Results of clinical study presented at Experimental Biology '99 meeting
WASHINGTON, D.C., April 21 -- Organ rejection occurs less often and is less severe in patients who receive infusions of bone marrow from the same donor, researchers from the University of Pittsburgh's Thomas E. Starzl Transplantation Institute report today at Experimental Biology '99. Their findings, which represent six years of study of patients who received the extra boost of donor immune system cells, indicate the procedure is safe and augments the cellular environment that the research team believes is necessary for long-term acceptance of a transplanted organ.
Results of the study--the largest of its kind--are particularly encouraging for the recipients of hearts, lungs and combined kidney and pancreas, reports Abdul Rao, M.D., D.Phil., assistant professor of surgery and pathology and director, section of cellular transplantation. In addition, the outcomes for liver transplant patients suggest that some patients can be weaned from the drugs that control organ rejection. The researchers are selecting these patients for a step-wise weaning protocol, which has not yet been initiated.
Controlling rejection is the key to successful organ transplantation. For the most part, surgeons rely on drugs that suppress the patient's immune response as their main line of defense against an immune system attack. But despite newer and better drugs, organ rejection can still occur, even years after transplantation. Even if the drugs effectively control rejection, they can produce serious medical complications and make the patient more susceptible to cancers and infections, some which can be deadly.
"While the ultimate goal in some of the bone marrow patients is to take them off immunosuppressive drugs, we do not want to interfere with the natural peace-keeping process between the recipient and donor immune systems. In other words, the drugs are necessary, at least initially, to allow the donor bone marrow and the recipients' immune system to more effectively work in concert with each other," explains Dr. Rao.
The study included 268 patients who received donor bone marrow along with transplants of livers, pancreases, pancreatic islet cells, kidneys, intestines, hearts and lungs. Of these, 229 received the bone marrow during their transplant operations. The remaining 39 received one infusion during surgery and two more infusions the first and second days after transplantation. The results were compared to 131 patients who received organ transplants without bone marrow.
By giving donor bone marrow, the researchers' aim was to enhance the cellular environment called chimerism, defined as the coexistence of recipient and donor immune cells. Having already proved that chimerism is present in long-term survivors of organ transplants, some of whom have been weaned from a life-long regimen of immunosupressant drugs, researchers wanted to promote, even hasten this biological process with bone marrow.
"We believe chimerism is a prerequisite for but not synonymous with long-term acceptance of the donor organ. Achieving a stable chimeric state is the first step to long-term tolerance," says Dr. Rao.
The study of combined solid organ and bone marrow transplants is the clinical centerpiece of a large research effort directed by Thomas E. Starzl, M.D., Ph.D., professor of surgery and director of the university's transplant institute. In 1992, Dr. Starzl brought to Pittsburgh 25 long-surviving recipients of kidney and liver transplants. Biopsies taken from the transplanted organs, lymph nodes, skin and other tissues revealed that donor leukocytes, or white blood cells, had migrated from the transplanted organs to recipient tissues, where they persisted years--in one case, for 29 years--after transplantation. Researchers also found recipient cells continuing to coexist with donor cells within transplanted organs. Such an observation provided confirmation that in organ transplantation, surgeons are not only replacing organ function but they are also exposing the recipient to the donor's immune system.
Augmenting this process with donor bone marrow cells seems to be paying clinical dividends, their current findings suggest. Dr. Rao reports that the overall incidence of acute cellular rejection was significantly less in the bone marrow patients (52 percent) as compared to the control group (67 percent). More importantly, most of the rejection episodes in the group of bone marrow-augmented patients were mild as compared to moderate to severe in the control recipients. There are currently 82 percent of the bone marrow patients with functioning grafts and 77 percent of control patients with functioning grafts.
For heart transplant patients, acute cellular rejection occurred in 38 percent of those who received bone marrow, compared to 82 percent of those who did not. In lung transplant patients, the most significant result was a reduced incidence of chronic rejection. Obliterative bronchiolitis, the telltale marker for chronic rejection that prevents air exchange in the lung's bronchioles, occurred in 4.7 percent of the bone marrow patients and 31 percent in those who did not receive bone marrow. Similarly, the incidence of acute cellular rejection was much lower in the study kidney/pancreas recipients.
In studies of peripheral blood taken at most recent follow-up, the researchers found that levels of chimerism were two times higher in the bone marrow patients. In addition, those receiving bone marrow had higher measures of donor-specific hyporeactivity. This indicates that the recipient's immune defense is capable of fighting unwanted infections but is less likely to initiate an attack against the donor organ.
The safety of the bone marrow procedure was also a parameter studied. Patients were not pre-treated with irradiation to "make space" for the bone marrow, nor was the bone marrow modified in any way. As a result, the researchers believe the risk of graft vs. host (GVHD) disease was minimized. GVHD, a common complication of bone marrow transplantation, occurs when donor immune cells attack recipient tissues.
In addition to Drs. Rao and Starzl, other authors of the abstract are: Shashikumar Salgar, M.D.; Ron Shapiro, M.D.; Robert Corry, M.D.; S. Forrest Dodson, M.D.; Si Pham, M.D.; Adrianna Zeevi, Ph.D.; Robert Keenan, M.D.; Mark Jordan, M.D.; Kareem Abu-Elmagd, M.D.; Bartley P. Griffith, M.D.; and John J. Fung, M.D., Ph.D.