A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis

The strong association of HLA-DR2b (DRB1*15:01) with multiple sclerosis (MS) suggests this molecule as prime target for specific immunotherapy. Inhibition of HLA-DR2b-restricted myelin-specific T cells has the potential to selectively prevent CNS pathology mediated by these MHC molecules without undesired global immunosuppression. Here we report development of a highly selective small molecule inhibitor of peptide binding and presentation by HLA-DR2b. PV-267, the candidate molecule used in these studies, inhibited cytokine production and proliferation of myelin-specific HLA-DR2b-restricted T cells. PV-267 had no significant effect on T cell responses mediated by other MHC class II molecules including HLA-DR1, -DR4, or -DR9. Importantly, PV-267 did not induce nonspecific immune activation of human PBMC. Lastly, PV-267 showed treatment efficacy both in preventing experimental autoimmune encephalomyelitis (EAE) and in treating established disease. The results suggest that blocking the MS-associated HLA-DR2b allele with small molecule inhibitors may be a promising therapeutic strategy for the treatment of MS.

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“…(8,12,13). Most of these approaches have shown activity in preclinical animal models but were of limited efficacy in clinical trials (8,15,38).…”

Section: Discussionmentioning

confidence: 99%

Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic Strategy for the Treatment of Multiple Sclerosis

Somanaboeina

Dixit

et al. 2013

The Journal of Immunology

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“…Second, as regards the therapeutic implications, it is especially noteworthy that the T-cell response seems to be strictly "private" to each patient. This re-emphasizes the need for "individualized" approaches as far as selective, TCR-directed therapies, such as T-cell and TCR vaccination, are concerned [23][24][25]. Furthermore, intraindividual diversity implies that it would be necessary to simultaneously target multiple TCRs.…”

Section: Introductionmentioning

confidence: 94%

B- and T-cell responses in multiple sclerosis: Novel approaches offer new insights

Hohlfeld¹,

Meinl²,

Dornmair³

2008

Journal of the Neurological Sciences

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“…It has been hypothesised that the methylated Arg residue disrupts the three-dimensional structure of the protein, so that other arginyl residues are less accessible to PAD. 60,61 Treatment of SJL mice either before or after challenge with palmitoylated PLP(139-151), Pam-PLP (139-151), completely suppressed or considerably reduced both acute and relapsing stages of EAE induced with PLP (139)(140)(141)(142)(143)(144)(145)(146)(147)(148)(149)(150)(151). In the presence of Pertussis toxin, treatment with Pam-PLP(139-151) was less effective, but treatment with a mixture of Pam-PLP(139-151) and Pam-PLP(178-191) resulted in almost complete protection.…”

Section: Post-translational Modifications In Peptide Antigens and Msmentioning

confidence: 99%

“…The data demonstrate the markedly enhanced immunogenicity of the TCR tripeptide vaccine administered in IFA for inducing TCR-specific T cells. 143 …”

Section: Toward Peptide Antigen-specific Therapies For Ms Treatmentmentioning

confidence: 99%

Contribution of peptides to multiple sclerosis research

Alcaro

Papini

2006

Biopolymers

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Multiple sclerosis (MS) is an autoimmune disease associated with chronic inflammatory demyelination of the central nervous system in genetically susceptible individuals. Because of the disease complexity and heterogeneity, its pathogenesis remains unknown despite extensive research efforts, and specific effective treatments have not yet been developed. Peptide-based research has been important in attempts to unravel particular aspects of this complex disease, including the characterization of the different molecular mechanisms of MS, with the goal of providing useful products for immune-mediated therapies. In fact, in the past decade, peptide-based research has been predominant in research aimed to identify and/or develop target antigens as synthetic probes for specific biomarkers as well as innovative immunomodulating therapies. This review presents an overview of the contributions of peptide science to MS research and discusses future directions of peptide-based investigations.

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A highly immunogenic trivalent T cell receptor peptide vaccine for multiple sclerosis

Abstract: The trivalent TCR peptide in IFA vaccine represents a significant improvement in immunogenicity over previous TCR peptide vaccines and warrants investigation of its ability to treat MS.

Cited by 68 publications

References 49 publications

Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic Strategy for the Treatment of Multiple Sclerosis

Small Molecule Inhibitor of Antigen Binding and Presentation by HLA-DR2b as a Therapeutic Strategy for the Treatment of Multiple Sclerosis

B- and T-cell responses in multiple sclerosis: Novel approaches offer new insights

Contribution of peptides to multiple sclerosis research

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