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New Research Findings Being Presented by University of Pittsburgh Faculty at Transplant 2001 Scientific Meeting

CHICAGO, May 13, 2001— Clinical and basic science research findings of more than 65 studies are being presented by University of Pittsburgh School of Medicine researchers at Transplant 2001, the joint scientific meeting of the American Society of Transplant Surgeons and the American Society of Transplantation (AST). The scientific sessions are May 13 - 16 at the Sheraton Chicago Hotel and Towers and the Intercontinental Hotel Chicago. Highlights of the findings include:

  • The majority of small intestine transplant recipients experience at least one episode of rejection within the first month. But in a group of patients whose donor organs were exposed to radiation just prior to transplantation, the incidence was practically zero. (Tuesday)
  • A subtype of dendritic cell -- cells that typically are associated with initiating an immune response against a transplanted organ-- appears to do the opposite, by playing a key role in preventing organ rejection and promoting long-term graft survival. Researchers will now be looking to see if the same cells are present in patients successfully weaned off immunosuppressant drugs. (Tuesday)
  • A gene therapy technique tested in animals was successful in reducing the type of injury that occurs in donor organs when they are without a blood supply and may show promise in preventing cold ischemia in human donor organs as well. (Tuesday)
  • The development of tumors after transplantation is a serious complication for patients, especially children, who are at greater risk. Tumors disappeared in most children who were treated with a drug being evaluated in an ongoing multi-center trial. (Wednesday)


MONDAY, May 14

Laboratory studies indicate possible treatment for tumors in transplant patients

Post-transplant proliferative disorder (PTLD) is a complication associated with the Epstein Barr Virus (EBV), a virus that about 90 percent of the world population eventually will be exposed to. But many children and young adults have not yet been exposed to the virus, and because they must take drugs to control rejection, they are especially susceptible to the virus and the consequence of PTLD. If an EBV-negative transplant patient is exposed to the virus or receives an organ that is positive for EBV, B cells in the patient's lymphoid tissue are likely to grow wildly to form cancerous tumors.

Results of laboratory studies reported by Diana M. Metes, M.D., research assistant professor of surgery at the Thomas E. Starzl Transplantation Institute, could point to novel immunological strategies to prevent or treat PTLD in transplant patients whose immune systems have not been educated to fight EBV. Using blood samples from healthy individuals, she studied how certain immune system cells reacted when they were exposed to PTLD-like tumor cells. If the individual had previous exposure to EBV, specific types of immune system T cells -- those that fight infections -- tended to be much more active. Interestingly, when the PTLD-like cells were plunked into an environment with no EBV immune system recognition, the T cells reacted only in the presence of certain cytokines, proteins that can stimulate cell activity. Introducing these T cells primed to recognize EBV into patients at risk for PTLD could allow their immune systems to effectively fight the virus if they were to receive an EBV-positive organ or were unknowingly ever exposed to the virus. (See also Wednesday: New drug shows promise for children with post-transplant tumors.)



Small intestines exposed to radiation less likely to be rejected

The majority of small intestine transplant recipients experience at least one episode of rejection within the first month of transplantation. But in a group of patients whose donor organs were exposed to radiation just prior to transplantation, the incidence was practically zero. Rejection was observed in only one patient out of 13 in the study, reported Kareem Abu-Elmagd, M.D., Ph.D., F.A.C.S., associate professor of surgery and director of the Intestinal Rehabilitation and Transplant Center at the University of Pittsburgh's Thomas E. Starzl Transplantation Institute . The strategy involves exposing the donor intestine for a few minutes to a single low dose of irradiation, transplanting the organ (sometimes with a liver or other abdominal organs) and then delivering donor bone marrow infusions. The radiation aims to kill mature donor immune system cells that the small bowel is saturated with so that the donor organ is less likely to serve as a target for the recipient's immune system. The donor bone marrow infusion enhances a condition called chimerism, whereby certain types of donor and recipient cells learn to coexist peacefully. Chimerism is believed to influence the long-term survival of the transplanted organ. Three of five patients in a control group -- patients who received unconditioned small intestinal grafts and no donor bone marrow -- each had at least one serious episode of rejection.



Researchers identify subtype of cell that promotes graft acceptance

In one of the few studies of its kind, researchers from the Thomas E. Starzl Transplantation Institute have found that a subtype of dendritic cell plays a key role in preventing organ rejection and may be associated with transplant tolerance, the long-term survival of a transplanted organ without the need for immunosuppressant drugs. The findings are significant because dendritic cells, a rare type of white blood cell that is present in all tissues, have been thought only to be involved in prompting the rejection process. They do this by identifying and presenting antigens, or foreign substances, to other immune system cells that are programmed to destroy the antigen. But some dendritic cells apparently regulate the immune response, determining that a frontline attack by T cells can be unwarranted.

Peta J. O'Connell, Ph.D., a visiting research instructor working with Angus W. Thomson, Ph.D., D.Sc., reported that a pre-transplant infusion of lymphoid dendritic cell subtypes derived from tissue such as the spleen, allowed for prolonged survival in a mouse heart transplant model, even without the use of drugs to control rejection. In contrast, myeloid dendritic cells accelerated the rejection response. Dr. O'Connell, who received an AST Young Investigator's Award for her abstract, believes that the lymphoid-derived dendritic cells somehow disarm immune system T cells from doing their part to attack the donor organ by either causing their death or limiting their proliferation. Based on these studies, the researchers plan to see if these "good" dendritic cells are present in liver and kidney transplant recipients who are off all immunosuppression as part of a larger effort under the direction of Dr. Thomson and Adriana Zeevi, Ph.D., to identify laboratory profiles and tests consistent with tolerance.



Gene therapy technique tested in animals prevents common type of donor organ injury

Cold ischemia -- when the donor organ is without a blood supply -- accounts for a significant portion of transplanted organ injury. This injury is compounded when oxygenated blood is reintroduced into the organ during surgery. Both situations somehow cause cells in the organ to self-destruct, therefore compromising the function of the graft. A molecule that resides on the cell membrane is believed to play a key role in this process. Under certain conditions its activation induces a pathway to death by calling in a cascade of enzymes that break down the cell's nucleus. Reporting on animal studies with promising clinical implications, researchers at the University of Pittsburgh's Thomas E. Starzl Transplantation Institute observed activation of this molecule in kidneys deprived of oxygen. But when they delivered a substance especially manipulated to target the molecule's genetic structure, the gene therapy technique successfully disarmed its ability to signal the cell death process, and significant ischemic injury was prevented. According to Linlin Ma, M.D., a research fellow working with John Fung, M.D., Ph.D., the technique shows promise as a way that transplant surgeons can prevent ischemic injury in donor organs. Other uses could be for stroke or heart attack, when tissues are injured by lack of blood flow. Dr. Ma’s abstract won her an AST Young Investigator's Award.



Genetic profiles of hepatocellular cancers can predict recurrence after liver transplantation

Patients classified as having stage IV liver cancers do not qualify for liver transplantation, but based on an analysis of 69 patients transplanted for hepatocellular carcinoma at the University of Pittsburgh since 1981, some patients who are denied transplantation today because they meet criteria for advanced disease might actually be good candidates for transplantation and enjoy tumor-free long-term survival. Andy Bonham, M.D., assistant professor of surgery, reported that six of the patients they followed -- four of whom were transplanted 12 years ago -- who would have been denied transplantation under today's guidelines, were found to have genetic characteristics that would predict a more benign course than the classic staging would suggest. All are alive and well with no recurrence of their cancers despite the fact that at the time of transplantation they had very large tumors or multiple tumors in both lobes of the liver. Using tests to analyze the presence and mutations of tumor genes, Dr. Bonham reported that these patients' tumors were actually distinct early stage, non-aggressive ones. The technique was able to identify these six patients out of 39 classified as stage IV. Overall, their analysis of the 69 patients found that patients with more genetic mutations in their tumors were more likely to have recurrence and short-term survival. Fewer mutations, even in situations with several tumors, corresponded with less of a chance of recurrence and longer survival. Seventeen of the 69 patients are still alive. Performing such tests on patients as they are being evaluated for transplantation could help guide treatment strategies, reported Dr. Bonham.



Drug shows promise for children who develop post-transplant tumors

Pediatric transplant patients are especially at risk for developing a serious complication called post-transplant lymphoproliferative disorder (PTLD), whereby certain cells of the patient's immune system proliferate to form tumors that resemble a type of cancer called lymphoma. Standard treatment involves temporarily reducing or eliminating the doses of drugs that are taken to suppress the immune system and prevent organ rejection. Some children fail to respond to this therapy, and their tumors can progress, resulting in death. For many children, they face deadly consequences if the balancing act between protecting the organ from rejection and treating the cancerous tumors is done without precision. Steven Webber, MBChB, associate professor of pediatrics at the University of Pittsburgh School of Medicine and medical director of the heart and lung transplant program at Children's Hospital of Pittsburgh, reported preliminary results of an eight-center study indicating that a drug called rituximab was effective for the majority of children who were not responsive to conventional treatment for PTLD. Tumors disappeared in 14 of 16 children in the study -- recipients of heart, lung, liver, kidney or small bowel transplants. The drug targets a specific molecule on B cells, the cells that grow wildly and develop into tumors.

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