Presented at:
19th National Congress of the Polish Neurological Society, Lodz, Poland, Aug 31–Sept 3, 2005.
Decreased Foxp3 levels in MS patients are normalized by TCR peptide vaccination
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 CD4+C1>25+ T regulatory cells (Treg) that express the FOXP3 gene. Previous studies demonstrating abnormalities of Treg cell activity in MS using functional assays have given conflicting results.
Objectives: To determine whether expression of FOXP3, a gene associated with CD4+CD25+ Treg cells, is decreased in MS patients, and if so, whether administration of a T cell receptor (TCR) peptide vaccine can increase FOXP3 expression.
Methods: CD4+CD25 + T cells were isolated from PBMC of MS subjects prior to and 12 weeks after vaccination with a trivalent TCR peptide vaccine (NeuroVaxm), and from healthy controls (HC). Levels of FOXP3 message and protein were quantified by real time polymerase chain reaction and Western blotting, respectively.
Results: FOXP3 mRNA levels in C114+CD25+ T cells were decreased among MS subjects (n= 19) compared with HC (n=19) (p=0.02). FOXP3 protein was also significantly diminished in CD4+CI)25+ T cells in a subset of MS subjects compared with HC. Following administration of the TCR peptidc vaccine, FOXP3 levels in CD4+CD25+ T cells from MS patients increased to levels comparable with those in HC.
Conclusions: This is the first demonstration that FOXP3 expression is decreased in MS patients compared with HC, suggesting impaired immunoregulation by Treg cells. Importantly, a trivalent TCK peptide vaccine appears capable of boosting E'OXP3 expression, thus potentially representing a novel therapeutic treatment to enhance Treg activity in MS.