Treatment of spontaneous EAE by laquinimod reduces Tfh, B cell aggregates, and disease progression

Varrin‐Doyer, Michel; Pekarek, Kara; Spencer, Collin M.; Bernard, Claude Charles Andre; Sobel, Raymond A.; Cree, Bruce A.C.; Schulze-Topphoff, Ulf; Zamvil, Scott S.

doi:10.1212/nxi.0000000000000272

Cited by 35 publications

(31 citation statements)

References 42 publications

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“…correlated with reduced TFH frequency and B-cell aggregates in the CNS88 . This work suggests that TFH cells are linked with disease progression.…”

mentioning

confidence: 87%

Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Quinn¹,

Axtell²

2018

Preprint

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Multiple sclerosis is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and EAE. The curation of this literature has identified that CNS-infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS.shown to be critical for effective B-cell activity in many different models of infection and vaccination. These cells have also been shown to be associated with many different autoimmune diseases including Systemic Lupus Erythematosus (SLE) 15 , Rheumatoid Arthritis (RA) 16 , and Multiple sclerosis 17 .Currently, there is not a complete and though understanding of how naïve CD4+ helper T cells differentiate into mature TFH cells. However, many studies have provided some inroads on to the mechanisms involved in TFH differentiation. These studies have indicated that proper differentiation is "multistage and multifactorial" [18][19] . The cytokines IL-6 and IL-21 are important for effective differentiation 20-21 . IL-6 signaling through STAT3 and STAT1 leads to BCL6 expression in T cells in vitro 22 and IL-6 leads to IL-21 production. IL-21 can also lead to BCL6 expression in T cells though there appears to be substantial overlap in signaling between these cytokines 21 . Further complicating the process, experiments in knockout mice demonstrate that they are not the only factor involved [23][24] . There is also evidence that the quality and duration of TCR/MHCII interaction during initial stimulation can affect whether a naïve T cell will differentiate into a TFH cell. Certain models demonstrate that T cells with a high affinity TCR are more likely to differentiate into TFH cells 25 .Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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“…correlated with reduced TFH frequency and B-cell aggregates in the CNS88 . This work suggests that TFH cells are linked with disease progression.…”

mentioning

confidence: 87%

Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Quinn¹,

Axtell²

2018

Preprint

View full text Add to dashboard Cite

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“…Similar to human studies, many of the studies in mice examining TFH cells are simply looking at correlative data. For example, one study reported that Laquinomod effectively treated human MOG-induced and the efficacy was correlated with reduced TFH frequency and B-cell aggregates in the CNS [ 99 ]. This work suggests that TFH cells are linked with disease progression.…”

Section: Experimental Autoimmune Encephalomyelitis (Eae)mentioning

confidence: 99%

Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Quinn

Axtell

2018

IJMS

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Multiple sclerosis (MS) is an autoimmune disorder where both T cells and B cells are implicated in pathology. However, it remains unclear how these two distinct populations cooperate to drive disease. There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease. This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and experimental autoimmune encephalomyelitis (EAE). The curation of this literature has identified that central nervous system (CNS) infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation. This demonstrates that TFH cells and their products are promising targets for therapies in MS.

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“…Preclinical studies have shown that laquinimod reduces inflammatory cell infiltrates in the central nervous system (CNS), inhibits development of experimental autoimmune encephalomyelitis, decreases demyelination, and prevents axonal loss [ 7 , 8 ], and the formation of meningeal B cell aggregates [ 9 ]. Laquinimod is likely to exert its anti-inflammatory activity via suppression of Th1 and Th17 cells and induction of a Th2/3 shift of immune response in the peripheral blood [ 7 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS

Ziemssen

Tumani

Sehr

et al. 2017

J Neuroinflammation

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BackgroundLaquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS.MethodsOne hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments.ResultsTwenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo.ConclusionLaquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated.Trial registrationEudraCT Number: 2009-011234-99. Registered 23 June 2009.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0945-z) contains supplementary material, which is available to authorized users.

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Treatment of spontaneous EAE by laquinimod reduces Tfh, B cell aggregates, and disease progression

Cited by 35 publications

References 42 publications

Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Emerging Role of Follicular T Helper Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS

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