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

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

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19 Citations (Scopus)

Abstract

Objective: To evaluate the influence of oral laquinimod, a candidate multiple sclerosis (MS) treatment, on induction of T follicular helper cells, development of meningeal B cell aggregates, and clinical disease in a spontaneous B cell-dependent MS model. Methods: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG) protein. Spontaneous EAE was evaluated in C57BL/6 MOG p35-55-specific T cell receptor transgenic (2D2) 3 MOG-specific immunoglobulin (Ig)H-chain knock-in (IgHMOG-ki[Th]) mice. Laquinimod was administered orally. T cell and B cell populations were examined by flow cytometry and immunohistochemistry. Results: Oral laquinimod treatment (1) reduced CD11c+CD4+ dendritic cells, (2) inhibited expansion of PD-1+CXCR5+BCL6+ T follicular helper and interleukin (IL)-21-producing activated CD4+CD44+ T cells, (3) suppressed B cell CD40 expression, (4) diminished formation of Fas+GL7+ germinal center B cells, and (5) inhibited development of MOG-specific IgG. Laquinimod treatment not only prevented rMOG-induced EAE, but also inhibited development of spontaneous EAE and the formation of meningeal B cell aggregates. Disability progression was prevented when laquinimod treatment was initiated after mice developed paralysis. Treatment of spontaneous EAE with laquinimod was also associated with increases in CD4+CD25hiFoxp3+ and CD4+CD25+IL-10+ regulatory T cells. Conclusions: Our observations that laquinimod modulates myelin antigen-specific B cell immune responses and suppresses both development of meningeal B cell aggregates and disability progression in spontaneous EAE should provide insight regarding the potential application of laquinimod to MS treatment. Results of this investigation demonstrate how the 2D23Th spontaneous EAE model can be used successfully for preclinical evaluation of a candidate MS treatment.

Original languageEnglish
Article numbere272
Number of pages11
JournalNeurology: Neuroimmunology & Neuroinflammation
Volume3
Issue number5
DOIs
Publication statusPublished - Oct 2016

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