New research examining the production and function of the inflammatory cytokine interleukin 17 (IL-17) may pave the way for more effective ways to prevent and treat rheumatoid arthritis (RA) and other autoimmune and inflammatory conditions. The new research, released in the online edition of Nature Immunology on October 2, 2005,¹ suggests that a newly described T-helper (T_H) cell population of inflammatory T_H (T_Hi) cells produces IL-17. While researchers have long suspected that IL-17 is linked to autoimmune and inflammatory diseases, it is still unclear how production of the cytokine is regulated. 

After activation by antigen-presenting cells, T_H cells are thought to differentiate into either type 1 (T_H1) cells, which mediate cellular immunity, or type 2 (T_H2) cells, which mediate humoral immunity and allergic responses. Although it is generally accepted that IL-17 is produced by T_H cells, it was not known which T_H population produced the inflammatory cytokine.

In the current analysis, researchers evaluated in vitro the differentiation of naïve CD4 T cells into effector T_H cells that produce IL-17. They found that the differentiation of cells expressing IL-17 was inhibited by the cytokines and transcription factors associated with T_H1 or T_H2 differentiation, including IL-4, interferon-gamma (IFN-γ), and STAT4, providing evidence for a new lineage of T_H cells, T_Hi cells. 

In vivo analyses support the role of IL-17 in inflammation and autoimmunity. The study authors found that transgenic mice overexpressing IL-17 in lung epithelium exhibited airway inflammation and changes in mucus production. Furthermore, they demonstrated that injection of anti-IL-17 antibodies into mice with experimental autoimmune encephalomyelitis (EAE) inhibited inflammatory chemokine expression in the brain and reversed the disease process.

IL-17 may be an attractive potential target in RA

"We didn't know the pathway that would allow these cells to generate, and now we can try to develop strategies to interrupt this pathway," lead researcher Chen Dong, PhD, associate professor in the department of immunology at the MD Anderson Cancer Center in Houston, Texas, tells CIAOMed. "We now know that IL-17 and other cytokines are produced by this population of T cells, and now we can target IL-17, which has long been associated with RA."

As explained by Dr. Dong, the new research "suggests that shutting down the activity of these T_Hi cells might stop chronic inflammatory diseases from developing in the first place. Currently there are no IL-17 blockers commercially available. In the future, a new agent may benefit patients who do not respond to tumor necrosis factor-alpha [TNF-α] antagonists. In RA, I believe IL-17 blockers can be probably as effective as TNF-α antagonists, with fewer side effects, and would certainly be worth a try in all RA patients," he concluded.

American College of Rheumatology president-elect Mary K. Crow, MD, director of rheumatology research in the autoimmunity and inflammation program at the Hospital for Special Surgery in New York City, tells CIAOMed that she has been interested in the potential of IL-17 inhibition as a therapeutic strategy in RA for some time. "It is an interesting and attractive target to pursue," she says, because "it is made by a particular T-lymphocyte population that seems to be different than others in terms of its proinflammatory effects.  It has complex effects on angiogenesis, in synovial membrane, and in cartilage and bone damage."

Dr. Crow explained that it is still too early to determine what role a potential IL-17 blocker might play in RA. "I don't know if it would be used instead of anti-TNF drugs or tried in patients in whom anti-TNF therapies do not work, or if the two types of drugs would be used together in lower doses," she says. "It would have to be studied and, ideally, it would be nice to compare inhibition of IL-17 to inhibition of TNF."

Reference

1. Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol [serial online]. October 2, 2005.