Multiple Sclerosis: Comparison of Copolymer-1-Reactive T Cell Lines from Treated and Untreated Subjects Reveals Cytokine Shift from T Helper 1 to T Helper 2 Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 13; pp. 7452 - 7457
• Main Authors: Neuhaus, Oliver, Farina, Cinthia, Yassouridis, Alexander, Wiendl, Heinz, Bergh, Florian Then, Dose, Tatjana, Wekerle, Hartmut, Hohlfeld, Reinhard
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 20.06.2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Adolescent; Adult; Antigens; Biological Sciences; Cell Differentiation - immunology; Cell lines; Cells; Cloning; copolymer 1; Cryptogenic organizing pneumonia; Cytokines; Cytokines - immunology; Cytometry; Female; Glatiramer Acetate; Humans; Male; Middle Aged; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Neurology; Peptides; Peptides - immunology; Peptides - therapeutic use; Polymers; Secretion; T cell antigen receptors; T lymphocytes; Th1 Cells - immunology; Th2 Cells - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.97.13.7452

Copolymer 1 (COP), a standardized mixture of synthetic polypeptides consisting of L-glutamic acid, L-lysine, L-alanine, and L-tyrosine, has beneficial effects in multiple sclerosis and experimental autoimmune encephalomyelitis. We selected a panel of 721 COP-reactive T cell lines (TCL) from the blood of COP-treated and untreated multiple sclerosis patients and from healthy donors by using the split-well cloning technique. All TCL selected with COP proliferated in response to COP but not to myelin basic protein (MBP). Conversely, 31 control TCL selected with MBP proliferated in response to MBP but not to COP. We used intracellular double-immunofluorescence flow cytometry for quantitative analysis of cytokine production (IL-4, IFN-γ ) by the TCL. The majority of the COP-reactive TCL from untreated multiple sclerosis patients and normal donors predominantly produced IFN-γ and, accordingly, were classified as T helper 1 cells (TH1). In contrast, the majority of the COP-reactive TCL from COP-treated patients predominantly (but not exclusively) produced IL-4--i.e., were TH2 (P < 0.05 as assessed by using a suitable preference intensity index). Longitudinal analyses revealed that the cytokine profile of COP-reactive TCL tends to shift from TH1 to TH2 during treatment. Interestingly, although there was no proliferative cross-reaction, about 10% of the COP-reactive TCL responded to MBP by secretion of small amounts of IL-4 or IFN-γ , depending on the cytokine profile of the TCL. These results are consistent with a protective effect of COP-reactive TH2 cells. It is hypothesized that these cells are activated by COP in the periphery, migrate into the central nervous system, and produce immunomodulatory cytokines after local recognition of MBP.