A new $20 million grant to Emory University from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health will allow physician/researchers to develop better treatments for organ transplant recipients that help avoid both organ rejection and drug toxicity. The new grant builds on more than 18 years of groundbreaking research by Emory scientists that already has significantly advanced the transplant field.
Outstanding short-term outcomes have been achieved in organ transplantation with the development of anti-rejection drug therapies. The approval in 2011 of the new transplant drug belatacept was a breakthrough based on years of research by Emory scientists and industry collaborators, providing a less toxic alternative to the standard calcineurin inhibitors like cyclosporine.
Yet significant challenges remain for patients over the long term with organ rejection and drug toxicity that often leads to cardiovascular disease, infection or cancer.
"Despite tremendous advances in immune drug therapy, the fact remains that organ recipients still must take immunosuppressant drugs over their lifetimes," says Chris Larsen, MD, PhD, executive director of the Emory Transplant Center and principal investigator of the new grant. "Improvement in these transplant drugs is still a critical need for avoiding acute and late-stage rejection. Ultimately, we want to improve overall health while reducing cost through improved outcomes with fewer drugs."
In addition to Larsen, project leaders from the Emory Transplant Center will include Allan D. Kirk, MD, PhD, scientific director of the Emory Transplant Center and a Georgia Research Alliance Eminent Scholar; Leslie Kean, MD, PhD, Emory associate professor of pediatrics and director of the Pediatric Bone Marrow Transplant Division of the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta, Stuart J. Knechtle, MD, surgical director of the liver transplant program at Emory Transplant Center and Children’s Healthcare of Atlanta, and Andrew Adams, MD, PhD, assistant professor of surgery.
"The most important feature of this award is its support for multiple investigators attacking the problems of immunosuppression from different but complementary angles," says Kirk. "The team science approach is the best way to get results to our patients."
Belatacept represents a new class of drugs called "co-stimulation blockers," which inhibit one of two signals needed to generate an immune response by T cells. These drugs allow the body to accept transplanted organs while maintaining an immune response. Although belatacept avoids some of the toxicity of earlier transplant drugs, it is associated with higher rates of reversible acute rejection. And because it is a lifelong therapy, it still includes risks associated with a compromised immune system.
Several projects funded by the new grant will aim to develop more effective transplant drugs, adjuvant therapies combined with transplant drugs, and strategies to avoid immunosuppressant drugs altogether.
Earlier findings from animal studies at Emory’s Yerkes National Primate Research Center identified resistance to co-stimulation blocking drugs as an area for needed improvement. By better understanding the cellular and molecular pathways that contribute to this resistance, researchers hope to develop a new generation of costimulation blockers that will safely and more specifically block immune pathways in combination with a new type of antibody therapy.
Other strategies to induce long-term tolerance of transplanted organs include combining co-stimulation blocking drugs with transplant of the donor’s bone marrow along with the organ transplant. This strategy, referred to as "mixed-hematopoietic chimerism" could lead to acceptance by the body of the transplanted organ without the need for lifelong drug therapy.
The Emory team has been a leader in chimerism-based immune tolerance induction, and is also expert in managing the potential risks of chimerism-induction as they apply to solid organ transplant. Kean leads the bone marrow project for this grant, which seeks to "fine-tune" chimerism-based strategies, to permit successful, safe tolerance-induction.
An additional project will develop strategies to overcome immune sensitization in patients who have had previous transplants, pregnancies or blood transfusions. These patients often are not candidates for transplant because of their increased risk of rejection.
For more information about the Emory Transplant Center, its research projects and clinical programs see http://www.emoryhealthcare.org/transplant-center/.