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Systemic high-dose recombinant-alpha-2a-interferon therapy modulates lymphokine production in multiple sclerosis
M R Bongioanni1, L Durelli, B Ferrero
1Clinica delle Malattie del Sistema Nervoso, Torino, Italy.
Journal of the Neurological Sciences
|November 1, 1996
Summary
High-dose recombinant alpha 2a-interferon (rIFNA) therapy for relapsing/remitting multiple sclerosis (RR MS) reduces disease activity by decreasing pro-inflammatory cytokines. These immunologic effects are temporary, lasting only during treatment.
Area of Science:
- Immunology
- Neuroimmunology
- Pharmacology
Background:
- Relapsing/remitting multiple sclerosis (RR MS) is characterized by exacerbations and MRI-defined disease activity.
- Recombinant alpha 2a-interferon (rIFNA) has shown clinical efficacy in reducing MS exacerbations.
- The precise immunologic mechanisms underlying rIFNA's efficacy in MS require clarification.
Purpose of the Study:
- To investigate the immunologic mechanisms of high-dose rIFNA therapy in RR MS patients.
- To assess the impact of rIFNA on cytokine production, immune cell phenotype, and immunoglobulin levels.
- To determine the duration and reversibility of rIFNA's immunologic effects.
Main Methods:
- A pilot clinical trial involving 20 RR MS patients treated with rIFNA or placebo for 6 months.
- Analysis of cytokine production (interferon-gamma, TNF-alpha, TGF-beta2, IL-10) from cultured lymphocytes.
- Assessment of major histocompatibility complex class II (MHC-II) expression on macrophages.
- Evaluation of peripheral blood (PB) and cerebrospinal fluid (CSF) lymphocyte phenotypes.
- Measurement of IgG and beta 2 microglobulin levels.
- Immunologic parameters were assessed pre-therapy, post-therapy, and 6 months after cessation.
Main Results:
- rIFNA therapy significantly reduced interferon-gamma and tumor necrosis factor-alpha production by PB lymphocytes.
- No significant changes were observed in macrophage MHC-II expression or IL-4 production.
- Increased percentages of specific T-cell subsets (CD8+, CD8+ high CD11b+ low) and CD4+ cells were noted in CSF.
- Significant increases in both systemic and intrathecal IgG levels and serum beta 2 microglobulin were observed.
- Immunologic changes reverted to baseline 6 months after therapy discontinuation.
- Only one patient developed neutralizing antibodies against rIFNA.
Conclusions:
- The beneficial effects of high-dose rIFNA in RR MS are likely mediated by downregulating pro-inflammatory cytokine synthesis in PB lymphocytes.
- Macrophage MHC-II antigen expression does not appear to be a primary mechanism of rIFNA's action.
- The immunomodulatory effects of rIFNA are temporary and confined to the treatment period.