Newly discovered IL-17-producing T cells play key role in inflammatory and autoimmune diseases

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Newly discovered IL-17-producing T cells play key role in

inflammatory and autoimmune diseases



October 10, 2005



Janis



Seattle, WA and Houston, TX - A newly discovered type of CD4+ T cell,

dubbed the inflammatory T helper cell (THi), is the source of

interleukin-17 (IL-17), regulates tissue inflammation, and might be a

good target for treatment of inflammatory diseases such as rheumatoid

arthritis (RA) and lupus, according to a breakthrough paper published

online October 2, 2005 in Nature Immunology [1].

" We suspected that IL-17 is a player in autoimmune and inflammatory

diseases, but we didn't understand where IL-17 came from before this

finding. Now we have discovered the source of IL-17 and also have

solidly demonstrated that these are the crucial cells that regulate

tissue inflammation in autoimmune disease and asthma. These findings

suggest that shutting down the activity of these THi cells might stop

chronic inflammatory diseases from developing in the first place, "

said the study's lead investigator, Dr Chen Dong (University of Texas

MD Cancer Center, Houston).

THi is a previously unknown type of T helper cell

IL-17 emerged in 2000 as the " missing link " between the large numbers

of T cells in arthritic joints and destruction of cartilage and bone.

This had been a matter of some confusion, since typical T-cell-

derived cytokines are not present in high concentrations in

rheumatoid joints. IL-17 is there, however, and correlates with C-

reactive protein (CRP) levels.

The exact T cell that produces IL-17 was difficult to pin down,

however, since neither TH1 nor TH2 cells are associated with the

cytokine. This was a matter of some urgency, since IL-17 is now

thought to be at or near the top of the cytokine cascade, which is

especially important in early RA.

Dong and colleagues, including Drs Heon Park and Zhaoxia Li (both at

the University of Washington, Seattle) and Dr Xuexian O Yang (MD

Cancer Center) used a combination of cell-culture studies

and mouse studies to identify THi cells as the source of IL-17.

First they " educated " naïve T helper cells to become IL-17-producing

cells. This showed that the THi cells do not need the cytokines and

transcription factors needed for TH1 or TH2 differentiation but do

need the costimulatory molecules CD28 and ICOS. These studies also

showed that IL-17 production is downregulated by interleukin-4 (IL-4)

and interferon-.

The researchers next showed that an anti-IL-17 antibody could prevent

the development of an inflammatory disease. Anti-IL-17 both prevented

development of experimental autoimmune encephalomyelitis (AEA, a

model for multiple sclerosis) if given before disease induction in

mice and reversed the progression of EAE in mice with established

disease.

" We don't know why these dangerous helper T cells are activated in

patients, but we now know how they function, and that should take us

a long way to understanding and treating these and other inflammatory

and autoimmune diseases, " Dong says.

Dong tells rheumawire that treatment might be done " by [making]

antibodies to the cytokine or its receptor, by inhibiting IL-17-

mediated signaling, or by blocking upstream signals that turn on IL-17. "

These possibilities have already attracted the interest of

biotechnology companies, including Immunex, Genentech, and Human

Genome Sciences, all of which have lively IL-17 research programs and

pending patent applications.

" This is now an wide-open field to study and understand how these

cells are generated in immune diseases and how we can prevent this

process, " Dong says.

Park H, Li Z, Yang XO, et al. A distinct lineage of CD4 T cells

regulates tissue inflammation by producing interleukin 17. Nat

Immunol 2005; DOI:10.1038/ni1261. Available at: . 16200068

http://www.jointandbone.org/viewArticle.do?primaryKey=574247