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

• Published in: Neurology : neuroimmunology & neuroinflammation 2016-10, Vol.3 (5), p.e272-e272
• Main Authors: Varrin-Doyer, Michel, Pekarek, Kara L, Spencer, Collin M, Bernard, Claude C.A, Sobel, Raymond A, Cree, Bruce A.C, Schulze-Topphoff, Ulf, Zamvil, Scott S
• Format: Article
• Language: English
• ISSN: 2332-7812; 2332-7812
• DOI: 10.1212/NXI.0000000000000272

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) × MOG-specific immunoglobulin (Ig)H-chain knock-in (IgH [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 CD11cCD4 dendritic cells, (2) inhibited expansion of PD-1CXCR5BCL6 T follicular helper and interleukin (IL)-21–producing activated CD4CD44 T cells, (3) suppressed B cell CD40 expression, (4) diminished formation of FasGL7 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 CD4CD25Foxp3 and CD4CD25IL-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 2D2 × Th spontaneous EAE model can be used successfully for preclinical evaluation of a candidate MS treatment.