HOUSTON - Back when scientists viewed immune response as an either-or process strictly divided between two pathways, each driven by a separate T helper cell, Chen Dong, Ph.D., and colleagues at The University of Texas M. D. Anderson Cancer Center helped uncover a surprising and pivotal third path launched by a new cell.
To the black-and-white pallet of immune response, Dong added the vital color illustrating the roots of inflammatory diseases, such as asthma, and autoimmune illnesses, such as rheumatoid arthritis and multiple sclerosis.
His discovery of T helper cell 17 (Th17), its production of the inflammatory molecule interleukin-17 (IL-17), and their central role in both types of disease, helped Dong earn the AAI-BD Biosciences Investigator Award from The American Association of Immunologists (AAI). He will receive the honor and speak at Immunology 2009(tm), the 96th AAI annual meeting May 8-12 in Seattle. AAI is the largest professional association for research immunologists in the world.
The award for outstanding research achievement by an early career scientist is one of the top honors in the field. Dong, a full professor in M. D. Anderson's Department of Immunology and Director of the Center of Inflammation and Cancer, is only 41.
"Dr. Dong's work will have important implications in understanding the pathophysiology of human diseases such as autoimmune disease, allergy, and cancer," said Yong-Jun Liu, M.D., Ph.D., professor and chair of immunology. "He's absolutely a world leader in defining this new effector T cell pathway. He has made a major contribution in defining the molecular mechanism that regulates the pathway, from cytokine receptor signaling to transcription factor regulation."
T helper cells are crucial to the adaptive immune system, which conjures a specific response that builds long-lasting immunity to specific infections. When this system goes haywire and attacks self-tissue, autoimmune diseases result.
IL-17 was a suspect in autoimmune and inflammatory diseases, but its origins were unknown and function poorly understood. By revealing the Th17 pathway, Dong's team provided a new target for novel drugs for both types of disease. Pharmaceutical companies have advanced drugs to clinical trials for rheumatoid arthritis and psoriasis based on Dong's work.
"For about 20 years, people believed that immune responses were limited to either Th1 or Th2 pathways. It was black and white, one or the other," Dong said.
T cells are lymphocytes, a type of white blood cell produced by the thymus equipped with receptors that recognize and bind to antigens, pieces of invading organisms presented to the T cells by dendritic cells. The bound antigen converts the T cell to T helper cells that secrete signaling molecules called cytokines to launch an appropriate immune response.
Th1 mediates the immune response against microbial invaders such as viruses and bacteria, Dong said. Th2 coordinates attacks on large parasites that don't penetrate cells.
Evidence erodes conventional wisdom
Th1 was the prime suspect, Dong said, because it produces interferon-gamma (IFN-y), a powerful cytokine associated with autoimmune and inflammatory diseases.
In 2002, Dong and colleagues were busy characterizing molecules in addition to T cell receptors that control immune tolerance against self tissues, another field cited by the AAI award. They exposed mice that were missing one of these crucial receptors from their T cells to a mouse model of rheumatoid arthritis. There was plenty of interferon gamma present in the mice, but no arthritis.
"The mutants were completely resistant to developing rheumatoid arthritis. There was no joint inflammation, antibody responses were reduced. It was remarkable," Dong said. "I wished to know why."
His desire led to an intensive review of clinical research on autoimmune diseases, not the typical realm of a basic scientist. "I found papers about arthritis showing that the cytokine IL-17 was highly expressed in the joint tissue of patients," Dong recalled. Some studies indicated IL-17 was produced by a T cell of a type unknown.
Dong returned to his mutant mice and found minimal levels of IL-17. "So we thought maybe IL-17 is more important than interferon-gamma in autoimmune diseases," Dong said. IL-17 also turns out to rely on the ICOS receptor that was missing from the T cells of the mutant mice.
Paper reveals new path to autoimmune and inflammatory diseases
Dong's subsequent major paper in Nature Immunology in November 2005 showed that IL-17-producing T cells are distinct from Th1 or Th2, and they could be generated in mice without any of the cytokines or transcription factors needed for the known T cell helpers. They concluded that IL-17-secreting T cells are a new kind, the same conclusion reached independently by another group in Alabama in the same issue of the journal.
The researchers at M. D. Anderson also showed that lungs become inflamed when IL-17 is overexpressed in their inner lining. Blocking IL-17 in a mouse model of multiple sclerosis greatly reduced the inflammation caused by that autoimmune disease.
This influential paper helped jump-start a new era in T cell biology and has been cited by other scientists 540 times.
Dong and colleagues have continued to publish on Th17 cells, now regarded as one of the hottest areas of biological research. Their 2007 paper in Nature elucidated IL-21, another cytokine produced by Th17 cells, in self-propagation of these cells. They also demonstrated the transcriptional regulation of Th17 development, function of Th17 cytokines, environmental regulation of Th17 function and the cell's significant plasticity.
Dong and two other scientists recently organized the first international Keystone Symposium on Th17 cells. Keystone Symposia gather top experts across disciplines to generate new ideas, exchange information and accelerate development of beneficial scientific applications.
Unleashing IL-17 on cancer
While Dong's research has been crucial to launching a new attack on autoimmune diseases, he's exploring one instance where autoimmunity would be desirable - when it's turned against cancer.
"There's always an immune response to tumors, but it's not strong enough," Dong said. "You need the right type of response. If you can help immune cells target cancer cells, it would be very beneficial." Preliminary data in a mouse model of autoimmunity against cancer are "very encouraging."
Dong directs the new Center for Inflammation and Cancer at M. D. Anderson, whose mission is to understand and improve the good inflammatory responses to cancer and dampen the chronic "bad" inflammation associated with many tumors.
"There are always good Th17 cells and bad Th17 cells. Everything is designed for a purpose. To little of that or too much of that is always the problem," Dong said.
Dr. Dong has made a host of important contributions to the competitive fields of co-stimulation and peripheral T cell differentiation, most recently in the description of the inflammatory Th17 cell subset. This award recognizes Dr. Dong, already a leader in his field at an early stage of his career, for both his impressive accomplishments to date and for his clear promise of continued success in the future.
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center