Presented at:
5th Meeting of the European Neurological Society, Vienna, Austria, June 18 -22.
Expression of the Treg cell associated Foxp3 gene is decreased in MS patients and increases following immunization with a T cell receptor peptide vaccine
Offner H, Huan J, Bartholomew R, Bourdette D, and Vandenbark A
Oregon Health & Science University,Immune Response Corporation, Port- land VA Medical Center (Portland, Carlsbad, USA)
Background: Multiple sclerosis (MS) may result from the failure of toler- ance mechanisms that prevent expansion of pathogenic T cells that react against myelin antigens. These tolerance mechanisms include CD4+CD25+ Treg cells, which express the FOXP3 gene. Previous studies attempting to demonstrate abnormalities of Treg cell activity in MS using functional assays have given conflicting results.
Objective: To determine whether expression of FOXP3, a gene associ- ated with CD4+CD25+ Treg cells, is decreased in MS patients and whether administration of a T cell receptor (TCR) peptide vaccine can increase FOXP3 expression. Methods: CD4+CD25+ cells were isolated from peripheral blood mononuclear cells from 19 MS subjects entering an open label trial of a trivalent TCR peptide vaccine (NeuroVax") and from 19 healthy controls. RNA isolated from the CD4+CD25+ cells was subjected to real time poly- merase chain reaction to quantitate FOXP3 mRNA expression. Western blot analysis was also performed on a subset of these subjects to detect FOXP3 protein expression. FOXP3 mRNA in CD4+CD25+ cells from MS subjects also was determined 12 weeks after initiating immunisation with the trivalent TCR peptide vaccine.
Results: FOXP3 mRNA in CD4+CD25+ cells was decreased among MS subjects (n = 19) compared with healthy controls (n = 19) (p = 0.02). FOXP3 protein in CD4+CD25+ cells was also significantly diminished in MS sub- jects compared with healthy controls. Following administration of the trivalent TCR peptide vaccine, FOXP3 mRNA in CD4+CD25+ cells in- creased to levels comparable to that of healthy controls.
Conclusion: This is the first demonstration that FOXP3 expression is decreased in MS patients compared with healthy controls, suggesting im- paired immunoregulation by Treg cells. Importantly, a trivalent TCR pep- tide vaccine appears capable of boosting FOXP3 expression and this may represent a novel treatment that can enhance Treg activity in MS.