Exacerbation of viral and autoimmune animal models for multiple sclerosis by bacterial DNA.
Theiler's murine encephalomyelitis virus (TMEV) infection and relapsing-remitting experimental allergic encephalomyelitis (R-EAE) have been used to investigate the viral and autoimmune etiology of multiple sclerosis (MS), a possible Th1-type mediated disease. DNA immunization is a novel vaccination strategy in which few harmful effects have been reported. Bacterial DNA and oligodeoxynucleotides, which contain CpG motifs, have been reported to enhance immunostimulation. Our objectives were two-fold: first, to ascertain whether plasmid DNA, pCMV, which is widely used as a vector in DNA immunization studies, could exert immunostimulation in vitro; and second, to test if pCMV injection could modulate animal models for MS in vivo. We demonstrated that this bacterially derived DNA could induce interleukin (IL)-12, interferon (IFN)gamma, (Th1-promoting cytokines), and IL-6 production as well as activate NK cells. Following pCMV injections, SJL/J mice were infected with TMEV or challenged with encephalitogenic myelin proteolipid protein (PLP) peptides. pCMV injection exacerbated TMEV-induced demyelinating disease in a dose-dependent manner. Exacerbation of the disease did not correlate with the number of TMEV-antigen positive cells but did with an increase in anti-TMEV antibody. pCMV injection also enhanced R-EAE with increased IFNgamma and IL-6 responses. These results caution the use of DNA vaccination in MS patients and other possible Th1-mediated diseases.
Department of Neurology, University of Utah School of Medicine, Salt Lake City 84132, USA.
I
I
Tsunoda
N D
ND
Tolley
D J
DJ
Theil
J L
JL
Whitton
H
H
Kobayashi
R S
RS
Fujinami
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D018899:CpG Islands / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D003587:Cytomegalovirus / Q000276:immunology; D004269:DNA, Bacterial / Q000009:adverse effects* / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D005822:Genetic Vectors / Q000009:adverse effects / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D018991:Myelin Proteolipid Protein / Q000276:immunology; D013116:Spinal Cord / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D017945:Theilovirus / Q000276:immunology; D019444:Vaccines, DNA / Q000009:adverse effects / Q000276:immunology
D000914:Antibodies, Viral; D016207:Cytokines; D004269:DNA, Bacterial; D007074:Immunoglobulin G; D018991:Myelin Proteolipid Protein; D019444:Vaccines, DNA