Anti-IL-16 therapy reduces CD4+ T-cell infiltration and improves paralysis and histopathology of relapsing EAE.
Infiltration of the central nervous system (CNS) by CD4+ Th1 cells precedes onset and relapses of experimental autoimmune encephalomyelitis (EAE). We reported that (B6xSJL) F1 (H-2b/s) mice with severe relapsing-remitting disease had extensive infiltration by CD4+ T cells compared to that in C57BL/6 (B6) (H-2b) mice, which developed mild low-relapsing disease in response to myelin oligodendrocyte peptide 35-55 (MOG(35-55)). This observation led us to search for mechanisms that specifically regulate trafficking of CD4+ cells in relapsing H-2b/s mice. We show that the CD4+ cell chemoattractant cytokine interleukin (IL)-16 has an important role in regulation of relapsing EAE induced by MOG(35-55) in the (B6xSJL) F1 (H-2b/s) mice. We found production of IL-16 in the CNS of mice with EAE. IL-16 levels in the CNS correlated well with the extent of CD4+ T-cell and B-cell infiltration during acute and relapsing disease. Infiltrating CD4+ T cells, B cells, and to a lesser extent CD8+ T cells all contained IL-16 immunoreactivity. Treatment with neutralizing anti-IL-16 antibody successfully reversed paralysis and ameliorated relapsing disease. In treated mice, diminished infiltration by CD4+ T cells, less demyelination, and more sparing of axons was observed. Taken together, our results show an important role for IL-16 in regulation of relapsing EAE. We describe a novel therapeutic approach to specifically impede CD4+ T cell chemoattraction in EAE based on IL-16 neutralization. Our findings have high relevance for the development of new therapies for relapsing EAE and potentially MS.
Skundric
Dusanka S
DS
Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. skundric@cmb.biosci.wayne.edu
Dai
Rujuan
R
Zakarian
Vaagn L
VL
Bessert
Denise
D
Skoff
Robert P
RP
Cruikshank
William W
WW
Kurjakovic
Zlatan
Z
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D006023:Glycoproteins; D007114:Immunization / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D007167:Immunotherapy; D007211:Indoles; D019410:Interleukin-16 / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D063308:Myelin-Oligodendrocyte Glycoprotein; D010243:Paralysis / Q000209:etiology / Q000628:therapy*; D010446:Peptide Fragments; D010641:Phenotype; D011930:Reaction Time / Q000187:drug effects; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors
D000906:Antibodies; D015704:CD4 Antigens; D006023:Glycoproteins; D007211:Indoles; D019410:Interleukin-16; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); C007293:DAPI; D017493:Leukocyte Common Antigens