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History of Intestinal Transplantation
Although experiments were being conducted in the early 20th century, intestinal transplantation has only recently become a viable clinical procedure. As the largest lymphoid organ in the body and host to a multitude of foreign antigens, the small bowel has presented an arduous challenge for transplantation.
The relatively recent emergence of intestinal transplantation has depended on the development of more potent immunosuppression, and particularly the advent of tacrolimus. Within the last decade, what was once a completely experimental procedure has evolved into one that is likely to someday replace chronic total parenteral nutritional (TPN) support as the preferred treatment for many patients with irreversible intestinal failure.
The University of Pittsburgh has played an important role in the rapid progress of intestinal transplantation techniques. Over the past eight years, surgeons at the Thomas E. Starzl Transplantation Institute have performed approximately 45 percent of intestinal transplants worldwide. Throughout this time, Drs. John Fung and Kareem Abu-Elmagd – together with Dr. Jorge Reyes and other clinicians of Children’s Hospital of Pittsburgh – have collaborated to shape and enhance the process for small bowel transplant.
Because of the greatly improved survival rates permitted by recent advances, Dr. Abu-Elmagd formally requested that the United States Health Care Financing Administration (HCFA) investigate the possibility of Medicare approval of intestinal transplantation for coverage. Medicare coverage of the procedures was officially approved (with some restrictions) as of October 4, 2000.
Intestinal Transplantation Timeline
1902 – French Nobel laureate Alexis Carrel performs experiments in which intestinal segments are implanted in the necks of dogs.
1959 – R. E. Billingham defines three prerequisites for the development of graft-versus-host disease (GVHD):
- In a donor graft, the presence of mature, immunologically competent cells
- Sufficient time for these cells to react before they are rejected by the host
- In the recipient, important antigens that promote histocompatibility – a state in which recipient’s immune system does not interfere with or reject the grafting of tissue or the transfusion of blood
During GVHD, widespread damage to the transplant recipient’s organs is caused by immune cells from the transplanted intestine, or donor graft. Because the intestine contains a large number of lymphocytes [white blood cells that fight infection and disease], GVHD is thought to represent a major obstacle to human intestinal transplants during this time.
In later years, researchers find that, contrary to what had been observed in animals, GVHD is rarely seen in humans after intestinal transplantation. The same immunosuppressive medications used to prevent graft rejection help to further decrease the chance of GVHD.
1959-1960 – Publication of three articles begins the modern era of intestinal transplantation. The first two, written by Richard C. Lillehei of the University of Minnesota, describe intestine-alone transplantation in dogs. All three articles make the important observation that autografts [tissue or organs grafted into a new position in or on the body of the same individual] provide good long-term nutritional support.
1960s – Initial attempts at intestinal transplantation are suspended due to poor graft and patient survival. Of eight human intestinal recipients recorded during this period, none survive; this is due to ineffective immunosuppressive regimen.
Other aspects of intestinal and multivisceral transplantation are similar to those in clinical use today, but practical application is forestalled another three decades because of multiple problems and concerns.
1962 – It is demonstrated that, in multivisceral transplants, the intestinal component fares better than in intestine-alone transplants. In addition, researchers observe that the liver
protects co-transplanted tissues and other organs.
Dr. Lillehei autotransplants cold preserved small bowel.
1967 – Working as a resident in General Surgery, Stanley J. Dudrick collaborates with Drs. Rhoads and Vars to perfect a technique of intravenous feeding in beagle puppies that supports normal growth and development.
1968 – Total parenteral nutrition (TPN) is introduced by Drs. Dudrick and D. W. Wilmore. The intravenous feeding technique developed the previous year is applied to a human infant. TPN begins as a treatment for babies born with catastrophic gastrointestinal (GI) conditions that prevent them from adequately absorbing nutrients through their GI tracts.
The babies treated with intravenous feeding exhibit dramatic growth and development; with additional refinements, TPN use soon expands to adult patients with a variety of gastrointestinal tract diseases and other difficulties that interfere with nutrition. Enthusiasm for TPN increases during the next decade. In subsequent decades, it proves critical to the success of intestinal transplantation.
Mid 1970s – Jean Borel discovers cyclosporine, an immunosuppressive medication that helps prevent the body’s rejection of transplanted organs.
Mid 1980s – Successful clinical use of cyclosporine for solid organ transplants triggers further clinical attempts at intestinal transplantation; however, the results are still unsatisfactory.
November, 1987 – In Pittsburgh, doctors perform a multivisceral transplant. The young recipient had suffered a mid-gut volvulus [abnormal twisting of the intestine that causes obstruction] perinatally. The child survived for more than six months after the operation.
1988 – The first international small bowel transplant symposium convenes in London. One of the main themes at this meeting is how to eliminate the lymphoid tissue in intestinal grafts; at this time, concern about GVHD is still a major issue. It has since been learned that the elimination of white blood cells from the intestine predisposes the graft to chronic rejection.
David Grant et al. report a landmark study in which extraordinary efforts were made to circumvent the unpredictable enteric absorption of cyclosporine by giving uninterrupted intravenous infusion. The majority of animals survived for more than 100 days; before this point, survival has not been recorded in any animal model of multivisceral transplantation.
This landmark accomplishment prompts a second wave of small clinical trials, from which a handful of hopeful observations emerge. Two patients achieve a greater than five-year rehabilitation, but only one other patient achieves long-term survival.
A key observation from these trials is that intestine and other non-hepatic [of, relating to, or resembling the liver] organs seem to have minimal rejection when accompanied by the donor liver.
1989 – An immunosuppressive drug called FK506 (later referred to as tacrolimus or Prograf®) is introduced to clinical transplants. It is thought to be superior to cyclosporine because of its greater ability to reverse ongoing or established rejection and dose adjustability. It is found to allow for rapid withdrawal or even complete discontinuation of corticosteroid therapy, another long-term advantage.
N. Murase, R. Hoffman, and R. Lee et al. later confirm tacrolimus’ superior effectiveness. They report permanent survival of multivisceral allografts [graft(s) of tissue obtained from a donor of the same species as, but with a different genetic make-up from, the recipient] in rats.
In Paris, Olivier Goulet et al. transplant a near-total cadaveric small bowel into a child who is still alive today. Along with the five other examples of prolonged human intestinal allograft function, this successful operation re-ignites interest in the field. However, although the intestine is no longer a “forbidden organ,” further progress awaits better immunosuppression.
May 2, 1990 – Tacrolimus becomes the primary immunosuppressive agent used by UPMC for intestinal and multivisceral transplants.
In Ontario, Canada, Dr. Grant performs the first successful liver-intestinal transplant.
1992 – Microchimerism [the coexistence of donor and recipient cells] is discovered in long-surviving human recipients of kidney, liver, and other kinds of allografts. This discovery gives rise to a new perception of transplantation among experts. Subsequent research provides unprecedented insight into the workings of tolerance, particularly allotolerance.
After beginning a clinical trial in 1990, five examples of long-surviving human intestinal transplant recipients were reported by Dr. Saturu Todo et al. in Pittsburgh.
1994 – The University of Pittsburgh discontinues its clinical intestinal transplantation program for nearly one year. The moratorium is declared because of a seemingly high fixed death rate and excessive complication rates.
2000 – As of October 4th, intestinal transplantation procedures qualify for funding as a service by the United States Health Care Financing Administration (HCFA).
Today, treatment principles for induction of transplantation tolerance continue to evolve. A group of strategies collectively known as “immune modulation” is currently undergoing clinical trial with all of the major organs, including the intestine.
Although rejection remains an important post- transplantation risk, GVHD has been less of a clinical problem than initially feared. Thanks to refined medication and patient selection strategies along with the use of bone marrow augmentation, one- and five-year adult survival rates are reported at 72 percent and 50 percent, respectively.
Transplantation is the only treatment available for patients diagnosed with irreversible intestinal failure resulting from three clinical conditions:
- Short gut syndrome is the primary indication for the procedure and results from Crohn’s disease, desmoid tumor, mesenteric vascular thrombosis, midgut volvulus, abdominal trauma, Gardner’s syndrome and several other disorders.
- Defective intestinal motility occurs less frequently and is caused by hollow visceral myopathy, neuropathy, and/or total intestinal aganglionosis.
- Impaired enterocyte absorptive capacity also occurs less frequently than short gut syndrome, and is caused by radiation enteritis, extensive inflammatory bowel disease, microvillus inclusion disease, and several other conditions.
The Future of Intestinal Transplantation
Within the last 12 years, transplantation of the intestine alone or as a component of multivisceral grafts has progressed from a completely experimental procedure to one that appears destined to replace chronic total parenteral nutritional support as the preferred method of treatment.
While TPN has been used for more than 30 years to maintain patients with temporary or permanent intestinal failure, the therapy can result in life-threatening complications including liver failure. Surgery at an earlier stage is expected to reduce or eliminate the need for combined organ replacement, which will save a significant number of donor livers and reduce patients’ time on the waiting list.
With further enhancements in the areas of immunosuppressive therapy, infection control, and patient selection, transplant surgeons believe that intestinal transplantation could be offered to patients diagnosed with Crohn’s disease or similar benign conditions that will require TPN indefinitely but have not yet developed the complications associated with long-term TPN therapy.
Learn more about Long-Term Survival and Quality of Life for intestine transplant patients.
January 12, 2011
January 12, 2011