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7 mai 2011 6 07 /05 /mai /2011 11:21

A major role for the cytokine interleukin-17 (IL-17) has now been described in various models of immune-mediated tissue injury, including organ-specific autoimmunity in the brain, heart, synovium and intestines, allergic disorders of the lung and skin, and microbial infections of the intestines and the nervous system.

 

Trends Immunol. 2011 Apr 28.

Interferon-β exacerbates Th17-mediated inflammatory disease.

Axtell RC, Raman C, Steinman L.

 

Department of Neurology and Neurological Sciences, Interdepartmental Program in Immunology, Stanford University CA 94305, USA.

 

Interferon (IFN)-β is the treatment most often prescribed for relapsing-remitting multiple sclerosis (RRMS).

30-50% of MS patients, however, do not respond to IFN-β.

In some cases, IFN-β exacerbates MS, and it consistently worsens neuromyelitis optica (NMO).

To eliminate unnecessary treatment for patients who are non-responsive to IFN-β, and to avoid possible harm, researchers are identifying biomarkers that predict treatment outcome before treatment is initiated.

These biomarkers reveal insights into the mechanisms of disease.

Recent discoveries on human samples from patients with RRMS, NMO, psoriasis, rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis, indicate that IFN-β is ineffective and might worsen clinical status in diverse diseases when a Th17 immune response is prominent.

 

 

Nat Med. 2010 Apr;16(4):406-12. Epub 2010 Mar 28.

T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis.

Source

Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.

Interferon-beta (IFN-beta) is the major treatment for multiple sclerosis.

However, this treatment is not always effective.

Here we have found congruence in outcome between responses to IFN-beta in experimental autoimmune encephalomyelitis (EAE) and relapsing-remitting multiple sclerosis (RRMS).

 

IFN-beta was effective in reducing EAE symptoms induced by T helper type 1 (T(H)1) cells but exacerbated disease induced by T(H)17 cells.

Effective treatment in T(H)1-induced EAE correlated with increased interleukin-10 (IL-10) production by splenocytes.

In T(H)17-induced disease, the amount of IL-10 was unaltered by treatment, although, unexpectedly, IFN-beta treatment still reduced IL-17 production without benefit.

 

Both inhibition of IL-17 and induction of IL-10 depended on IFN-gamma.

 

In the absence of IFN-gamma signaling, IFN-beta therapy was ineffective in EAE. In RRMS patients, IFN-beta nonresponders had higher IL-17F concentrations in serum compared to responders.

 

Nonresponders had worse disease with more steroid usage and more relapses than did responders.

 

Hence, IFN-beta is proinflammatory in T(H)17-induced EAE.

 

Moreover, a high IL-17F concentration in the serum of people with RRMS is associated with nonresponsiveness to therapy with IFN-beta.

 

      Nat Immunol. 2010 Jan;11(1):41-4. Epub 2009 Dec 17.

Mixed results with modulation of TH-17 cells in human autoimmune diseases.

Source

Department of Neurological Sciences and Interdepartmental Program in Immunology, Beckman Center for Molecular Medicine, Stanford University School of Medicine, Stanford, California, USA. steinman@stanford.edu

The outcomes of clinical trials provide the most convincing data to clarify the role of particular cytokines in the pathogenesis of human diseases.

The immunology community, for a variety of practical reasons, spends most of its research time and funds on studies in model systems, mainly mice.

In this perspective I discuss results of clinical trials assessing the effect of blocking the differentiation and/or function of interleukin-17-producing CD4(+) T cells on human autoimmune disease, and devote more limited attention to corroborating preclinical studies from animal models.

Thus far, these outcomes in human trials have been mixed, with notable success in psoriasis and Crohn's disease but a negative result in relapsing-remitting multiple sclerosis.

PMID:
 
20016509
 
[PubMed - indexed for MEDLINE]

Nat Med. 2007 Feb;13(2):139-45.

A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage.

Source

Interdepartmental Program in Immunology, Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, Stanford, California 94305, USA. steinman@stanford.edu

Erratum in

  • Nat Med. 2007 Mar;13(3):385.

For over 35 years, immunologists have divided T-helper (T(H)) cells into functional subsets.

T-helper type 1 (T(H)1) cells-long thought to mediate tissue damage-might be involved in the initiation of damage, but they do not sustain or play a decisive role in many commonly studied models of autoimmunity, allergy and microbial immunity.


A major role for the cytokine interleukin-17 (IL-17) has now been described in various models of immune-mediated tissue injury, including organ-specific autoimmunity in the brain, heart, synovium and intestines, allergic disorders of the lung and skin, and microbial infections of the intestines and the nervous system.

 

A pathway named T(H)17 is now credited for causing and sustaining tissue damage in these diverse situations.

 

The T(H)1 pathway antagonizes the T(H)17 pathway in an intricate fashion.

 

The evolution of our understanding of the T(H)17 pathway illuminates a shift in immunologists' perspectives regarding the basis of tissue damage, where for over 20 years the role of T(H)1 cells was considered paramount.


PMID:
 
17290272
 
[PubMed - indexed for MEDLINE]

 

Copyright © 2011 Elsevier Ltd. All rights reserved.

PMID: 21530402 [PubMed - as supplied by publisher]

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