ADDITIVE EFFECTS OF COPOLYMER-1 AND INTERFERON BETA-1B ON THE IMMUNE-RESPONSE TO MYELIN BASIC-PROTEIN

Copolymer-1 (Cop-1) inhibits the T cell response to myelin basic protein (MBP), suppresses experimental autoimmune encephalomyelitis in many animal species, and was recently shown to be effective in the treatment of multiple sclerosis (MS). Interferon beta-1b (IFN-beta), an immune modulator with no antigenic specificity, is already approved for treatment of relapsing-remitting MS. We investigated the combined effect of these two agents on the cellular immune response to MBP. Antigen-specific Th1-like cell lines were generated from two healthy individuals with different MHC phenotypes. Cop-1 inhibited the proliferation of all MBP-specific lines but had no suppressive effect on tuberculin (PPD) or tetanus toroid (TT)-specific T cell lines from either donor, while IFN-beta non-specifically reduced proliferation of all T cell lines. When combined in vitro, Cop-1 and IFN-beta had additive suppressive effects on proliferation of MBP-specific T cell lines, with 70-100% inhibition depending on the concentration of antigen. Synthesis of the pro-inflammatory cytokines interleukin-2 and IFN-gamma by MBP-specific lines was also inhibited additively (up to 100%). When antigen-presenting cells (APC) were pretreated with Cop-1, IFN-beta or both, T cell proliferation was inhibited in the same additive pattern, even though the inhibitors were not present in culture, indicating that they acted primarily through modulation of APC function. Additive effects were not found with PPD- or TT-specific cell lines. Pretreatment of APC with IFN-beta resulted in dose-dependent reduction in HLA-DR and HLA-DQ expression, which paralleled inhibition of T cell proliferation. Pretreatment of APC with Cop-1 had no effect on MHC class II expression. Reductions in proliferation and MHC class II expression were not the result of toxicity, as viability of T cell lines and APC was not altered by exposure to Cop-1 or IFN-beta. These results suggest that inhibition of proliferation and pro-inflammatory cytokine production by MBP-specific T cell lines may be mediated through complementary effects on antigen presentation, with IFN-beta down-regulating the expression of MHC class II molecules on APC, and Cop-1 competing with MBP for antigen binding sites on the remaining MHC molecules.