Glatiramer acetate‐specific T‐helper 1‐ and 2‐type cell lines produce BDNF: implications for multiple sclerosis therapy

• Published in: Brain (London, England : 1878) Vol. 125; no. 11; pp. 2381 - 2391
• Main Authors: Ziemssen, Tjalf, Kümpfel, Tania, Klinkert, Wolfgang E. F., Neuhaus, Oliver, Hohlfeld, Reinhard
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2002; Oxford Publishing Limited (England)
• Subjects: altered peptide ligand (APL); APC = antigen presenting cell; APL = altered peptide ligand; BDNF = brain‐derived neurotrophic factor; Biological and medical sciences; ELISA = enzyme‐linked immunosorbent assay; FACS = fluorescence‐activated cell sorter; FITC = fluorescein isothiocyanate; GA = glatiramer acetate; glatiramer acetate; IL = interleukin; Immunomodulators; immunotherapy; MBP = myelin basic protein; Medical sciences; multiple sclerosis; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; neuroprotection; PBMC = peripheral blood mononuclear cell; Pharmacology. Drug treatments; PMA = phorbol 12‐myristate 13‐acetate; RT‐PCR = reverse transcription‐polymerase cell reaction; TCL = T‐cell line; TCR = T‐cell receptor; TH1 = T‐helper 1; TH2 = T‐helper 2; trk = tyrosine‐receptor kinase; Human; Nervous system diseases; Multiple sclerosis; Th1 lymphocyte; Reverse transcription; Neuroprotective agent; glatiramer acetate; Inflammatory disease; Polymerase chain reaction; Chemotherapy; Treatment; Immunotherapy; neuroprotection; Central nervous system disease; Th2 lymphocyte; altered peptide ligand (APL); Brain derived neurotrophic factor; Molecular biology; Mechanism of action
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awf252

The clinical effects of glatiramer acetate (GA), an approved therapy for multiple sclerosis, are thought to be largely mediated by a T‐helper 1 (TH1) to T‐helper 2 (TH2) shift of GA‐reactive T‐lymphocytes. Current theories propose that activated GA‐reactive TH2 cells penetrate the CNS, release anti‐inflammatory cytokines such as interleukin (IL)‐4, IL‐5 and IL‐10, and thus inhibit neighbouring inflammatory cells by a mechanism termed ‘bystander suppression’. We demonstrate that both GA‐specific TH2 and TH1 cells produce the neurotrophin brain‐derived neurotrophic factor (BDNF). As the signal‐transducing receptor for BDNF, the full‐length 145 tyrosine kinase receptor (trk) B, is expressed in multiple sclerosis lesions, it is likely that the BDNF secreted by GA‐reactive TH2 and TH1 has neurotrophic effects in the multiple sclerosis target tissue. This may be an additional mechanism of action of GA, and may be relevant for therapies with altered peptide ligands in general. To demonstrate that GA‐reactive T cells produce BDNF, we selected four GA‐specific, long‐term T‐cell lines (TCLs), which were characterized according to their cytokine profile by intracellular double‐fluorescence flow cytometry. Three TCLs (isolated from a normal subject) had the phenotypes TH1, TH1/TH0, and TH0; the fourth, derived from a GA‐treated patient, had the phenotype TH2. To demonstrate BDNF production, we used a combination of RT‐PCR (reverse transcription‐polymerase chain reaction) and two specially designed techniques for BDNF protein detection: one was based on ELISA (enzyme‐linked immunosorbent assay) 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 four GA‐specific T‐cell lines, representing the major different TH phenotypes, could be stimulated to produce BDNF.