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

Copolymer 1 (COP), a standardized mixture of synthetic polypeptides consist ing of L-glutamic acid, L-lysine, L-alanine, and I-tyrosine. has beneficial effects in multiple sclerosis and experimental autoimmune encephalomyeliti s. We selected a panel of 721 COP-reactive T cell lines CTCL) from the bloo d of COP-treated and untreated multiple sclerosis patients and from healthy donors by using the split-well cloning technique. All TCL selected with CO P proliferated in response to COP but not to myelin basic: protein (MBP), C onversely, 31 control TCL selected with MBP proliferated in response to MBP but not to COP. We used intracellular double-immunofluorescence flow cytom etry for quantitative analysis of cytokine production (IL-4. lFN-gamma) by the TCL, The majority of the COP-reactive TCL from untreated multiple scler osis patients and normal donors predominantly produced IFN-gamma and, accor dingly, were classified as T helper 1 cells (TH1). In contrast, the majorit y 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 t he cytokine profile of COP-reactive TCL tends to shift from TH1 to TH2 duri ng treatment. Interestingly, although there was no proliferative cross-reac tion, about 10% of the COP-reactive TCL responded to MBP by secretion of sm all amounts of IL-4 or IFN-gamma depending on the cytokine profile of the T CL, These results are consistent with a protective effect of COP-reactive T H2 cells. It is hypothesized that these cells are activated by COP in the p eriphery, migrate into the central nervous system, and produce immunomodula tory cytokines after local recognition of MBP.