title: Antibody to α4 integrin suppresses natural killer cells infiltration in central nervous system in experimental autoimmune encephalomyelitis.
abstract: Natalizumab inhibits the influx of leukocytes into the central nervous system (CNS) via blockade of alpha-4 subunit of very late activation antigen (VLA)-4. The association of natalizumab therapy with progressive multifocal leukoencephalopathy (PML) suggests a disturbance of CNS immune surveillance in a small percentage of Multiple Sclerosis (MS) patients exposed to the medication. Natural killer (NK) cells are known to play an important role in modulating the evolution of different phases of this lymphocyte mediated disease, and we investigated the effects of natalizumab on the NK cell phenotype and infiltration in the CNS in experimental autoimmune encephalomyelitis (EAE), a murine model of MS. Our data show that both resting (from naïve mice) and activated (from EAE mice) NK cells express high levels of VLA-4, and anti-VLA-4 antibody treatment significantly decreases NK cells frequency in the CNS of EAE mice. Moreover, we find that anti-VLA-4 possibly impairs NK cells migratory potential, since unblocked VLA-4 expression levels were downregulated on those NK cells that penetrate the CNS. These data suggest that treatment with antibody to VLA-4 may alter immune surveillance of the CNS by impacting NK cell functions and might contribute to the understanding of the mechanisms leading to the development of PML in some MS patients.
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gan
authors.forename: Ruolan
authors.initials: R
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Roberto
authors.initials: R
authors.lastname: Bomprezzi
authors.forename: Fu-Dong
authors.initials: FD
authors.lastname: Shi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D006023:Glycoproteins / Q000009:adverse effects / Q000276:immunology; D039441:Integrin alpha4 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D063308:Myelin-Oligodendrocyte Glycoprotein; D020556:Neutrophil Infiltration / Q000187:drug effects*; D010446:Peptide Fragments / Q000009:adverse effects / Q000276:immunology
chemical_list: D000906:Antibodies; D015703:Antigens, CD; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D039441:Integrin alpha4