One of the major issues with transplantation are the risks posed by immunosupression.
A 24-year-old former Marine who received a wrist-level hand transplant in March 2009 is back at work as an electrician. "He has shown remarkable progress with func-tion and an encouraging return of quality of life. He has had only a few episodes of rejection that were completely resolved with topical immunosuppressant creams alone without additional treatment," according to Vijay Gorantla, MD, PhD, assistant professor in the department of surgery, University of Pittsburgh, and director of the Composite Tissue Allotransplantation Program at the University of Pittsburgh Medical Center. Two other patients have achieved similar levels of functionality and success. One is a 57-year-old Air Force Veteran who was the first person in the U.S. to have both hands transplanted in May 2009. The other is a 41-year-old mechanic who is the first patient in the U.S. to receive a combined bilateral hand and full above-the-elbow forearm transplant in February 2010.
AdvertisementThese three patients are the first in the world to have a novel cell-based treatment for modulating the immune system after upper extremity transplantation. The therapy known as "The Pittsburgh Protocol" is unique in utilizing bone marrow cells to enable reduction of the need for multiple anti-rejection drugs after transplantation. The University of Pittsburgh Medical Center is currently the only transplantation center in the world to offer it. An early report of the initial experience with the "Pittsburgh Protocol" in three recipients of upper extremity transplants was presented during the 2010 Annual Clinical Congress of the American College of Surgeons.
Composite Tissue Allografts (CTAs), such as hand transplants, are different from solid organ transplants, such as kidney, heart, or liver, because they consist of multiple tissues like skin, muscle, bone, bone marrow, tendons, and blood vessels. Furthermore, the skin component of certain CTAs confers an added degree of immunogenicity (immunogenicity: ability to provoke an immune response) due to the presence of antigen presenting cells (such as Langerhans Cells and native keratinocytes).
Conventional immunosuppression uses combinations of two or more immunosuppressive agents in high doses over prolonged duration. The majority of centers in the U.S. and around the world have relied on such conventional regimens to maintain CTAs, particularly for upper extremity transplant patients. Although these regimens have extended graft survival, they have resulted in metabolic complications such as diabetes, hypertension, and high blood cholesterol as well as necrosis (death) of bone and opportunistic infections. Rarely, multiple-drug immuno-suppression may even cause cancer of the skin and lymph nodes.
The "Pittsburgh Protocol" involves only one immunosuppressive agent (monotherapy) and an infusion of bone marrow stem cells from the limb donors. Transplant recipients receive maintenance therapy with a drug, tacrolimus, starting the day of the operation. The drug is titrated carefully for the first three months and adjusted at six- and 12-month follow-up periods. "To date, the transplants have been maintained on only one drug. That''s all the patients take," Dr. Gorantla said. The patients also have a one-time infusion of bone marrow cells obtained from nine of the donors'' vertebral bodies two weeks after the surgical procedure. "By using stem cells, we aim to facilitate an immunomodulatory state, which could help enable minimi-zation of maintenance immunosuppressive therapy from two or more drugs down to one drug," Dr. Gorantla explained.
Surgeons at the University of Pittsburgh are working with the American Society for Reconstructive Transplantation to share their insights and fine-tune transplantation procedures and protocols. The American Society for Reconstructive Transplantation is the only medical society in the world that focuses on composite tissue and reconstructive transplantations. "We want to improve our protocol by sharing our experiences and learning from other centers. We hope to conduct multicenter trials that will compare results from transplant patients who have received triple or double immunosuppressive therapy or who have received low-dose monotherapy with cellular therapy. We want to see which protocol works better and why and achieve consensus at the society level about standardizing protocols that are proven for safety, efficacy, and long term outcomes," Dr. Gorantla said.
"The insights we gain going forward will help us balance treatment in a manner that modulates or suppresses the immune system of the transplant recipient to prevent rejection of the graft but does not expose the patient to the potential toxic effects of high-dose immuno-suppressive drugs. The primary goals of protocols like ours are to reduce the risk and optimize the benefits that can be achieved in upper extremity transplants," he explained. "[However], even with these early promising results, we are still carefully evaluating all of our recipients and more time is needed to judge the ultimate success of this protocol," Dr.Gorantla concluded.
The study coauthors are Stefan Schneeberger, MD; Gerald Brandacher, MD; Galen S. Wachtman, MD; Jonathan D. Keith, MD; Jaimie Shores, MD; Kodi K. Azari, MD, FACS; Joseph Imbriglia, MD; Thomas E. Starzl, MD, PhD, FACS; and W.P. Andrew Lee, MD, FACS.