CHICAGO, May 17, 1999 — Providing patients with bone marrow from the same donor as the organ being transplanted significantly reduces rejection, especially if multiple doses of the donor bone marrow cells are given, according to results of a major, ongoing study at the University of Pittsburgh. In addition, preliminary results of the first-ever human trial involving children who received bone marrow injections into the thymus during heart transplantation indicate the procedure is both safe and feasible and has potential to promote long-term acceptance of the organ. Findings from both studies are being presented at the 18th Annual Scientific Meeting of the American Society of Transplantation May 15–19 and at the 25th Annual Scientific Meeting of the American Society of Transplant Surgeons May 19–21 in Chicago.
How to achieve long-term acceptance, or tolerance, of transplanted organs is a major area of study at the University of Pittsburgh. Much of the clinical research has evolved from the landmark observation by Thomas E. Starzl, M.D., Ph.D., that donor and recipient cells continue to coexist many years after transplantation. Dr. Starzl is professor of surgery and founder of the University of Pittsburgh’s Thomas E. Starzl Transplantation Institute . For the past six years, UPMC researchers have been conducting a study—the largest of its kind—to determine if infusions of donor bone marrow at the time of transplant surgery can boost the cellular environment the team believes is necessary for tolerance.
Recently, the Pittsburgh team initiated a similar study with children undergoing heart transplantation. But instead of infusing bone marrow into the peripheral blood, researchers inject the bone marrow into the patient’s thymus, where key cells of the immune system are educated to recognize self and non-self. This study represents the first human trial of its kind.
Following are summaries of the results of these clinical studies with contact information.
Donor Bone Marrow Reduces Rejection of Transplanted Organs
Patients who receive donor bone marrow, a rich source of donor immune system cells, experience less organ rejection, report University of Pittsburgh researchers at the American Society of Transplantation annual meeting. Rejection might be less of a problem for these patients because the bone marrow makes the recipient’s immune system more passive to the donor organ, their findings also suggest.
Moreover, those patients who receive multiple infusions of bone marrow have the lowest risk of acute rejection.
There were 402 organ transplant recipients in the study, 271 of whom received bone marrow with their transplants of either liver, heart, lung, kidney, pancreas, intestine or pancreatic islet cells. While the risk of acute rejection was 69 percent for the overall group of bone marrow patients, compared to 79 percent for the 131 patients who did not receive bone marrow, the risk of acute rejection for those who had multiple infusions was 54 percent. Of the 271 bone marrow patients, 229 received a single infusion of bone marrow during transplant surgery and 42 patients received the bone marrow in three separate doses—one during surgery, and one each in the following two days.
As previously reported, 62 percent of the heart and bone marrow recipients were free of acute cellular rejection in the first six months versus 18 percent in the control group. Similar results are being seen in those patients followed for more than 18 months. Chronic rejection in lung transplant patients was also significantly less for the bone marrow patients, 4.7 percent in the bone marrow patients and 31 percent in those who did not receive bone marrow.
Donor-specific hyporeactivity was more prevalent in the overall bone marrow group than the control patients. This indicates the recipient’s immune system is capable of fighting unwanted infections but is less likely to initiate an attack against the donor organ.
"We believe this measure of unresponsiveness to the donor graft is correlated to the reduced incidence of rejection. Bone marrow augmentation not only is safe, but it confers an immunological advantage to some patients," says Abdul Rao, M.D., D.Phil., assistant professor of surgery and pathology, and director, section of cellular transplantation, at the Thomas E. Starzl Transplantation Institute.
The researchers believe that by giving donor bone marrow, anti-rejection drugs can work more effectively and the cellular environment seen in long-term survivors of organ transplants can be landscaped more swiftly. For some, the presence of stable chimerism—the coexistence of donor and recipient immune system cells—might allow the drugs to be reduced or weaned altogether.
Early Results of First Human Trial of Bone Marrow Infusion to Thymus Reported
For years, animal studies have suggested that bone marrow injections into the thymus can induce tolerance of a transplanted organ from the same donor, but the procedure has never been tried before in humans. Reporting at the American Society of Transplantation preliminary results of the first-ever human trial of its kind, a team from the University of Pittsburgh and Children’s Hospital of Pittsburgh say they are encouraged by their observations in pediatric heart transplant recipients.
The thymus, where immune system T cells from bone marrow are educated to distinguish cells of self from those that are foreign, is most active during infancy and childhood. Because of its location behind the breastbone, it is accessible during heart transplant surgery.
The idea behind infusing donor bone marrow is to fool the recipient’s T cells that are being educated in the thymus into thinking that the donor bone marrow is "self" as well. Those T cells that see the donor tissue as foreign are not permitted to leave the thymus and die. Without these cells in circulation, an immune system attack against the donor organ is avoided.
In fact, routine biopsies taken from the transplanted hearts of the seven children who received bone marrow indicated their immune systems were not sounding the usual alarms, as measured by the number of activated recipient T cells infiltrating the organs. In addition, three of the seven patients had some evidence of donor-specific hyporeactivity, whereas only one of the eight controls showed such evidence. Such a measure indicates the degree to which a recipient’s immune system is indifferent to the donor organ but is still responsive to other foreign substances.
While rates of acute rejection were comparable in the two groups of patients, more patients will need to be studied and longer follow-up will be required to determine if chronic rejection can be abated. Within five years of transplantation, chronic rejection occurs in about 15 to 20 percent of all pediatric heart recipients and is the leading cause of death.
"Animal studies to date gave us every indication that the time was right for a human trial, and we have proven the procedure is safe and feasible. Time will tell if we are able to effectively induce tolerance in these children," says Steven A. Webber, MBChB, associate professor of pediatrics at the University of Pittsburgh and medical director of the pediatric heart/lung transplant program at Children’s Hospital of Pittsburgh.
None of the patients who received bone marrow developed graft vs. host disease, a common complication of bone marrow transplantation whereby donor immune cells attack recipient tissues. Dr. Webber and his team are also looking at the feasibility of bone marrow infusions in lung transplant patients.
Bone Marrow Improves Outcomes for Pancreas Transplant Patients
Patients who had kidney/pancreas transplants with donor bone marrow augmentation were more likely to be weaned from steroid medications, had fewer episodes of rejection and - had better pancreas graft function and survival than patients who did not receive added bone marrow, researchers from the University of Pittsburgh report at the American Society for Transplant Surgeons annual meeting.
As part of a large trial involving all types of organ transplants, 53 patients undergoing kidney/pancreas transplantation between 1994 and 1998 also received donor bone marrow infusions immediately following surgery, providing a boost of donor immune system cells to enhance the cellular environment the team believes is necessary for long-term acceptance of organs. Various clinical parameters were compared to 98 kidney/pancreas patients who did not receive bone marrow.
Acute cellular rejection occurred in 67 percent of the bone marrow patients and in 83 percent of the control patients. Three months after transplantation, seven of the 98 patients who did not receive bone marrow had to have their pancreata removed due to rejection, yet none in the bone marrow group lost their grafts. And while about half in each group could be weaned off steroids one year after transplantation, by three years, 83 percent of the bone marrow patients were completely off steroids, but 62 percent of the other patients were steroid-free.
"Donor bone marrow may have a protective effect in pancreas transplantation. If we are able to achieve a significant reduction in rejection-related graft loss, more patients with diabetes could benefit from pancreas transplantation," reports Robert J. Corry, M.D., professor of surgery and director of pancreas transplantation at the Thomas E. Starzl Transplantation Institute.