title: Therapeutic vaccination with a trivalent T-cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis.
abstract: Therapeutic vaccination using T-cell receptor (TCR) peptides from V genes commonly expressed by potentially pathogenic T cells remains an approach of interest for treatment of multiple sclerosis (MS) and other autoimmune diseases. We developed a trivalent TCR vaccine containing complementarity determining region (CDR) 2 peptides from BV5S2, BV6S5 and BV13S1 emulsified in incomplete Freund's adjuvant that reliably induced high frequencies of TCR-specific T cells. To evaluate induction of regulatory T-cell subtypes, immunological and clinical parameters were followed in 23 treatment-naïve subjects with relapsing-remitting or progressive MS who received 12 monthly injections of the trivalent peptide vaccine over 1 year in an open-label study design. Prior to vaccination, subjects had reduced expression of forkhead box (Fox) P3 message and protein, and reduced recognition of the expressed TCR repertoire by TCR-reactive cells compared with healthy control donors. After three or four injections, most vaccinated MS subjects developed high frequencies of circulating interleukin (IL)-10-secreting T cells specific for the injected TCR peptides and significantly enhanced expression of FoxP3 by regulatory T cells present in both 'native' CD4+ CD25+ and 'inducible' CD4+ CD25- peripheral blood mononuclear cells (PBMC). At the end of the trial, PBMC from vaccinated MS subjects retained or further increased FoxP3 expression levels, exhibited significantly enhanced recognition of the TCR V gene repertoire apparently generated by perturbation of the TCR network, and significantly suppressed neuroantigen but not recall antigen responses. These findings demonstrate that therapeutic vaccination using only three commonly expressed BV gene determinants can induce an expanded immunoregulatory network in vivo that may optimally control complex autoreactive responses that characterize the inflammatory phase of MS.
authors.affiliation: Neuroimmunology Laboratory, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA. vandenba@ohsu.edu
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Culbertson
authors.forename: Richard M
authors.initials: RM
authors.lastname: Bartholomew
authors.forename: Jianya
authors.initials: J
authors.lastname: Huan
authors.forename: Marci
authors.initials: M
authors.lastname: Agotsch
authors.forename: Dorian
authors.initials: D
authors.lastname: LaTocha
authors.forename: Vijayshree
authors.initials: V
authors.lastname: Yadav
authors.forename: Michele
authors.initials: M
authors.lastname: Mass
authors.forename: Ruth
authors.initials: R
authors.lastname: Whitham
authors.forename: Jesus
authors.initials: J
authors.lastname: Lovera
authors.forename: June
authors.initials: J
authors.lastname: Milano
authors.forename: Georgia
authors.initials: G
authors.lastname: Theofan
authors.forename: Yuan K
authors.initials: YK
authors.lastname: Chou
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
authors.forename: Dennis N
authors.initials: DN
authors.lastname: Bourdette
mesh_terms: D000328:Adult; D000368:Aged; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D022801:Complementarity Determining Regions / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000097:blood*; D019672:Genes, T-Cell Receptor / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007156:Immunologic Memory; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000628:therapy*; D009419:Nerve Tissue Proteins / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014611:Vaccination / Q000379:methods; D022223:Vaccines, Subunit / Q000627:therapeutic use*
chemical_list: D001324:Autoantigens; D022801:Complementarity Determining Regions; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D011948:Receptors, Antigen, T-Cell; D022223:Vaccines, Subunit