Additive effects of copolymer-1 and interferon β-1b on the immune response to myelin basic protein

doi:10.1016/0165-5728(95)00085-G

Journal of Neuroimmunology

Volume 61, Issue 2, September 1995, Pages 185-193

https://doi.org/10.1016/0165-5728(95)00085-G Get rights and content

Abstract

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-β), 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 toxoid (TT)-specific T cell lines from either donor, while IFN-β non-specifically reduced proliferation of all T cell lines. When combined in vitro, Cop-1 and IFN-β 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-γ by MBP-specific lines was also inhibited additively (up to 100%). When antigen-presenting cells (APC) were pretreated with Cop-1, IFN-β 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-β 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-β. 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-β 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.

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¹: Present address: Department of Neurology, Assaf Harofeh Medical Center, Zerifin 70300, Israel.

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Research paperAdditive effects of copolymer-1 and interferon β-1b on the immune response to myelin basic protein

Abstract

J. Neuroimmunol.

Lancet

J. Neuroimmunol.

J. Neuroimmunol.

J. Neuroimmunol.

Lancet

J. Neuroimmunol.

Neurol. Clin.

Immunol. Today

T suppressor hybridomas and interleukin-2-dependent lines induced by copolymer-1 or spinal cord homogenate downregulate experimental allergic encephalomyelitis

Eur. J. Immunol.

T cells responsive to myelin basic protein in patients with multiple sclerosis

Science

Suppression of demyelinating disease by synthetic copolymers

A pilot trial of Cop 1 in exacerbating—remitting multiple sclerosis

N. Engl. J. Med.

Interferongamma regulates an antigen specific for endothelial cells involved in lymphocyte traffic

Direct binding of myelin basic protein and synthetic copolymer I to class II major histocompatibility complex molecules on living antigen presenting cells: specificity and promiscuity

Results of a phase III trial of intramuscular recombinant beta interferon as treatment for multiple sclerosis

Ann. Neurol.

Copolymer 1 (Cop I) reduces the relapse rate and progression of disability in relapsing-remitting multiple sclerosis: results of a phase III multi-center, double-blind, placebo-controlled trial

Neurology

Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals

J. Immunol.

Research paper
Additive effects of copolymer-1 and interferon β-1b on the immune response to myelin basic protein