title: Treatment of spontaneous EAE by laquinimod reduces Tfh, B cell aggregates, and disease progression.
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) × 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 2D2 × Th spontaneous EAE model can be used successfully for preclinical evaluation of a candidate MS treatment.
authors.affiliation: Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
authors.forename: Michel
authors.initials: M
authors.lastname: Varrin-Doyer
authors.affiliation: Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Pekarek
authors.affiliation: Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
authors.forename: Collin M
authors.initials: CM
authors.lastname: Spencer
authors.affiliation: Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
authors.forename: Claude C A
authors.initials: CC
authors.lastname: Bernard
authors.affiliation: Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.affiliation: Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
authors.forename: Bruce A C
authors.initials: BA
authors.lastname: Cree
authors.affiliation: Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
authors.forename: Ulf
authors.initials: U
authors.lastname: Schulze-Topphoff
authors.affiliation: Department of Neurology (M.V.-D., K.L.P., C.M.S., B.A.C.C., U.S.-T., S.S.Z.) and Program in Immunology (M.V.-D., K.L.P., C.M.S., U.S.-T., S.S.Z.), University of California, San Francisco; Multiple Sclerosis Research Group (C.C.A.B.), Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; and Department of Pathology (R.A.S.), Stanford University, CA.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil