Building new bridges from lab to patient

Over the past two decades, researchers in the School of Medicine’s immunobiology group have led the way in unlocking the secrets of the immune system. Richard A. Flavell, Ph.D., chair of the newly designated Department of Immunobiology pioneered the use of genetically engineered mice to study the fundamental principles of organization and regulation of immune responses. Using mice to mimic human diseases, researchers found evidence of immune system involvement in many maladies, including cancer and heart disease.

But there are enough differences between the immune systems of mice and humans that Flavell and his colleagues hit a wall when it came time to test their theories in people with diseases. Frustrated by the barriers to moving laboratory findings into the clinic, Flavell devised a plan to bridge the chasm between mouse and man.

His solution, embedding clinical researchers in the Department of Immunobiology, resulted in the medical school’s newly launched program in Human and Translational Immunology (HTI), which will eventually include six new faculty members whose research spans both basic and human experimentation. The program will also reach out to clinical researchers in a variety of medical departments with an interest in immunology.

The new program will be headed by Jordan S. Pober, M.D., Ph.D., the founder and former director of Yale’s highly successful interdepartmental translational research program in Vascular Biology and Transplantation. Pober, whose own research has elucidated the role of the immune system in vascular disease and organ transplantation, became the vice-chair of the Department of Immunobiology for the Section of HTI in January.

“To make translation work, you need a way to connect physicians and basic scientists, and that is best done by people with both interests who are willing to work in the middle,” says Pober. “That’s what HTI is going to provide.”

The work of the program’s first recruit, Kevan Herold, M.D., is a model of translational research. While at Columbia University, Herold, now professor of immunobiology and medicine at the School of Medicine, advanced the most promising new treatment for type 1 diabetes in children. The disease starts when the immune system mistakenly attacks insulin-producing islet cells in the pancreas. As the cells die, insulin production declines, and children become dependent on multiple daily injections of insulin.

First in mice, and then in human clinical trials, Herold and Jeffrey A. Bluestone, Ph.D., of the University of California, San Francisco, and their research teams have shown that administering antibodies designed to inhibit a particular immune response in children with early symptoms of type 1 diabetes delays, and may even prevent, the full-fledged development of the disease. The antibody formulation, further refined by MacroGenics of Rockville, Md., under the name MGA301, is currently in advanced-phase clinical trials for Food and Drug Administration (FDA) approval. The FDA recently named MGA301 an “orphan drug,” a designation that provides special incentives to companies developing compounds to treat rare diseases.

Herold and his work represent “the best kind of bridge,” says Carolyn W. Slayman, Ph.D., Sterling Professor of Genetics and deputy dean for academic and scientific affairs at the School of Medicine. “He brings together a track record for excellent basic research with a new treatment for an important human disease.” Slayman adds that Herold’s work links immunobiology with another strong Yale academic unit, the internal medicine/endocrinology group led by diabetes researcher Robert S. Sherwin, M.D., the C.N.H. Long Professor of Medicine.

The HTI initiative comes at an opportune time for translational research at Yale. In October, the newly formed Yale Center for Clinical Investigation received a five-year, $57 million Clinical and Translational Science Award from the National Institutes of Health, funding that will help provide the infrastructure HTI investigators need to conduct research and to train a new generation of clinical immunologists.

By removing roadblocks to clinical research, Flavell, Pober and their HTI colleagues hope to see Yale discoveries turned into treatments for a wide range of diseases, from diabetes and cancer to heart disease and stroke.

“For 18 years, immunobiology has been focused on studying the basic mechanisms of immunology and applying that to disease, but almost all our focus has been on mice,” Flavell explains. “So the new program is the same thing, really, just now in humans.”