Presented at:
21st Congress of the European Committee for Treatment and Research in Multiple Sclerosis and 10th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS), Thessaloniki, Greece, Sept 28 – Oct 1, 2005.
TCR peptide vaccination in MS induces high levels of IL-10 and restores decreased Foxp3 levels
Vandenbark A, Huan J, Bartholomew R, Offner H, Bourdette D
Oregon Health & Science University, Immune Response Corporation, Portland VA Medical Center (Portland, Carlsbad, USA)
Multiple sclerosis (MS) may result from the failure of tolerance mechanisms to limit the expansion of pathogenic T cells reacting against myelin antigens. These tolerance mechanisms include T cell receptor (TCR) specific T cells that induce enhanced IL-10 production, and CD4+CD25+ T regulatory cells (Treg) that express the FOXP3 gene. We sought to determine whether vaccination with a trivalent TCR peptide vaccine (NeuroVaxB) could boost frequencies of IL-10 secreting TCR-specific T cells, and increase FOXP3 expression and Treg suppression in MS patients. PBMC were isolated from healthy controls (HC) and relapsing and progressive MS patients prior to and 12 weeks after vaccination with NeuroVaxB for analysis of IL-10 levels in culture supernatants and FOXP3 expression in CD4+CD25+ T cells.
Pre-vaccination, we found 1) background frequencies of TCR-reactive T cells that secreted low levels of IL-10; 2) that FOXP3 levels in CD4+CD25+ T cells were correlated with suppressive activity; and 3) that FOXP3 mRNA levels were decreased in MS subjects (n=19) vs. HC donors (n=19)(p= 0.02). Following three monthly injections of NeuroVaxB, there was a striking increase in the frequency of TCR- reactive T cells in PBMC that produced high levels of the anti-inflammatory cytokine IL-10, as well as normalized expression of FOXP3 in CD4+CD25+ T cells. These results demonstrate that NeuroVaxC3 can boost TCR-reactive T cells which mediate immunosuppression of target and bystander T cells through two distinct regulatory pathways.