Suppressive DNA Vaccination in Myelin Oligodendrocyte Glycoprotein Peptide-Induced Experimental Autoimmune Encephalomyelitis Involves a T1-Biased Immune Response

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. MOG91–108 is encephalitogenic in DA rats and MHC-congenic LEW.1AV1 (RT1av1) and LEW.1N (RT1n) rats. We examined the effects of DNA vaccines encoding MOG91–108 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-γ, TNF-α, 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.

Gene therapy in autoimmune, demyelinating disease of the central nervous system

“…Gene therapy has not yet been attempted in MS, but there have been a number of studies in EAE that have invariably shown some level of efficacy at inhibiting the disease (Table 1), although in many cases this has only been an amelioration rather than elimination of disease. As the majority of the CNS is postmitotic, this puts constraints on the nature of the vector that can be used, and to date administration of plasmid DNA, [32][33][34][35][36][37][38][39][40][41] viral infection, [42][43][44][45][46][47][48][49][50][51][52][53] and retrovirally transduced cell (RVC)-carriers 47,[54][55][56][57][58][59][60][61][62][63] have been investigated in EAE (Table 1). These have largely focused on inhibition of the immune response either applied centrally to target the local pathological events within the CNS or peripherally administered to inhibit: initial sensitization, the activities of circulating cells or perivascular events in areas of local BBB breakdown.…”

“…In addition, some studies have attempted to promote repair or inhibition of the demyelination process. 40,44,49,57,61 Cytokines are dynamically expressed as lesions evolve and resolve [12][13][14][15][16] and are of major importance in the development and control of autoimmunity. 12 Many studies in EAE focus on the use of knockout mice.…”

“…Injection of plasmid DNA exhibits poor transduction efficiencies and when used successfully, this has used multiple injections often in regenerating (muscle) tissue. 32,33,[35][36][37][38][39][40] The regulatory sequences of plasmid DNA is important for efficacy 40 and these (eg CG repeats) can modulate cytokine production in vivo and can either suppress or worsen EAE, probably because of a secondary effect on sensitization. 69,70 As an alternative approach to achieving local CNS delivery, the migratory potential of primed T lymphocytes has been harnessed and thus allows for systemic delivery.…”

“…89 A number of approaches aimed at preventing the generation of encephalitogenic T cells have been assessed (Table 1). 32,[36][37][38]40,62,63 In some EAE models such as the PL/J mouse and Lewis rat, the disease is caused by activity of cells with very limited T-cell receptor (Tcr) subtype heterogeneity. Here, the majority of encephalitogenic cells express TcrVb8 90 and prophylactic, systemic DNA vaccination against this Tcr subtype has induced EAE amelioration.…”

“…[36][37][38]62,63 This approach should offer the most specific form of therapy and thus limit potential side effects. This has been shown to be active in disease, either as a secreted fusion protein 62,63 or DNA vaccination, [36][37][38]40 induced with all of the three major encephalitogenic myelin proteins (Table 1). In EAE it is clear that different strains respond to different peptide epitopes because of the restrictions imposed by the MHC haplotype(s) expressed, and the pathogenic T-cell repertoire expands with disease progression.…”