| 1. |
- Andersson, Åsa, et al.
(författare)
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Impaired autoimmune T helper 17 cell responses following DNA vaccination against rat experimental autoimmune encephalomyelitis
- 2008
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Ingår i: PLoS ONE. - : PLoS. - 1932-6203. ; 3:11, s. e3682-
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Tidskriftsartikel (refereegranskat)abstract
- 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. PRINCIPAL FINDINGS: 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.
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| 2. |
- Wefer, Judit, et al.
(författare)
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Protective DNA vaccination against experimental autoimmune encephalomyelitis is associated with induction of IFNbeta
- 2004
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Ingår i: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 149:1-2, s. 66-76
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- DNA vaccines encoding encephalitogenic peptides protect against subsequent development of rat experimental autoimmune encephalomyelitis (EAE) through unknown mechanisms. We investigated immune cell phenotypes at different time points after DNA vaccination with vaccine encoding myelin oligodendrocyte glycoprotein peptide 91-108 and subsequent induction of EAE. In protected rats, we observed (i) no alterations in antigen-specific Th2 or Th3 responses, (ii) reduced MHC II expression on splenocytes early after EAE induction, (iii) antigen-specific upregulation of IFNbeta upon recall stimulation and (iv) reduced IL-12Rbeta2 on lymphocytes. We suggest that the underlying mechanism of DNA vaccination is associated with immunomodulation exerted by induced IFNbeta.
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| 3. |
- Wefer, Judit
(författare)
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Studies of cellular pathogenesis in experimental autoimmune encephalomyelitis
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, I have studied antigen-specific therapeutic interventions of experimental autoimmune encephalomyelitis (EAE) and aimed to understand the respective roles of different cell subsets in initiation and perpetuation of disease. EAE is a commonly used animal model for the human disease Multiple Sclerosis (MS), a demyelinating disease mainly affecting young adults. The disease etiology is thought to be of autoimmune origin, where immunological attacks and subsequent destruction of myelin sheaths surrounding neurons result in neurological deficiencies and muscle paralysis. The molecular cause of initiation and progression of MS is still not clearly understood, despite extensive studies. In order to understand and develop measures to alleviate the effects of neurological deficiencies occurring in MS, EAE is induced by immunisation of myelin antigens in rodents that develop an MS-like disease with gradual progressive paralysis and myelin breakdown. Previous studies have established that the disease is mainly driven by T cells producing pro-inflammatory cytokines. Additional cell types work in an intriguing network in which they support each other to enact autoaggression. Therapeutic interventions are likely to affect the whole network, and thus it is important to understand the interaction and communication between these different cell types. The role of CD8+ T cells in perpetuating EAE was studied using genetically modified mice, and CD8+ T cells were determined to have an integral part in pathogenesis being linked with demyelination. In order to explore disease inducing and prevention mechanisms we employed antigen-specific interventions in EAE. Therapeutic administration of either protein antigen in adjuvant as well as DNA vaccine encoding antigen were both proven to be efficient in suppressing disease development. The protective mechanisms were long-lived, lacked shifts from a pathogenic type 1 cytokine response towards a proposed protective type 2 cytokine biased response, and were characterised by the survival of antigen-specific T cells. Further investigations of DNA vaccine-mediated protection revealed IFNbeta as being associated with disease suppression. The cell type hypothesised to be responsible for inducing protective immunity rather than pathology was plasmacytoid Dendritic cells (pDCs). We revealed a potential protective role of pDCs in EAE possibly due to induced IFNbeta production. This is consistent with the current use of IFNbeta in MS therapy where IFNbeta reduces relapse frequency via unknown mechanisms. Our studies might prove helpful in further characterising the role of pDCs and IFNbeta in EAE and MS.
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| 4. |
- Lobell, Anna, et al.
(författare)
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Suppressive DNA vaccination in myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis involves a T1-biased immune response
- 2003
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 170:4, s. 1806-1813
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Vaccination with DNA encoding a myelin basic protein peptide suppresses Lewis rat experimental autoimmune encephalomyelitis (EAE) induced with the same peptide. Additional myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG), may be important in multiple sclerosis. Here we demonstrate that DNA vaccination also suppresses MOG peptide-induced EAE. MOG(91-108) is encephalitogenic in DA rats and MHC-congenic LEW.1AV1 (RT1(av1)) and LEW.1N (RT1(n)) rats. We examined the effects of DNA vaccines encoding MOG(91-108) in tandem, with or without targeting of the hybrid gene product to IgG. In all investigated rat strains DNA vaccination suppressed clinical signs of EAE. There was no requirement for targeting the gene product to IgG, but T1-promoting CpG DNA motifs in the plasmid backbone of the construct were necessary for efficient DNA vaccination, similar to the case in DNA vaccination in myelin basic protein-induced EAE. We failed to detect any effects on ex vivo MOG-peptide-induced IFN-gamma, TNF-alpha, IL-6, IL-4, IL-10, and brain-derived neurotropic factor expression in splenocytes or CNS-derived lymphocytes. In CNS-derived lymphocytes, Fas ligand expression was down-regulated in DNA-vaccinated rats compared with controls. However, MOG-specific IgG2b responses were enhanced after DNA vaccination. The enhanced IgG2b responses together with the requirement for CpG DNA motifs in the vaccine suggest a protective mechanism involving induction of a T1-biased immune response.
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