Elsevier

Journal of Hepatology

Volume 30, Issue 3, March 1999, Pages 376-382
Journal of Hepatology

Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile

https://doi.org/10.1016/S0168-8278(99)80093-2Get rights and content

Abstract

Background/Aims: The therapeutic benefit of ribavirin, a nucleoside analog, in the treatment of chronic HCV infection is seen even in the absence of any apparent direct antiviral effect. We surmised that ribavirin may act by eliciting altered virus-specific immune responses. Because antiviral immunity is predominantly mediated by cytotoxic T cells and antiviral cytokines, we sought to determine whether ribavirin could promote antiviral (Type 1) cytokine expression in human T cells.

Methods: Isolated human T cells were activated in vitro with enterotoxin B or with phorbol ester plus ionomycin. Cytokine ELISAs were performed on culture supernatants, cytokine mRNA was detected following RT-polymerase chain reaction of T cell RNA, and T cell proliferation measured using MTT assay.

Results: Ribavirin enhanced a Type 1 (IL-2, IFNγ, TNFα) while suppressing a Type 2 cytokine response (IL-4, IL-5 and IL-10), at the level of both protein and mRNA expression. Ribavirin mediated comparable effects on cytokine expression both following activation of specific T cell subpopulations with superantigen and following activation of a larger percentage of T cells via pharmacologic means. The in vitro effect on cytokine expression following ribavirin treatment was comparable in both CD4+ or CD8+ T cell subsets and was observed in a dose range that promoted T cell proliferation.

Conclusions: These data support the view that ribavirin promotes a Type 1 cytokine-mediated immune response, a property which may account in part for its ability to enhance the antiviral activity of interferonalpha in the treatment of chronic HCV infection.

Section snippets

Preparation of human T-cells and activation in vitro

Peripheral blood mononuclear cells were isolated from healthy donors by density gradient centrifugation followed by T cell enrichment using Lymphokwik (One Lambda, Canoga Park CA, USA). Contaminating monocytes were removed by adherence to plastic. Purified T cells were >99% CD2+, <1% HLA-DR+ and <5% CD25+ and were maintained in RPMI-AP5 (RPMI-1640 medium containing 20 mM HEP-ES buffer, pH 7.4, 5% autologous plasma, 1% L-glutamine, 1% penicillin/streptomycin and 0.05% 2-mercaptoethanol). For

Ribavirin enhances Type 1 but suppresses Type 2 cytokine secretion by isolated human T cells stimulated with phorbol ester plus ionomycin

Previous data have shown that ribavirin has antiviral activity in vivo and can suppress a T helper cell-dependent, Ab-mediated response. We speculated that these effects may be related to ribavirin-mediated induction of a distinct Type 1/Type 2 cytokine pattern in activated T cells. Therefore we investigated the influence of ribavirin at 5 μM or 10μM on the cytokine pattern in isolated human T cells from 12 donors following polyclonal activation with 10 ng PMA plus 0.5 μg ionomycin (PMA-ION).

Discussion

The results we report here show that the nucleoside analog ribavirin can selectively modulate Type 1 and Type 2 cytokine expression in stimulated human T cells. The ability of this drug to enhance Type 1 responses and diminish Type 2 responses was a function of the dose of ribavirin, and occurred at concentrations substantially below its antiproliferative concentration and in both helper CD4+ and cytotoxic CD8+ T cells. Ribavirin was able to produce a bias toward a Type 1 cytokine response,

Acknowledgements

We thank Dr G. Benichou for critical evaluation of this manuscript and Dr F. N. Zeytin for helpful discussion, and J. Avalos for collection of blood from normal donors and for excellent technical assistance.

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