Therapeutic vaccination with a trivalent T‐cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis

Abstract

Summary 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.

Critical evaluation of regulatory T cells in autoimmunity: are the most potent regulatory specificities being ignored?

“…Blood samples were collected from the subjects before vaccination and at weeks 8/9, 12, 24 and 48 of the trial and cultured as described in ref. 59. Data are presented as mean frequency ± SD for subjects with MS at entry, the maximum post-vaccination response, and at exit from the trial.…”

T cell receptors in an IL-10-secreting amino acid copolymer-specific regulatory T cell line that mediates bystander immunosuppression

“…No sequences have been reported for TCR derived from Tr1 or Th3 Treg. However, regulatory T cells derived by vaccination with DNA encoding a V␤ peptide from an autoimmune TCR or by immunization with V␤ peptides secrete IL-10 and IL-4 and are likely to belong to this category (16,21,22). In the 1 case studied in detail, B10.PL mice (H-2 u ) were immunized with a peptide (B5) from the framework region of a V␤8.2 TCR found in mice with induced EAE (18), the polyclonal Treg obtained were predominantly V␤14.…”

“…In parallel work, TCR blocking antibodies were also shown to be useful in therapy (19,20). Moreover, immunization with peptides derived from TCR V␤ segments may induce T cells that secrete a large amount of IL-10 in addition to IL-4 (16,21,22). Thus, the mechanisms by which immunization with TCR peptide and that in which blocking antibody ameliorate disease are distinct.…”

Postulated vasoactive neuropeptide immunopathology affecting the blood–brain/blood–spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment?

“…For example, Crohn's disease (CD) and MS are infl ammatory disorders with known Th1-directed cytokines and loss of Foxp3 Treg function. 33,34 In one study in MS patients Treg numbers were unchanged but their function may have been diminished. 92 As VRS have important roles in controlling macrophage and perivascular infi ltrates in MS, 35 of considerable interest.…”