Transplant, Surgical | Research & Encyclopedia Articles

Transplant, Surgical

Stories of transplanted tissue and body parts go far back in myth and legend. Chinese folklore tells of organ transplants; in the sixth century A.D., the Western patron saints of medicine, Cosmos and Damian, supposedly replaced the cancerous leg of a white man with the healthy leg of a recently-deceased black man. Records of transplants begin in India in the sixth century A.D. with skin grafts to replace amputated noses (the penalty for adultery). This practice was introduced to Western medicine in the sixteenth century by Italian surgeon Gaspare Tagliacozzi who grafted to a patient's nose a flap of skin from the forearm. Portion of this flap was left in tact on the arm until the graft took several weeks later when the flap was severed and the arm released. Tagliacozzi used a patient's own skin because he felt that an individual's "force and power" would reject foreign tissue--thus anticipating the problem of rejection which remains a major impediment to successful transplantation to this day. Scottish anatomist John Hunter revived some interest in tissue transplantation in the eighteenth century and, during the nineteenth century, skin grafting was reintroduced with increasingly successful results when, in 1869, a young French surgeon, Jacques Louis Reverdin, discovered grafts needed to be thin.

Scottish surgeon William MacEwen reported success with bone allografts (transplants from one person to another) in children in 1881, and von Hippel carried out a corneal transplant in 1877. In 1902 the French surgeon Alexis Carrel developed a method of sewing together small blood vessels with tiny needles and fine thread, making transplantation technically feasible. Testing these methods with Dr. Charles Guthrie of the University of Chicago, Carrel performed a series of organ transplants on animals. Organs functioned well only for a short time. Other researchers experienced similar results and transplantation came to a standstill. Researchers, including Guthrie, began to suspect rejection of the implanted organ was an immune system response to foreign tissue. British biologist Peter Medawar became interested in skin graft problems while working with severely burned soldiers during World War II. He found that a second set of skin grafts between the same two subjects was rejected twice as quickly as the first set. To Medawar, this was clearly an immune response. In 1948 he found that grafts between twins were successful and, in 1954, showed that immune tolerance was acquired during embryo development and that injection of foreign substances into embryos or newborn mice would produce permanent tolerance to those substances later in life.

Meanwhile, researchers began focusing on kidney transplantation because of the kidney's relatively simple blood-supply system. Russian surgeon Yuri Voronoy performed the first human kidney transplant in Kiev, Ukraine in 1933, and several more during the 1940s. Ten kidney transplants were carried out in Paris, France from 1950 to 1953, one in Chicago, Illinois in 1950, and several at Peter Bent Brigham Hospital in Boston, Massachusetts. All failed except one--a 26-year-old Boston doctor who lived for six months. Discouragingly, matching donor and recipient blood types didn't improve outcomes. Drs. Joseph Murray and John Merrill and The Peter Bent Brigham team finally achieved success in 1954 when they transplanted a kidney donated by 24-year-old Ronald Herrick for his dying twin brother, Richard, and the Boston team performed 23 identical-twin kidney transplants between 1954 and 1966.

Transplants between non-twins still resulted in rejection, however, and unsuccessful attempts were made to suppress immune response using whole-body X-rays and X-rays of the organ to be transplanted. Two major breakthroughs occurred in the early 1960s. The first began with the 1931 observation by Karl Landsteiner (1868-1943), that blood could be classified by types, indicating that human tissue types might also exist. Also after George Snell found the major histocompatibility complex (MHC), a system of tissue-compatibility genes in mice in the 1940s, Jean Dausset identified a similar genetic set of human white blood cell antigens called human lymphocyte antigens (HLA). Beginning in Paris in 1962, HLA characteristics were increasingly used to closely match donor and recipient tissue markedly decreasing the likelihood of rejection. The second breakthrough began in 1959 when Robert Schwartz and William Dameshek of Tufts University in Boston showed that a drug called 6-mercaptopurine was a strong suppressor of the immune response in animals; this response was given the name immunosuppression. The Murray transplant team at Peter Bent Brigham, and the visiting British surgeon Roy Calne, worked with a derivative of 6-MP developed by Dr. George Hitchings at Burroughs-Wellcome. After us of this improved immunosuppressant, called Imuran (azathioprine), became standard procedure in 1962, kidney transplantation--with extended survival--was possible. Dr. Thomas Starzl of the University of Colorado developed the current procedure of administering steroids along with azathioprine in 1963. Immunosuppressant therapy was greatly improved, with a dramatic shift in transplantation success, by the discovery of cyclosporin, a substance isolated from soil samples. Microbiologist, Jean-Francois Borel, with the Swiss drug firm Sandoz, discovered in 1972 that cyclosporin inhibited the activity of the T lymphocytes, the immune system components that attack and destroy transplanted tissue. Trials carried out by British physicians Calne and David White in 1976-78 demonstrated cyclosporin's effectiveness in preventing rejection, and its widespread use ushered in the era of organ transplantation. Again, Starzl showed cyclosporin to be more effective when used with steroids.

Until cyclosporin, organ transplants other than kidneys fared poorly. This included the early heart transplants, the first of which electrified the world. South African doctor, Christiaan Barnard, drawing on techniques developed by Drs. Norman Shumway and Richard Lower of the United States, transplanted the heart of a young woman into Louis Washansky, a 55-year-old grocer. Washansky survived only 18 days, but Barnard's second patient, dentist Philip Blaiberg, lived for 17 months. Heart transplantation rapidly mushroomed, with Dr. Denton Cooley of Houston, Texas, performing more than 20 in 1968. Outcomes, however, remained poor because of rejection, and heart transplantation virtually died out until the use of cyclosporin in 1983 when heart transplants began again with much greater success, and other organ transplants have also become more common. Starzl and Calne pioneered the field of liver transplantation when Starzl performed the first successful liver transplant at the University of Colorado in 1967. Human pancreas transplantation was first performed by Drs. Richard Lillehei and William Kelly of the University of Minnesota in 1966, and the first successful combined heart-lung transplant was carried out in 1981 at Stanford University Medical Center by Drs. Bruce Reitz and Shumway.

Other body parts are often transplanted, however problems remain: Many grafts do not survive permanently; cyclosporin and tacrolimus (another major immunosuppressant) are expensive and have serious side effects; and graft-vs.-host reaction, discovered by Simonsen in 1957, in which lymphocytes in the transplanted tissue attack the "foreign" host tissue, is difficult to control. In the 1990s, investigations by Starzl at the Starzl Transplantation Institute at the University of Pittsburgh into tolerance induction and the state of chimerism (the coexistence of donor and recipient cells), achieved particularly through simultaneous donor bone marrow infusion with the organ transplant, hold promise for reducing or eliminating the need for immunosuppressive drugs.

With the success rate of organ transplantation increasing, surgeons and patients alike face a new dilemma-- shortage of donor organs. As of April 1, 1998, more than 60,000 patients in the United States alone awaited donor organs; in 1996, almost 4,000 Americans died awaiting organs. An area of serious research to help solve this dilemma is xenotransplantation-- transplanting the organ from another species into a human. In 1992, Dr. John Fung, chief of transplant surgery and his team at the Starzl Transplantation Institute, performed the world's first liver transplant from a baboon to a man dying of hepatitis B. Although the man died of a brain hemorrhage shortly after the transplant was completed, researchers learned from the attempt that that rejection could be managed with immunosuppressants. A second failed xenotransplant brought a temporary halt to the practice until further research, along with the decision to use organs from non-primates. Pigs were chosen for several reasons; however, human antibodies trigger hyperacute rejection of the xenograft organ. To overcome this obstacle, research is now focusing on three fascinating possibilities: the combination of chimerism and genetic engineering to breed "transgenic" animals which express human "inhibitory" proteins and prevent host destruction of the transplanted organ; infusion of bone marrow cells into a pig fetus in order to modify its immune system as an adult and allow cohabitation of organ and recipient cells; and genetic manipulation of dendritic cells (DCs)--specialized white blood cells which control the activity of other immune cells--to either "teach" host T cells not to attack the transplanted organ, or by altering donor DCs (which enter the host with the transplanted organ) to produce their own supply of immunosuppressants, thus protecting the transplanted organ from rejection by the host.