title: Protection from experimental autoimmune encephalomyelitis by polyclonal IgG requires adjuvant-induced inflammation.
abstract: BACKGROUND
  Intravenous immunoglobulin (IVIG) proved to be an efficient anti-inflammatory treatment for a growing number of neuroinflammatory diseases and protects against the development of experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS).
  
  
  METHODS
  The clinical efficacy of IVIG and IVIG-derived F(ab')2 fragments, generated using the streptococcal cysteine proteinase Ide-S, was evaluated in EAE induced by active immunization and by adoptive transfer of myelin-specific T cells. Frequency, phenotype, and functional characteristics of T cell subsets and myeloid cells were determined by flow cytometry. Antibody binding to microbial antigen and cytokine production by innate immune cells was assessed by ELISA.
  
  
  RESULTS
  We report that the protective effect of IVIG is lost in the adoptive transfer model of EAE and requires prophylactic administration during disease induction. IVIG-derived Fc fragments are not required for protection against EAE, since administration of F(ab')2 fragments fully recapitulated the clinical efficacy of IVIG. F(ab')2-treated mice showed a substantial decrease in splenic effector T cell expansion and cytokine production (GM-CSF, IFN-γ, IL-17A) 9 days after immunization. Inhibition of effector T cell responses was not associated with an increase in total numbers of Tregs but with decreased activation of innate myeloid cells such as neutrophils, monocytes, and dendritic cells. Therapeutically effective IVIG-derived F(ab')2 fragments inhibited adjuvant-induced innate immune cell activation as determined by IL-12/23 p40 production and recognized mycobacterial antigens contained in Freund's complete adjuvant which is required for induction of active EAE.
  
  
  CONCLUSIONS
  Our data indicate that F(ab')2-mediated neutralization of adjuvant contributes to the therapeutic efficacy of anti-inflammatory IgG. These findings might partly explain the discrepancy of IVIG efficacy in EAE and MS.
authors.affiliation: Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zürich, Zürich, Switzerland. isaak.quast@uzh.ch.
authors.forename: Isaak
authors.initials: I
authors.lastname: Quast
authors.affiliation: Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zürich, Zürich, Switzerland. keller@immunology.uzh.ch.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Keller
authors.affiliation: Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zürich, Zürich, Switzerland. weber@immunology.uzh.ch.
authors.forename: Patrick
authors.initials: P
authors.lastname: Weber
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland. christoph.schneider@pki.unibe.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Institute of Pharmacology, University of Bern, Bern, Switzerland. stephan.vongunten@pki.unibe.ch.
authors.forename: Stephan
authors.initials: S
authors.lastname: von Gunten
authors.affiliation: Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zürich, Zürich, Switzerland. jan.luenemann@uzh.ch.
authors.forename: Jan D
authors.initials: JD
authors.lastname: Lünemann
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005620:Freund's Adjuvant / Q000633:toxicity; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use*; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013154:Spleen / Q000473:pathology; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C445081:myelin oligodendrocyte glycoprotein (35-55); D005620:Freund's Adjuvant