Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis.
BACKGROUND
We have previously shown that vaccination with DNA encoding the encephalitogenic peptide myelin oligodendrocyte glycoprotein (MOG)(91-108) (pMOG) suppresses MOG(91-108)-induced rat Experimental Autoimmune Encephalomyelitis (EAE), a model for human Multiple Sclerosis (MS). The suppressive effect of pMOG is dependent on inclusion of CpG DNA in the plasmid backbone and is associated with early induction of Interferon (IFN)-beta.


RESULTS
In this study we examined the mechanisms underlying pMOG-induced protection. We found that in the DNA vaccinated cohort proinflammatory Interleukin (IL)-17 and IL-21 responses were dramatically reduced compared to in the control group, but that the expression of Foxp3 and Tumor Growth Factor (TGF)-beta1, which are associated with regulatory T cells, was not enhanced. Moreover, genes associated with Type I IFNs were upregulated. To delineate the role of IFN-beta in the protective mechanism we employed short interfering RNA (siRNA) to IFN-beta in the DNA vaccine. SiRNA to IFN-beta completely abrogated the protective effects of the vaccine, demonstrating that a local early elaboration of IFN-beta is important for EAE protection. IL-17 responses comparable to those in control rats developed in rats injected with the IFN-beta-silencing DNA vaccine.


CONCLUSIONS
We herein demonstrate that DNA vaccination protects from proinflammatory Th17 cell responses during induction of EAE. The mechanism involves IFN-beta as IL-17 responses are rescued by silencing of IFN-beta during DNA vaccination.
Andersson
Asa
A
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
Isaksson
Magnus
M
Wefer
Judit
J
Norling
Anna
A
Flores-Morales
Amilcar
A
Rorsman
Fredrik
F
Kämpe
Olle
O
Harris
Robert A
RA
Lobell
Anna
A
D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control*; D005260:Female; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014162:Transfection; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D000098546:Interleukin-21
D007166:Immunosuppressive Agents; D020381:Interleukin-17; D007378:Interleukins; C571326:MOG protein, human; C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D034741:RNA, Small Interfering; D019444:Vaccines, DNA; D016899:Interferon-beta; D000098546:Interleukin-21