HSCI investigators have developed a better picture of why a recently discovered therapy for graft-versus-host disease (GVHD) is more effective than anything currently available to patients.
In 2011, human clinical trials showed that immune system signaling molecule interleukin 2 (IL-2) both improved GVHD symptoms in patients and completely stopped the progression of the condition. Surprisingly, HSCI Executive Committee member Jerome Ritz, MD, and his team at the Dana-Farber Cancer Institute found that patients who received a continuous low dose of IL-2, which is an FDA-approved drug that stimulates immune cells to attack certain types of cancers, saw reduced GVHD symptoms because their immune response was suppressed. “It’s interesting because it changes the paradigm,” Ritz said. “You think something stimulates the immune system, but actually what it does is the opposite.”
Bone marrow transplants are life-saving treatments for patients with leukemia and lymphoma that completely replace a recipient’s faulty blood-forming stem cells with those of a matching donor. Despite immunologic differences between the donor and recipient, the donor immune system often recognizes that it is in a new place and adapts. When the new immune system does not adapt, the donor’s immune system begins to attack the recipient’s tissues, causing the uncomfortable and difficult-to-manage symptoms of GVHD.
Ritz’s team found that IL-2 affects the relationship between the immune cells that mount the body’s immune response (effector T cells) and the immune cells that maintain the body’s ability to differentiate between self and non-self tissue (regulatory T cells). The researchers observed that patients with GVHD have a lower level of regulatory T cells and higher level of effector T cells than normal. Low doses of IL-2 can increase the presence of regulatory T cells sevenfold and help them survive longer. The growing population of regulatory T cells then competes for IL-2 with effector T cells, preventing them from getting switched on. In fact, GVHD did not get worse in any of the patients receiving low dose IL-2.
“The immune system functions in checks and balances,” Ritz said. “We found that not only was their relatively less IL-2 in GVHD patients, but there was relative more other cytokines, IL-7 and IL-15, that primarily supported effector T cells and didn’t support regulatory T cells.” Ritz’s work is inspiring multi-center studies looking at how IL-2 can work in other immune diseases, and whether early use of IL-2 can reduce tissue damage caused by GVHD.
John Koreth, MBBS, DPhil, led the clinical trial in patients with GVHD. Other collaborators included Ken-ichi Matsuoka, MD, PhD, Haesook Kim, PhD, and Robert Soiffer, MD, also of Dana-Farber Cancer Institute.
Source: Low-Dose Interluekin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease. Science Translational Medicine. April 3, 2013.
Photo: Interleukin 2 (Emw/wikimedia commons)