This study will explore the role of a bacterial toxin (endotoxin), which normally resides in the intestine but enters the bloodstream as a consequence of chemo- and radio-therapy in patients with leukemia or lymphoma undergoing bone marrow transplantation, in initiating Graft-versus-Host Disease (GVHD) in transplant recipients.
Bone marrow transplant is the preferred treatment for patients with bone marrow cancers, including leukemia and lymphoma, who are not cured by conventional chemotherapy and for patients with genetic defects effecting the bone marrow elements (white cells, red cells, and platelets). These transplants are often lifesaving, but they frequently result in severe and sometimes deadly GVHD, in which donor immune T cells (white blood cells) recognize host tissues as foreign and mount an inflammatory attack against the patients' tissues.
Prior to transplantation, radiation and chemotherapy is used to reduce or try to eliminate the patient's own immune cells, so that they do not attack the transplanted bone marrow. This gives the transplanted immune cells (which are produced in bone marrow) the opportunity to take hold and fight the cancer. Chemo- and radiation therapy weakens the patient's immune cells and damages the intestinal lining, allowing bacterial endotoxins that normally reside in the intestine to seep into the patient's bloodstream and initiate inflammatory responses that can trigger GVHD.
Consortium researchers will examine how bacterial endotoxin helps to trigger GVHD. They will use complementary areas of expertise, including oncology/hematology (Dana-Farber), infectious diseases (Children's Hospital Boston), and microbiology (University of Iowa), to examine how GVHD is initiated in bone marrow transplant recipients. Their study will be conducted as part of an ongoing pilot clinical trial, funded by XOMA L.L.C., of Berkeley California, of the effectiveness of an experimental agent known as recombinant (because it is manufactured using recombinant DNA technology) bactericidal/permeability-increasing protein (BPI) (rBPI21) in preventing GVHD. This agent is a natural host defense protein that can neutralize the harmful effects of endotoxin and is produced by human white blood cells. Of note, BPI is severely depleted during chemotherapy, as shown by the investigators in preliminary studies.
While XOMA will assess how effective (rBPI21) is in preventing GVHD, consortium researchers will examine how (rBPI21) may work, and whether it neutralizes the effects of the bacterial endotoxin in transplant patients. Consortium researchers hypothesize that the endotoxin molecule, located on the surface of intestinal bacteria, seeps into the patient's bloodstream and induces an immune “cytokine” (called tumor necrosis factor-α or TNF-α) to initiate inflammation. The inflammatory response, they hypothesize, then activates donor T cells to attack the recipient's inflamed tissues, producing GVHD. They further hypothesize that replenishing BPI, which is depleted by the chemotherapy, by intravenous administration of rBPI21 may neutralize this bacterial molecule, preventing this chain of events and reducing the occurrence of GVHD. They will analyze blood samples from patients undergoing transplantation and receiving (rBPI21) to see if their hypotheses are correct.
Significance: The research may reveal how bacterial endotoxin, which seeps from the intestine into the bloodstream in bone marrow transplant patients whose own immune system has been suppressed, helps to trigger GVHD, and how an experimental treatment may interrupt this process to prevent GVHD.