The research suggests ways to increase the effectiveness and use of bone marrow transplants from related and unrelated donors — known as allogeneic transplants — in treating cancers, genetic deficiencies and autoimmune diseases.
In mice, the SHIP gene plays a key role in helping the body distinguish between itself and tissue from a donor other than self. When the gene is missing or knocked out, the mouse's immune system apparently fails to recognize the donor's bone marrow as a foreign substance and allows the graft to survive.
"If the SHIP gene plays a similar role in humans, then drugs to temporarily block SHIP could be given to a patient before they undergo an allogeneic bone marrow transplant so they won't reject the transplant and the transplant won't attack them," said William Kerr, PhD, lead investigator for the study. Dr. Kerr is an associate professor of oncology and biochemistry at USF and a member of Moffitt Cancer Center's Immunology Program.
In the USF/Moffitt study, less than a third of the mice with the SHIP gene survived the allogeneic bone marrow transplants. But, Dr. Kerr's team found that 85 percent of the SHIP-deficient mice survived without two major complications that limit the success of allogeneic bone marrow transplants. First, the mice did not reject the transplant. Secondly, in the weeks following the transplants, the grafts did not launch an immune attack against the mice's bodies — a potentially life-threatening reaction known as graft-versus-host disease.
"This is an exciting breakthrough because a molecular target, such as the SHIP gene, would give us a novel and more selective approach for preventing and treating graft-versus-host disease." said Karen Fields MD, professor of medicine and oncology at USF and director of the Bone Marrow Transplant Program at Moffitt Cancer Center.
While graft-versus-host disease is largely treatable, the immunosuppressive drugs administered for it create serious side effects for patients. In fact, graft-versus-host disease and its consequences remain the number one cause of death following transplant.
Bone marrow transplant rejection is rare when the person donating the bone marrow or stem cells is a genetically matched family member, most often a sibling. However, the chances of rejection increase if the donor is unrelated to the patient and the tissue is incompletely matched. Despite the increasing number of bone marrow transplants performed, more than 75 percent of patients who need an allogeneic transplant each year go without one because a suitable bone marrow cannot be found.
The pool of available donors would increase significantly if Dr. Kerr's SHIP gene finding holds true in humans, because less well-matched grafts could be tolerated as transplants, Dr. Fields said.
Widely used in the treatment of blood cell cancers, bone marrow transplants from healthy donors help restore the cancer patient's blood system following its destruction by chemotherapy and radiation. The immune cells in these transplants may also attack lingering cancer cells that remain in the body following chemotherapy and radiation, thereby increasing the patient's chances for disease-free survival.
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