Cytokine networks in multiple sclerosis: lost in translation.
OBJECTIVE
This review will discuss aspects of cytokine networks in neuroinflammatory diseases and attempt to provide some explanation for our failures and successes in translating preclinical data to benefit patients with multiple sclerosis (MS). We will discuss innate cytokines such as tumor necrosis factor alpha and interferon (IFN) beta and will then go on to cover recent findings on the role of interleukin-23 and the so-called T(H)17 cells and how they are implicated in the pathogenesis of neuroinflammation.


RESULTS
Even though IFN-beta has been used for the treatment of MS for many years, it is only recently that the mechanistic underpinnings of the IFN-beta-mediated immune modulation was discovered in preclinical models. The timeline is at odds with the idea that preclinical data should shape the design of therapeutic strategies in the clinic. Conversely, the discovery of the so-called T(H)17 cells and their association with neuroinflammation has broken the dogma that IFN-gamma-producing T(H)1 cells have the exclusive capacity to invade and destroy the central nervous system tissue. So why then did a clinical trial targeting the T(H)17-promoting cytokine interleukin-23 fail?


CONCLUSIONS
Preclinical studies using the animal models for MS have yielded promising results, but unfortunately the translation into the clinic is often disappointing. The reason for this may be the complex nature of the pathogenesis of autoimmune neuroinflammation, but more often an oversimplified interpretation of preclinical observations appears to hinder our progress.
Codarri
Laura
L
Department of Pathology, Institute of Experimental Immunology, University Hospital of Zurich, Zurich, Switzerland.
Fontana
Adriano
A
Becher
Burkhard
B
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D020278:Demyelinating Autoimmune Diseases, CNS / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000639:trends; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D057170:Translational Research, Biomedical / Q000379:methods* / Q000639:trends
D016207:Cytokines; D007155:Immunologic Factors