his or her organ or whose family has given permission) is under their care. Organ bank staff will go to the hospital to assess the patient to determine whether their organs are healthy enough for transplantation. For example, most donor organs are harvested from people under age 65 years, and organs from someone who was an intravenous drug user may also be precluded from use since the organs may be infected with AIDS (acquired immunodeficiency syndrome) or hepatitis. Once the patient is pronounced dead, a team of surgeons begin to remove the eyes, heart, liver, and kidneys. The next step is to determine who receives the organ. This is usually done on a geographic basis with those patients in the same general geographic area as the donor receiving first consideration to receive the organ.

However, since these organs are a precious commodity, a nationwide computer list of potential transplant recipients is also maintained. The National Organ Procurement and Transplantation Network was established by the National Organ Transplant Act of 1984. Potential donor recipients are prioritized to receive organs according to the length of time they have been on the UNOS list and on the compatibility to the donor organ in terms of blood types, body sizes, and genetic similarities.

The future of transplantation

Although many transplants, especially organ transplants, would not be needed if people took better care of their bodies by exercising and not smoking or drinking alcohol, the number of organ transplants performed each year is likely to continue to grow as long as donor organs can be obtained. In addition, new kinds of transplants are being pioneered.

One of the more exciting advances is the transplantation of tissues and cells from the central nervous system (CNS). These cells have been transplanted into the brains of people suffering from neurological (or nervous system) diseases, like Parkinson disease. CNS cells and tissues have the unique ability to regenerate, or grow back. In the case of Parkinson patients, the substantia nigra area of the brain can no longer produce the neurotransmitter (chemical messenger) dopamine, which usually results in the progressive loss of many motor skills to the point where patients can no longer walk or feed themselves. One of the surgical treatments under investigation is to transplant adrenal medullary tissue in hopes that the transplanted tissue will permanently regenerate new cells in the brain.

Artificial organs and xenografts

Due to the lack of available organs for transplantation, researchers are constantly experimenting with developing new sources of organs and tissues for transplantation. Artificial organs, for example, are being developed. These include electronic devices to make the heart beat and pumps implanted into the body that can supply necessary substances like insulin. Many of these devices are used as bridges to transplantation. In other words, they are temporary therapies to keep the patient alive while a suitable donor organ can be found. Artificial skin is also under development as are mechanical implants to help cure deafness.

Although current transplantation deals primarily in allografts, or transplantation within the same species, transplantation between species, called xeno grafts, is also a rapidly advancing area of study. The first partially successful xenografts were performed over a quarter of a century ago when surgeons transplanted organs from chimpanzees to humans.

But since the use of primates, which are closer to humans in nature, raises certain ethical questions, recent research has focused on non-primate animals. Pigs, for example, are relatively easy to breed and have large litters. They also share with humans many similar anatomical structures, like the heart, that function in similar ways in the body. Although pig organ transplants have, to date, been unsuccessful, advances in the development of immunosuppressive drugs have led some transplant scientists to think that success in this area can be achieved. Another advance in medical science, the ability to manipulate genes (hereditary components found in cells), has led to genetic engineering. This process involves manipulating and combining specific genetic components to achieve desirable traits or effects. In the case of pig organs, the goal is to make them more compatible to humans. However, the primary obstacle to xenografts remains rejection by the host’s immune system. Even using immunosuppressant drugs does not guarantee the immune system will not eventually recognize and destroy the non-human organ.

A transplant technology that is still in the developmental stage is biorubber, also called poly (glycerol sebacate). It is a new type of polymer that is classified as an elastomer, a polymer with stretchy properties. Biorubber is also biodegradable (meaning that is degrades quickly

KEY TERMS

Allografts —Tissues and organs used for transplantation that come from donors of the same species.

Autografts —Tissues and organs used for transplantation that come from the patients themselves.

Bone marrow —A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones. Bone marrow is the site of blood cell generation.

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.

Immunocompromised —A condition in which the immune system suppressed so that it is not functioning completely.

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

Lymphocytes —White blood cells that play a role in the functioning of the immune system.

Vascular anastomosis —A technique for reconnecting blood vessels.

Xenografts —Tissues and organs used for transplantation that come from different animal species, like pigs or baboons.

and safely) and biocompatible (safe for use inside the body). Its two main ingredients are glycerol, a syrupy liquid found in fats and oils, and sebacic acid, a white acid that helps to oxidize fatty acids. The property that makes biorubber different from other polymers is its ability to stretch back like rubber bands.

Most materials used before biorubber were hard and breakable. These characteristics made them difficult to use in medicine because most tissues and organs are flexible. Biorubber meets those features, especially for use in tissue engineering. Some of the many uses for biorubber include the making of bioengineered blood vessels, bones, cartilage, heart tissue, heart valves, lungs, and various other tissues. Eventually, complete organs needed for transplantation, like hearts and lungs, could be made with biorubber.

Ethical issues surrounding transplantation

The primary ethical issue associated with transplanted is the extreme shortage of available donors. 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. Questions surrounding the limited supply of donor organs include who should get the donor. For example, should the organ go to someone who is poor and on welfare or someone who can afford to pay for the operation. There is also concern over buying organs from people before they have died or from their families after the person has died. Some organs, like kidneys, corneas, bones, and bone marrow could even be bought and removed before death since they would not fatally harm the donor if removed.

Another ethical issue surrounding transplantation is the high costs associated with obtaining and transplanting an organ. Some transplant procedures can cost more than $200,000. Since most people cannot afford such operations, the burden falls on society in the form of higher insurance premiums and government subsidies. Even after the surgery is over, it can cost tens of thousands of dollars each year to keep the person alive because of the high cost of anti-rejection drugs.

Despite the difficulty of obtaining organs, the high costs, and the many ethical concerns, transplantation will continue to thrive since it is the only hope for many terminally ill patients. Society’s mandate is to develop ethical regulations to ensure that growing demands are met fairly and humanely.

See also Antibody and antigen; Cyclosporine.

Resources

BOOKS

Childress, James F. and Catharyn T. Liverman, eds. Organ Donation: Opportunities for Action. London, UK: Elsevier Saunders, 2006.

Drake, Richard, et al., eds. Gray’s Anatomy for Students. Philadelphia, PA: Elsevier Churchill Livingstone, 2005.

Flores, Maria. How to Receive the Gift of Life. Chicago, IL: Maria Flores, 2006.

Forsythe, John L.R. Transplantation: A Companion to Specialist Surgical Practice. London, UK: Elsevier Saunders, 2005.

Stonebridge, Peter, ed. Surgery: An Oxford Core Text. Oxford, UK: Oxford University Press, 2006.

PERIODICALS

Fox, Mark D. “The Transplantation Success Story.” Journal of the American Medical Association (December 7, 1994): 1704.

“National Registry Creation Helps Assess Donor Risk.” Transplant & Tissue Weekly (June 4, 2000).

Starzl, T.E. “The Early Days of Transplantation.” Journal of the American Medical Association (December 7, 1994): 1705.

OTHER

Current Science and Technology Center. “Robotic Surgery.” <http://www.mos.org/cst/article/1623/> (accessed December 2, 2006).

David Petechuk

Transplant, surgical

A surgical transplant involves the removal of body parts, organs, or tissues from one person and implanting them into the body of another person. Although the idea of transplantation to cure disease dates back several centuries, transplantation has been considered a viable therapy for only a few decades. The relatively recent growth in transplantation stems primarily from expanding knowledge about the body's immune system and the ability to suppress its natural response to attack foreign tissue . Another advance has been the ability to preserve organs out of the body for longer periods of time until they can be transplanted. Although most transplants involve the transference of tissues or organs between two humans, research is rapidly advancing toward using animal organs for transplantation into humans. Unfortunately donor organs are scarce, which has led to ethical questions concerning what patients would most benefit from receiving a transplant. For example, some believe that alcoholics suffering from cirrhosis of the liver should not receive a liver transplant that they may eventually destroy again because of alcohol abuse.

The history of transplants

The idea of transplanting animal or human parts dates back for many centuries. The mythical Chimera, animals made up of different animal parts, was believed to be the work of the gods. Perhaps the most famous chimera is the Sphinx in Egypt, which has the head of a man and the body of a lion.

The first viable transplantation occurred in the sixteenth century when a technique was developed for replacing noses lost during battle or due to syphilis. The technique involved using skin from the upper inner arm and then grafting and shaping it onto the nose area. In the eighteenth century, Scottish surgeon John Hunter successfully transplanted a cock's claw to the animal's comb. Corneal transplants between two gazelles were also successfully performed in the latter part of the century.

During the nineteenth century, advances in surgery (like the development of antiseptic surgery to prevent infection and anesthetics to the lessen the pain ) increased the success rates of most surgical procedures. However, transplantation of organs languished as surgeons had no knowledge of how to "reconnect" the organ to the new body. It was not until techniques for vascular anastomosis, or the ability to reconnect blood vessels, was developed near the twentieth century that transplant surgery began to move ahead. The first long-lasting renal transplant was performed in Germany in 1902, when a dog kidney was transplanted into another dog by using tube stents (a slender tube used to support the structural integrity of the artery during an operation) and ligatures (wires used to tie off the blood vessels) to make the vascular connections.

The next major advance in transplantation would not occur for more than 40 years. Although renal and kidney transplants were attempted, the transplant recipient's body always rejected the organ. In 1944, Peter Medawar

showed 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. Although short-term successful renal transplants from donor to recipient were achieved in the early 1950s, these transplants usually were rejected by the patient's immune system. As a result, scientists began to focus on manipulating the immune system so it would accept the transplant.

By the early 1960s radiation and drugs were being used to suppress the immune system, in effect, shutting it down to prevent rejection. As a result, that decade saw the first bone marrow transplant, kidney transplant, and kidney/pancreas transplant. In 1967, Christiaan Barnard, a South African surgeon, received world wide notoriety for achieving the first successful heart transplant.

The next major advance came in 1978 with the development of the extremely effective antirejection (also called immunosuppressant) drug cyclosporin. Continued research on how to selectively control the immune system has grown to the point that transplantation is now a relatively common operation with more than 35,000 surgical transplants performed in medical centers throughout the world each year.

Transplantation and the immune system

Once surgeons acquired the ability to sever and reconnect arteries , the ability to control the immune system has been the primary concern in transplant surgery. The immune system is a complex biological network intricately linked to cells found in the blood. Many individuals share similar antigens, (small molecular proteins found on the surface of tissues that can stimulate an immune response,) and one of the first goals is to match antigens between organ donors and the recipients. The idea is to increase the likelihood that the patient's immune system will not attack because it recognizes a foreign antigen in the donor tissue.

Scientists have identified six primary types of antigens, called histocompatibility-locus antigens. Transplantation between people whose tissues and organs share all of these antigens generally is successful. For example, family members, particularly identical twins, usually have the same antigens. (In fact, the first successful kidney transplant was performed in 1955 when a young man received one of the kidneys of his twin brother.) As a result, relatives are often the source of donor tissues for patients who need kidneys and bone marrow transplants because one kidney or some bone marrow can be donated without causing harm to the donor.

As the number of matching antigens between donor and recipient decreases, the need to suppress the immune system with drugs becomes increasingly important. Unfortunately, many of these drugs have side effects and can suppress the immune system to the point that the patient becomes susceptible to other infections and diseases, which can cause the transplant to be rejected and lead to the patient's death. The advantage of cyclosporin is that it can be targeted somewhat to work in specific tissues and organs of the body, thus keeping the patient from becoming entirely immunocompromised, which can lead to death from any number of diseases and infections not directly related to the transplanted organ's functioning.

The immune responses

Although there are probably many types of immune responses, scientists have only identified a few associated with organ rejection. Hyperacute rejection occurs when the patient's body has already produced a large number of antibodies (proteins manufactured by the immune system to battle disease and infection) that immediately recognize the antigens from the donor organ. This type of rejection, which usually occurs because of incompatible blood types, is often instantaneous, sometimes causing the patient to die even before the surgery is completed.

Acute rejection usually takes several days to occur because the immune system's white blood cells called lymphocytes, which are integral to its functioning because they initiate the production of antibodies, are lying dormant until the patient receives the organ. As the immune system initiates a response to the antigens in the donor organ, specific immune cells in the blood begin to attack. Acute rejection is combated by the use of immunosuppressive drugs. The longer the patient survives without a immune response attacking the organ, the greater the chances for keeping the immune system under control and for long-term survival.

However, chronic rejection can occur several months or years later. Although this type of rejection is rare, when it occurs, the donor organ slowly deteriorates despite all efforts at immunosuppression. Scientists do not fully understand why the immune response may kick in months or years after an organ has been successfully transplanted.

Types of transplants

There are many types of transplant surgeries, from specific cell and tissue transplants to entire organs. Cornea tissue transplants for the eye were one of the first successful transplants routinely performed. A thin transparent membrane found in front of the eye, the cornea can cause blindness or clouded vision if it is scarred by injury or infection. The transplant procedure involves cutting out part of the damaged cornea and replacing it with cornea from a donated eye. Cornea transplants are relatively simple procedures because they require no reconnection of blood supplying arteries, thus removing the danger of an adverse immune response. These procedures are successful 90% of the time.

The transplantation of bone tissue was first performed in the 1890s and involved replacing diseased or injured bone with pieces of bone from donors. The modern procedure involves using donor bone as a type of scaffolding built over metal nails that immobilizes and connects the patient's remaining bone sections.

Unlike bones and the cornea, most other transplants are more difficult to achieve because they involve circulating blood and the immune system. Skin grafts for burn patients, for example, are often achieved using autografts (meaning from the self), in this case, segments of skin from other areas of the patient's own body. A flap graft begins with the partial separation of skin from its original site until adequate blood circulation is achieved, then it is completely severed and grafted onto the transplant site. This technique has a high success rate for curing scars or deformities. A full thickness autograft entails removing small pieces of all the layers of skin for transplantation; these types of skin grafts are particularly suitable for the face to achieve the least amount of scarring. A split-thickness autograft removes tissue-thin layers of skin that heal easily when transplanted. The one drawback to this type of skin graft is that the transplanted tissue usually appears reddish, which makes them more noticeable. Some skin grafts come from the skin of human donors or other animals, like pigs , and are used when large areas must be covered. Unlike the cosmetic goals of other grafts, these grafts are used primarily to stop the patient from losing fluids through the burned area and to prevent infection. Research is also underway to grow skin for grafting from a few donated skin cells.

Bone marrow transplants are often used to treat patients with blood diseases, like leukemia . The transplant procedure involves taking the tissue from the center of bones through a needle, a technique called bone marrow aspiration. The marrow may be an autograft taken from a patient while the disease is in remission and stored until they need the healthy blood cells. Bone marrow taken from other donors of the same species are called allografts. Unlike most immune responses in transplantation in which the donor's body rejects the transplant, in bone marrow allografts it is often the transplanted marrow that reacts against the host. This is known as graft-versus-host disease.

Organ transplants

By far, organ transplantation has received the most attention in the popular press. People who would be severely debilitated or die because of failing organs are the recipients of organ transplants. The primary organ transplants are heart, liver, pancreas, lung, and kidney transplants. Under certain circumstances, a patient may receive more than one transplant, the most common multiple transplant procedure is the dual heart/lung transplant.

Kidney transplants are designed to treat patients whose kidneys are failing, making them unable to process body waste products. These transplants have approached a 90% success rate. If the transplant fails, the patient may be put on dialysis until a new donor kidney can be found. Dialysis uses a machine to artificially remove blood from the body, clean the waste products by filtering the blood, and then return the blood to the body.

Other transplantable organs include the liver, the heart, and the lungs. With the development of immunosuppressive drugs, liver transplants have been growing in their success rates, although many patients still die because of organ rejection or from infections. Heart and lung transplants are often performed simultaneously since they share an interrelated vascular system and survival rates are higher for lung transplant patients when they also receive a new heart.

Organ transplants are delicate and complex procedures that require a well trained staff and usually take several hours or much longer to perform. As the surgeon removes the organ, sutures (wire or some other material) are used to close or tie off arteries and other connections to the organ. The new organ is then placed in position and the painstaking task of reconnecting the organ begins. Although the techniques, like vascular anastomosis, for making these connections are well established, they can be difficult procedures. For example, many of the connections to the liver lie underneath the liver and out of the surgeons' immediate view.

Organ preservation

Unlike tissues or cells, which can be maintained in functioning condition by placing them in life sustaining cultures (specially prepared nourishing fluids places in a dish or a bowl), organs that have been donated for transplantation require a more complex approach for their preservation. Perfusion is the process of using a pump or other mechanical device to circulate specific electrolyte solutions through the organ's vascular system.

These solutions may support the organ's metabolic (or chemical and physical) functioning. Some solutions are used, in effect, to freeze the organ. For instance, in cornea, skin, kidney, liver, heart, and pancreas transplants, some solutions are designed to cause hypothermia (subnormal body temperatures) in the organ. Organ tissues maintain their ability to function 10 or more times longer when kept at a temperature of 32–39°F (0–4°C), and kidneys have been preserved for more than 50 hours using this approach.

Donor organ and tissue networks

Most organs and tissues used for transplantation come from nationwide networks designed to provide quick access to organs when they become available. For example, the United Network for Organ Sharing (UNOS) provides access to organs and tissues throughout North America . The more than 70 organ procurement agencies in the United States are crucial to the success of transplants since they facilitate access to and transportation of organs and tissues that remain viable for transplanting for only a limited amount of time after they are removed from the donor's body.

The procurement begins when a hospital notifies a local organ bank that a seriously ill or dying patient (who is willing to donate his or her organ or whose family has given permission) is under their care. Organ bank staff will go to the hospital to assess the patient to determine whether their organs are healthy enough for transplantation. For example, most donor organs are harvested from people under age 65, and organs from someone who was an intravenous drug user may also be precluded from use since the organs may be infected with the AIDS disease or hepatitis . Once the patient is pronounced dead, a team of surgeons begin to remove the eyes, heart, liver, and kidneys. The next step is to determine who receives the organ. This is usually done on a geographic basis with those patients in the same general geographic area as the donor receiving first consideration to receive the organ.

However, since these organs are a precious commodity, a nationwide computer list of potential transplant recipients is also maintained. The National Organ Procurement and Transplantation Network was established by the National Organ Transplant Act of 1984. Potential donor recipients are prioritized to receive organs according to the length of time they have been on the UNOS list and on the compatibility to the donor organ in terms of blood types, body sizes, and genetic similarities.

The future of transplantation

Although many transplants, especially organ transplants, would not be needed if people took better care of their bodies by exercising and not smoking or drinking alcohol, the number of organ transplants performed each year is likely to continue to grow as long as donor organs can be obtained. In addition, new kinds of transplants are being pioneered.

One of the more exciting advances is the transplantation of tissues and cells from the central nervous system (CNS). These cells have been transplanted into the brains of people suffering from neurological (or nervous system) diseases, like Parkinson disease. CNS cells and tissues have the unique ability to regenerate, or grow back. In the case of Parkinson's patients, the substantia nigra area of the brain can no longer produce the neuro-transmitter (chemical messenger) dopamine , which usually results in the progressive loss of many motor skills to the point where patients can no longer walk or feed themselves. One of the surgical treatments under investigation is to transplant adrenal medullary tissue in hopes that the transplanted tissue will permanently regenerate new cells in the brain.

Artificial organs and xenografts

Due to the lack of available organs for transplantation, researchers are constantly experimenting with developing new sources of organs and tissues for transplantation. Artificial organs, for example, are being developed. These include electronic devices to make the heart beat and pumps implanted into the body that can supply necessary substances like insulin . Many of these devices are used as "bridges" to transplantation. In other words, they are temporary therapies to keep the patient alive while a suitable donor organ can be found. Artificial skin is also under development as are mechanical implants to help cure deafness.

Although current transplantation deals primarily in allografts, or transplantation within the same species, transplantation between species, called xenografts, is also a rapidly advancing area of study. The first partially successful xenografts were performed over a quarter of a century ago when surgeons transplanted organs from chimpanzees to humans.

But since the use of primates , which are closer to humans in nature, raises certain ethical questions, recent research has focused on non-primate animals. Pigs, for example, are relatively easy to breed and have large litters. They also share with humans many similar anatomical structures, like the heart, that function in similar ways in the body. Although pig organ transplants have, to date, been unsuccessful, advances in the development of immunosuppressive drugs have led some transplant scientists to think that success in this area can be achieved. Another advance in medical science, the ability to manipulate genes (hereditary components found in cells), has led to genetic engineering . This process involves manipulating and combining specific genetic components to achieve desirable traits or effects. In the case of pig organs, the goal is to make them more compatible to humans. However, the primary obstacle to xenografts remains rejection by the host's immune system. Even using immunosuppressant drugs does not guarantee the immune system will not eventually recognize and destroy the non-human organ.

Ethical issues surrounding transplantation

The primary ethical issue associated with transplanted is the extreme shortage of available donors. 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. Questions surrounding the limited supply of donor organs include who should get the donor. For example, should the organ go to someone who is poor and on welfare or someone who can afford to pay for the operation. There is also concern over buying organs from people before they have died or from their families after the person has died. Some organs, like kidneys, corneas, bones, and bone marrow could even be bought and removed before death since they would not fatally harm the donor if removed.

Another ethical issue surrounding transplantation is the high costs associated with obtaining and transplanting an organ. Some transplant procedures can cost more than $200,000. Since most people cannot afford such operations, the burden falls on society in the form of higher insurance premiums and government subsidies. Even after the surgery is over, it can cost tens of thousands of dollars each year to keep the person alive because of the high cost of antirejection drugs.

Despite the difficulty of obtaining organs, the high costs, and the many ethical concerns, transplantation will continue to thrive since it is the only hope for many terminally ill patients. Society's mandate is to develop ethical regulations to ensure that growing demands are met fairly and humanely.

See also Antibody and antigen; Cyclosporine.

Resources

books

Gutkind, L. Many Sleepless Nights. Pittsburgh: The University of Pittsburgh Press, 1990.

Keyes, C.D. New Harvest: Transplanting Body Parts and Reaping the Benefits. Clifton, NJ: Humana Press, 1991.

periodicals

Fox, Mark D. "The Transplantation Success Story." Journal of the American Medical Association (December 7, 1994): 1704.

"National Registry Creation Helps Assess Donor Risk." Transplant & Tissue Weekly (June 4, 2000).

Pace, Brian. "Suppressing the Immune System for Organ Transplants." JAMA 283 no. 18 (May 10, 2000): 2484.

Starzl, T.E. "The Early Days of Transplantation." Journal of the American Medical Association (December 7, 1994): 1705.

White, D., and J. Wallork. "Xenografting: Probability, Possibility, or Pipe Dream?" The Lancet (October 9, 1993): 879-880.

other

Current Science and Technology Center. "Robotic Surgery" [cited April 2003]. <http://www.mos.org/cst/article/1623/>.

David Petechuk

KEY TERMS

Allografts

—Tissues and organs used for transplantation that come from donors of the same species.

Autografts

—Tissues and organs used for transplantation that come from the patients themselves.

Bone marrow

—A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones. Bone marrow is the site of blood cell generation.

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.

Immunocompromised

—A condition in which the immune system suppressed so that it is not functioning completely.

Immunosuppressant

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

Lymphocytes

—White blood cells that play a role in the functioning of the immune system.

Vascular anastomosis

—A technique for reconnecting blood vessels.

Xenografts

—Tissues and organs used for transplantation that come from different animal species, like pigs or baboons.

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.

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.

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 (1939–45), British biologist Peter Medawar (1915–1987) 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 ]