title: Presence of CpG DNA and the local cytokine milieu determine the efficacy of suppressive DNA vaccination in experimental autoimmune encephalomyelitis.
abstract: We here study the adjuvant properties of immunostimulatory DNA sequences (ISS) and coinjected cytokine-coding cDNA in suppressive vaccination with DNA encoding an autoantigenic peptide, myelin basic protein peptide 68-85, against Lewis rat experimental autoimmune encephalomyelitis (EAE). EAE is an autoaggressive, T1-mediated disease of the CNS. ISS are unmethylated CpG motifs found in bacterial DNA, which can induce production of type 1 cytokines in vertebrates through the innate immune system. Because ISS in the plasmid backbone are necessary for efficient DNA vaccination, we studied the effect of one such ISS, the 5'-AACGTT-3' motif, in our system. Treatment with a DNA vaccine encoding myelin basic protein peptide 68-85 and containing three ISS of 5'-AACGTT-3' sequence suppressed clinical signs of EAE, while a corresponding DNA vaccine without such ISS had no effect. We further observed reduced proliferative T cell responses in rats treated with the ISS-containing DNA vaccine, compared with controls. We also studied the possible impact of coinjection of plasmid DNA encoding rat cytokines IL-4, IL-10, GM-CSF, and TNF-alpha with the ISS-containing DNA vaccine. Coinjection of IL-4-, IL-10-, or TNF-alpha-coding cDNA inhibited the suppressive effect of the DNA vaccine on EAE, whereas GM-CSF-coding cDNA had no effect. Coinjection of cytokine-coding cDNA with the ISS-deficient DNA vaccine failed to alter clinical signs of EAE. We conclude that the presence of ISS and induction of a local T1 cytokine milieu is decisive for specific protective DNA vaccination in EAE.
authors.affiliation: Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden. Anna.Lobell@mtc.ki.se
authors.forename: A
authors.initials: A
authors.lastname: Lobell
authors.forename: R
authors.initials: R
authors.lastname: Weissert
authors.forename: S
authors.initials: S
authors.lastname: Eltayeb
authors.forename: C
authors.initials: C
authors.lastname: Svanholm
authors.forename: T
authors.initials: T
authors.lastname: Olsson
authors.forename: H
authors.initials: H
authors.lastname: Wigzell
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D018899:CpG Islands / Q000276:immunology*; D006224:Cricetinae; D016207:Cytokines / Q000008:administration & dosage / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control*; D006801:Humans; D007117:Immunization, Secondary; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007273:Injections, Intramuscular; D008297:Male; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D019444:Vaccines, DNA; C110235:myelin basic protein 68-86