Secretion of brain-derived neurotrophic factor by glatiramer acetate-reactive T-helper cell lines: Implications for multiple sclerosis therapy

Abstract

Treatment with glatiramer acetate (GA) is thought to induce an in vivo change of the cytokine secretion pattern and the effector function of GA-reactive T helper (TH) cells (TH1-TH2-shift). Current theories propose that GA-reactive TH2 cells can penetrate the CNS, since they are activated by daily immunization. Inside the CNS, GA-reactive T cells may cross-react with products of the local myelin turnover presented by local antigen-presenting cells (APCs). Thus, some of the GA-specific TH2 cells may be stimulated to release anti-inflammatory cytokines inhibiting neighbouring inflammatory cells by a mechanism called bystander suppression. We demonstrate that both GA-specific TH2 and TH1 cells produce the neurotrophin brain-derived neurotrophic factor (BDNF). To demonstrate that GA-reactive T cells produce BDNF, we analyzed GA-specific, long-term T-cell lines (TCLs) and used a combination of reverse-transcription PCR and two specially designed techniques for BDNF protein detection: one was based on ELISA of supernatants from co-cultures of GA-specific TCLs plus GA-pulsed antigen-presenting cells, and the other, on the direct intracellular staining of BDNF in individual T cells and flow-cytometric analysis. The different assays and different TCLs yielded similar, consistent results. All GA-specific TH1, TH2 and TH0 lines could be stimulated to produce BDNF.