Interferon-γ suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease

Werner Krenger, Giorgio Falzarano, John Delmonte, Kurt M. Snyder, John C.H. Byon, James L.M. Ferrara

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98 Scopus citations

Abstract

The development of graft-versus-host disease (GVHD) is associated with long-lasting and profound deficits in immune function that lead to increased morbidity and mortality after bone marrow transplantation (BMT). We investigated a mechanism of T-cell immunodeficiency in response to mitogen or alloantigen in an experimental model of acute GVHD by analyzing the roles of two immunosuppressive moieties: interferon gamma (IFN-γ) and nitric oxide (NO). Splenocytes from mice with GVHD did not proliferate either to the T-cell mitogen, concanavalin A (Con A), or to host alloantigens, but only mitogen- activated cultures produced increased levels of NO. The abrogation of NO synthesis with LG-mono-methyl-arginine (NMMA) restored mitogen-induced proliferation but not the response to host antigens. The mechanism of impaired proliferation to mitogen was dependent on IFN-γ because blockade of this cytokine in culture inhibited NO production and restored proliferation to Con A to levels similar to those in transplanted control mice without GVHD. NMMA did not substantially reduce IFN-γ levels, demonstrating that NO acted distally to IFN-γ in the pathway of immunosuppression in response to mitogen. Furthermore, the prevention of IFN-γ production in vivo after allogeneic BMT, by transplantation of polarized type 2 donor T cells (secreting interleukin- 4 but not IFN-γ), also prevented NO production and restored splenocyte responses to mitogen. Our data demonstrate the existence of NO-dependent and NO-independent pathways involved in suppression of T-cell proliferation during acute GVHD. Excess NO synthesis appears to be one mechanism by which IFN-γ induces immunodeficiency after allogeneic BMT.

Original languageEnglish
Pages (from-to)1113-1121
Number of pages9
JournalBlood
Volume88
Issue number3
DOIs
StatePublished - 1 Aug 1996

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