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Pierre AmarencoINSERM U-698, Clinical Research in Atherothrombosis and Denis Diderot University, Paris VII, Bichat Stroke Centre, Paris, Francepierre.amarenco@bch.aphp.fr

As the principal investigator of the TRUST-tPA trial, I have received funding from the French Ministry of Health (PHRC-AOM03103), and from Boehringer-Ingelheim France.

1 The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333: 1581–87.

2 The European Stroke Organisation (ESO) Executive Committee, the ESO Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovascular Dis 2008; 25: 457–507.

3 Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke: the eighth ACCP consensus conference on antithrombotic therapy. Chest 2008; 133: 630S–669S.

4 Meyer BC, Raman R, Hemmen T, et al. Effi cacy of site-independent telemedicine in the STRokE DOC trial: a randomised, blinded, prospective study. Lancet Neurol 2008; 7: 787–95.

5 Saver JL. Time is brain—quantifi ed. Stroke 2006; 37: 263–66.

Neutralisation of IL12 p40 or IL23 p40 does not block infl ammation in multiple sclerosis

Crohn’s disease, psoriasis, rheumatoid arthritis (RA), and multiple sclerosis (MS) are deemed to be autoimmune diseases that develop in genetically predisposed indi-vid uals.1 CD4+, Th1, and Th17 T-cell populations have been seen as main factors in the pathogenesis of MS, on the basis of the strong genetic association of certain HLA-class II molecules with MS, immunological fi ndings in the animal model of experimental autoimmune encephalomyelitis (EAE), and in patients with MS.1 However, several immune cells—including CD8+ T cells, dendritic cells (DC), natural killer cells, and B cells—and soluble mediators, such as autoantibodies, cytokines, and chemokines, all have important roles, with varying eff ects, at diff erent stages of the disease.1

A range of immunomodulatory drugs are currently in development for relapsing-remitting MS, including oral compounds and monoclonal antibodies that target specifi c receptors or molecules that are thought to be crucial for the pathogenesis of MS. Among the latter, the cytokines IL12 and IL23 are of particular interest because they have central roles in the diff erentiation of the two main proinfl ammatory CD4+ T-cell populations: Th1 cells and Th17 cells. IL12 and IL23 are heterodimers that have a common subunit (p40) and have either p35 (IL12) or p19 (IL23) as a second subunit.2 IL12 and IL23 are produced by myeloid cells and bind to receptors that are expressed on T cells. IL12 signaling is thought crucial for Th1

diff erentiation, and IL23 signaling for the diff erentiation and maintenance of Th17 cells.3 Both IL12 p40 and IL23 p40 have been detected in MS lesions, and mononuclear cells in patients with MS have increased concentrations compared with controls. The neutralisation of IL12 p40 or IL23 p40 inhibits EAE in rodents and non-human primates.4 Furthermore, mice that are genetically defi cient in IL12 p40 and IL23 p19 are resistant to EAE.5 Thus, there is strong evidence that blocking IL12 p40 or IL23 p40 would be benefi cial to patients with MS.

Contrary to this expectation, Segal and co-workers,6 in this issue of The Lancet Neurology, show that diff erent doses of ustekinumab, an antibody that neutralises IL12 p40 and IL23 p40, do not inhibit disease activity in patients with relapsing-remitting MS. 249 patients were treated with four diff erent dosing regimens of ustekinumab or placebo for 19 weeks. A sensitive readout–the cumulative number of contrast-enhancing cranial MRI lesions–was chosen, and there was no diff erence from placebo in the ustekinumab treatment arms.

The authors off er several explanations as to what went wrong. They posit that ustekinumab might not have crossed the blood brain barrier, or that crucial events in T-helper cell diff erentiation had occurred much earlier during the course of the disease and were not aff ected by inhibition of IL12 p40 or IL23 p40. The assumption that treatment might have come too late is unlikely because

6 Levine SR, Gorman M. Telestroke: the application of telemedicine for stroke. Stroke 1999; 30: 464–69.

7 Wiborg A, Widder B. Teleneurology to improve stroke care in rural areas: the telemedicine in stroke in Swabia (TESS) project. Stroke 2003; 34: 2951–56.

8 Hess DC, Wang S, Hamilton W, et al. REACH: clinical feasibility of a rural telestroke network. Stroke 2005; 36: 2018–20.

9 Wang S, Gross H, Lee SB, et al. Remote evaluation of acute ischemic stroke in rural community hospitals in Georgia. Stroke 2004; 35: 1763–68.

10 Audebert HJ, Kukla C, Clarmann von Claranau S, et al. Telemedicine for safe and extended use of thrombolysis in stroke: the telemedic pilot project for integrative stroke care (TEMPiS) in Bavaria. Stroke 2005; 36: 287–91.

11 Audebert HJ, Kukla C, Vatankhah B et al. Comparison of tissue plasminogen activator administration management between telestroke network hospitals and academic stroke centers: the telemedical pilot project for integrative stroke care in Bavaria/Germany. Stroke 2006; 37: 1822–27.

12 Audebert HJ, Schenkel J, Heuschmann PU, et al. Eff ects of the implementation of a telemedical stroke network: the telemedic pilot project for integrative stroke care (TEMPiS) in Bavaria, Germany. Lancet Neurol 2006; 5: 742–48.

13 Amarenco P, Nadjar M. Telemedicine for improving emergent management of acute cerebrovascular syndromes. Int J Stroke 2007; 2: 47–50.

Published OnlineAugust 7, 2008DOI:10.1016/S1474-4422(08)70174-1

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Refl ection and Reaction

766 www.thelancet.com/neurology Vol 7 September 2008

B cells, antibodies, and tertiary lymphoid tissue in MS brains

the patients in the study had short disease courses, and there is no reason to assume that T-helper priming and diff erentiation into Th1 or Th17 lineages only occur during early stages and are not important later. With regard to the insuffi cient penetration into the CNS, the data from ustekinumab in non-human primates, and the fact that the blood-brain barrier is defi nitely open in MS lesions, argue that at least some of the antibody should have reached the CNS. However, the results of experiments in rodents with EAE have shown that priming of naive T cells with Th17 and presentation of autoantigens by myeloid DC (and subsequent epitope spreading) indeed occur in the CNS.7 Furthermore, IL12 p40 or IL23 p40 expression by CNS-endogenous cells is crucial for EAE,8 and these events might precede the opening of the blood-brain barrier. In this case, penetration of ustekinumab to the site of infl ammation would have come too late and with no eff ect on local immunological events. Although the study by Segal and co-authors contains no mechanistic data, the observation that lower doses of ustekinumab eff ectively block disease in patients with psoriasis9 argue that the antibody must have been active in MS. As a fi nal alternative, the failure of ustekinumab in patients with MS might show that IL12 and IL23, and hence Th1 and Th17 cells, do not have a role in MS pathogenesis. There are several other examples of similar discrepancies between EAE and MS. IFN-γ is partially protective in EAE but led to relapses in MS. TNF-α is thought to be pathogenic in EAE, and blocking TNF-α is the major therapeutic approach in RA; however, blocking TNF-α led to prolonged and more relapses in patients with MS. Hence, neither extrapolations from EAE data to MS nor from one supposedly T cell-mediated autoimmune disease to another are straightforward. The diff erences in ustekinumab responsiveness between MS on one hand and psoriasis and infl ammatory bowel disease on the other might be explained, in part, by the observation that

the genetic risk for psoriasis and Crohn’s disease, but not MS, is associated with mutations in the gene that encodes the IL23 receptor. The results of the ustekinumab trial can be deemed an earthquake for our current concepts oft the pathogenesis of MS. What was considered fi rm evidence for the role of IL12 or IL23 in MS has been shaken by this study. The possibility remains that inhibition of IL12 p40 or IL23 p40 only failed because of poor CNS availability, or that there are alternative proinfl ammatory pathways in MS that are not aff ected. Further insight might come from mechanistic studies, which were unfortunately not provided by Segal and co-workers.

Roland MartinInstitute for Neuroimmunology and Clinical Multiple Sclerosis Research, Center for Molecular Neurobiology Hamburg, University Medical Center Eppendorf, Hamburg, Germanyroland.martin@zmnh.uni-hamburg.de

I have no confl icts of interest.

1 McFarland HF, Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 2007; 8: 913–19.

2 Kikly K, Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune infl ammation. Curr Opin Immunol 2006; 18: 670–75.

3 Hunter, CA. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 2005; 5: 521–31.

4 ‘t Hart BA, Brok HPM, Remarque E, et al. Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody. J Immunol 2005; 175: 4761–68.

5. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune infl ammation of the brain. Nature 2003; 421: 744–48.

6 Segal BM, Constantinescu CS, Raychaudhuri A, et al. Repeated subcutaneous injections of IL12p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised dose-ranging study. Lancet Neurol 2008; 7: 796–804.

7 Bailey SL, Schreiner B, McMahon EJ, Miller SD. CNS myeloid DCs presenting endogenous myelin peptides preferentially‘ polarize CD4+ T(H)-17 cells in relapsing EAE. Nat Immunol 2007; 8: 172–80.

8 Becher B, Durell BG, Noelle RJ. IL-23 produced by CNS-resident cells controls T-cell encephalitogenicity during the eff ector phase of experimental autoimmune encephalomyelitis. J Clin Invest 2003; 112: 1186–91.

9 Leonardi CL, Kimball AB, Papp KA, et al. Effi cacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: 1665–74.

The roles of B cells in the pathogenesis of multiple sclerosis (MS) have taken decades to appreciate. The recent clinical successes of B-cell-targeted therapies in patients with MS have thrust B cells back into the spotlight; yet, as discussed by Franciotta and coauthors in this issue of The Lancet Neurology,1 a clear understanding of B-cell-function in MS is elusive.

Elvin Kabat identifi ed oligoclonal bands (OCBs) by electrophoresis of the cerebrospinal fl uid (CSF) of patients with MS.2 The function of plasma cells as antibody-producing cells was discovered by Astrid Fagraeus in 1948.3 The presence of autoantibodies against acetylcholine receptors in patients with myasthenia gravis was rightfully interpreted as an autoimmune

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