T cell vaccination in multiple sclerosis patients with autologous CSF-derived activated T cells: results from a pilot study

Abstract

SUMMARYMyelin-reactive T cells are considered to play an essential role in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. We have previously studied the effects of T cell vaccination (TCV), a procedure by which MS patients are immunized with attenuated autologous myelin basic protein (MBP)-reactive T cell clones. Because several myelin antigens are described as potential autoantigens for MS, T cell vaccines incorporating a broad panel of antimyelin reactivities may have therapeutic effects. Previous reports have shown an accumulation of activated T cells recognizing multiple myelin antigens in the cerebrospinal fluid (CSF) of MS patients. We conducted a pilot clinical trial of TCV with activated CD4 + T cells derived from CSF in five MS patients (four RR, one CP) to study safety, feasibility and immune effects of TCV. CSF lymphocytes were cultured in the presence of rIL-2 and depleted for CD8 cells. After 5-8 weeks CSF T cell lines (TCL) were almost pure TCR ab + CD4 + cells of the Th1/Th0 type. The TCL showed reactivity to MBP, MOG and/or PLP as tested by Elispot and had a restricted clonality. Three immunizations with irradiated CSF vaccines (10 million cells) were administered with an interval of 2 months. The vaccinations were tolerated well and no toxicity or adverse effects were reported. The data from this small open-label study cannot be used to support efficacy. However, all patients remained clinically stable or had reduced EDSS with no relapses during or after the treatment. Proliferative responses against the CSF vaccine were observed in 3/5 patients. Anti-ergotypic responses were observed in all patients. Anti-MBP/PLP/MOG reactivities remained low or were reduced in all patients. Based on these encouraging results, we recently initiated a double-blind placebo-controlled trial with 60 MS patients to study the effects of TCV with CSFderived vaccines in early RR MS patients.

T-cell vaccination leads to suppression of intrapancreatic Th17 cells through Stat3-mediated RORγt inhibition in autoimmune diabetes

“…Third, the anti-IL-17 antibody treatment of sub-STZ-treated animals that received the adoptive transfer of 10 × 10 6 Th17-polarized cells decreased the blood glucose level, showing that the suppression of IL-17 protects against the progression of autoimmune diabetes induced by STZ. Previous study showed that TCV exerts immunomodulatory effect through the induction of both anti-idiotypic response, which was specific to the immunizing cells and anti-ergotypic T cells more toward activated T cells in other autoimmune diseases [46][47][48][49]. It is not unlikely that suppression of Th17 cells is the result of TCV-induced anti-ergotypic effect because Th17 cells are an activated T-cell subset.…”

CD4+regulatory T cell responses induced by T cell vaccination in patients with multiple sclerosis

“…The mechanism of this CD8 ϩ antiidiotypic T cell regulation is relatively well characterized and is found to involve components of target T cell receptor in the context of MHC class I molecules (3)(4)(5)(6). However, it remains to be determined whether depletion of circulating autoreactive T cells alone would be sufficient to induce or account for clinical improvements seen in some of MS patients treated with T cell vaccination (3,5,15,(20)(21)(22)(23). In this regard, it is insightful that Cohen and colleagues (7,12) and other investigators showed in experimental autoimmune encephalomyelitis experiments that only activated, but not resting, encephalitogenic T cells could induce full protection through T cell vaccination.…”

Autoimmune concepts of multiple sclerosis as a basis for selective immunotherapy: From pipe dreams to (therapeutic) pipelines

“…Similarly, the results of a pilot vaccination trial with cerebrospinal fluidderived activated T cells seem promising but need to be confirmed in a larger trial (123).…”