June 14, 2013 | by Darrin Joy
Patients struggling to overcome blood cancers face a wider threat than just the malignant cells menacing their bodies. They also face challenging — even life-threatening — treatment side effects. For many patients undergoing bone marrow transplantation, graft-versus-host disease (GVHD) ranks as one of the most dangerous.
Recent findings by Defu Zeng, Ph.D., professor in the Department of Hematology & Hematopoietic Cell Transplantation, and his colleagues may help keep one form of this challenging side effect under control.
GVHD arises in allogeneic transplantation, which uses cells from a donor. Newly transplanted donor T cells — immune system cells responsible for defending the body against disease — see the patient who receives them as foreign and launch an immune attack from within. This can cause complications ranging from severe digestive issues to life-threatening organ damage.
The acute form of GVHD usually begins early after transplant, and physicians most often can suppress the immune reaction with powerful drugs until the donor immune cells settle into their new home.
But in some cases, the donor immune cells seem to keep up the pressure despite efforts to quiet them. This persistence leads to chronic GVHD, which can be much more difficult to overcome and poses a stronger threat to a patient’s health. Current immunosuppressant drugs are not effective at preventing chronic GVHD.
No one is certain exactly how chronic GVHD sets in, but now Zeng’s team has found clues that could tell clinicians when a patient is at higher risk of developing it.
The answer is linked to two specific types of T cells: One type has a protein called CD4; the other has a protein called CD8. They’re known respectively as CD4+ T cells and CD8+ T cells.
Although both CD4+ and CD8+ T cells in transplants can cause acute graft versus host disease, CD8+ T cells alone can’t make the move to the chronic form of the reaction without the help of CD4+ T cells, the new findings show.
"CD8+ T cells damage the thymus and allow production of CD4+ T cells that recognize the recipient tissue as foreign," Zeng said. "Those CD4+ T cells are called 'autoreactive.' The autoreactive CD4+ T cells can help the CD8+ T cell expansion and mediate the development of chronic GVHD." The thymus is the organ in the body that programs T cells to recognize and attack foreign agents. When the thymus can’t maintain its ability to delete autoreactive T cells, the autoreactive CD4+ T cells rise to dangerous levels.
"The newly developed autoreactive CD4+ T cells can keep up the attack on the thymus, leading to chronic GVHD," he said.
Monitoring the autoreactive activity of CD4+ and CD8+ T cells in newly transplanted patients may give clinicians an early warning that chronic GVHD is a threat, Zeng said.
Also, Zeng believes one solution to chronic GVHD may lie in the elimination of autoreactive CD4+ T cells early after HCT."If we can find a treatment or drug that depletes the CD4+ T cells shortly after a transplantation, we may reduce the likelihood of chronic disease," he said. And that likely would improve the success of transplants overall.
City of Hope already has some of the best outcomes in bone marrow transplants despite the fact that its patients are among the sickest of those needing such care, based on national transplant statistics. These findings could further improve those outcomes.
The work was performed by international doctoral student Tao Wu in Zeng’s laboratory at City of Hope in collaboration with Zeng lab members. Wu is a student from the laboratory of Jianmin Wang, Ph.D., at Changhai Hospital, The Secondary Military Medical School in Shanghai, China.
The study was published online by the Journal of Immunology on May 24.
This work was supported by National Institutes of Health grant R01 AI066008 and by National Natural Science Foundation of China Grant NSFC 81090413.