Immune Cells May Help Treat Muscular Dystrophy, UCSF-Led Team Finds

A scientific team led by UC San Francisco researchers found that regulatory T cells (Tregs), a specialized subset of immune cells, suppress inflammation and muscle injury in a mouse model of Duchenne muscular dystrophy (DMD).

The scientists said that Tregs have potential as therapeutic agents for DMD, an inherited disease that strikes children – almost always boys – and leads to progressive muscle degeneration and early death.

They published their findings online October 15, 2014, in Science Translational Medicine.

The researchers discovered that Tregs, which dampen immune responses, are found in the muscles of mice and humans with genetic mutations that lead to the development of muscular dystrophy, but not in the muscles of healthy wild-type mice or healthy humans.

The finding indicates that the Tregs appear in muscle in response to the muscle injury, said lead investigator S. Armando Villalta, PhD, a postdoctoral fellow at the UCSF Diabetes Center.

“When we remove Tregs from the muscles of the genetically engineered mice, the disease gets worse,” said Villalta. “When we boost the cells in mice, we reduce inflammation and muscle injury.”

According to Villalta, the healing effect is due in large part to interleukin-10 (IL-10), an anti-inflammatory protein produced by Tregs and other immune-regulating cells. “IL-10 is what we see in these mice, and it is seen in the muscles of people with DMD as well,” said Villalta.

Jeffrey A. Bluestone, PhD, the A.W. and Mary Margaret Clausen Distinguished Professor in Endocrinology and Metabolism, the director of the Hormone Research Institute at UCSF, and UCSF executive vice chancellor and provost, led the research.

Bluestone predicted that in human therapy for DMD, the real value of Tregs will most likely not be as a stand-alone treatment, but in combination with gene therapy.

DMD is caused by an inherited defect in the gene that expresses dystrophin, a protein essential to muscle integrity. Clinical trials of gene therapies for DMD are underway. However, the therapy itself is known to cause inflammation, Bluestone said, a response to the virus that is used to introduce the healthy dystrophin gene into patients with the disease. Inflammation might also even arise in response to the production of new dystrophin protein made from the healthy gene, he said.

“This is where Tregs could potentially be of tremendous help,” Bluestone said. He observed that the cells could potentially have three simultaneous therapeutic effects: “They could reduce generalized inflammation caused by the disease, reduce inflammation caused by gene therapy, and lastly, produce factors that would promote healing and regeneration of muscle itself.”

Bluestone cautioned that such combination therapy is “clinically, always difficult to do, and difficult to get approved for human trials.” In addition, he said, the mouse model of DMD used by the scientists is not as severe as the human disease.

For years researchers have been developing the therapeutic potential of Tregs to combat autoimmune responses, and Tregs already are in clinical trials at UCSF to treat type 1 diabetes and organ-graft rejection. However, there have been no human trials so far of Tregs in non-autoimmune diseases such as DMD, Bluestone said.

Additional co-authors of the study are, from UCSF, Wendy Rosenthal, research associate, Amanjot Kaur, lab assistant and Marta Margeta, MD, PhD, assistant professor of pathology; from UCLA, James G. Tidball, PhD, chair of molecular, cellular and integrative physiology, Melissa J. Spencer, PhD, co-director of the Center for Duchenne Muscular Dystrophy, and Leonel Martinez, lab assistant; and Tim Sparwasser, MD, director of the Institute of Infection Immunology, Hannover, Germany.

The study was supported by the National Institutes of Health, the U.S. Department of Defense, the Muscular Dystrophy Association, and by a Ruth L. Kirschstein National Research Service Award training grant.

UCSF is the nation's leading university exclusively focused on health. Now celebrating the 150th anniversary of its founding as a medical college, UCSF is dedicated to transforming health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with world-renowned programs in the biological sciences, a preeminent biomedical research enterprise and two top-tier hospitals, UCSF Medical Center and UCSF Benioff Children's Hospital San Francisco.