title: Macrophage-specific chemokines induced via innate immunity by amino acid copolymers and their role in EAE.
abstract: The random amino acid copolymer poly(Y,E,A,K)(n) (Copaxone®) is widely used in multiple sclerosis treatment and a second generation copolymer poly(Y,F,A,K)(n) with enhanced efficacy in experimental autoimmune encephalomyelitis in mice has been described. A major mechanism through which copolymers function to ameliorate disease is the generation of immunosuppressive IL-10-secreting regulatory T cells entering the CNS. In addition, the antigen presenting cell to which these copolymers bind through MHC Class II proteins may have an important role. Here, both CCL22 (a Th2 cell chemoattractant) in large amounts and CXCL13 in much smaller amounts are shown to be secreted after administration of YFAK to mice and to a smaller extent by YEAK parallel to their serum concentrations. Moreover, bone marrow-derived macrophages secrete CCL22 in vitro in response to YFAK and to higher concentrations of YEAK. Strikingly, these chemokines are also secreted into serum of MHC Class II -/- mice, indicating that an innate immune receptor on these cells also has an important role. Thus, both the innate and the adaptive immune systems are involved in the mechanism of EAE amelioration by YFAK. The enhanced ability of YFAK to stimulate the innate immune system may account for its enhanced efficacy in EAE treatment.
authors.affiliation: Peptimmune, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kovalchin
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Krieger
authors.forename: Michelle
authors.initials: M
authors.lastname: Genova
authors.forename: Norio
authors.initials: N
authors.lastname: Kawamoto
authors.forename: Michael
authors.initials: M
authors.lastname: Augustyniak
authors.forename: Kathryn
authors.initials: K
authors.lastname: Collins
authors.forename: Troy
authors.initials: T
authors.lastname: Bloom
authors.forename: Allyson
authors.initials: A
authors.lastname: Masci
authors.forename: Tara
authors.initials: T
authors.lastname: Hittinger
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dufour
authors.forename: Jack L
authors.initials: JL
authors.lastname: Strominger
authors.forename: Eric
authors.initials: E
authors.lastname: Zanelli
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000008:administration & dosage / Q000097:blood / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D054422:Chemokine CCL22 / Q000378:metabolism; D054382:Chemokine CXCL13 / Q000378:metabolism; D018925:Chemokines / Q000097:blood / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D000068717:Glatiramer Acetate; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007377:Interleukin-3 / Q000378:metabolism; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000187:drug effects; D010455:Peptides / Q000008:administration & dosage / Q000097:blood / Q000276:immunology / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000596:Amino Acids; C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D054382:Chemokine CXCL13; D018925:Chemokines; C486386:Cxcl13 protein, mouse; D000949:Histocompatibility Antigens Class II; D007377:Interleukin-3; D010455:Peptides; D000068717:Glatiramer Acetate