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Clinical Use of Interferon-gamma.

ABSTRACT: Interferon gamma (IFN-gamma), a pleotropic cytokine, has been shown to be important to the function of virtually all immune cells and both innate and adaptive immune responses. In 1986, early clinical trials of this cytokine began to evaluate its therapeutic potential. The initial studies focused on the tolerability and pharmacology of IFN-gamma and systematically determined its antitumor and anti-infection activities. In the 20-plus years since those first trials, IFN-gamma has been used in a wide variety of clinical indications, which are reviewed in this article.

SUBMITTER: Miller CH

PROVIDER: S-EPMC6574079 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Clinical Use of Interferon-gamma.

Miller Catriona H T CH Maher Stephen G SG Young Howard A HA

Annals of the New York Academy of Sciences 20091201

Interferon gamma (IFN-gamma), a pleotropic cytokine, has been shown to be important to the function of virtually all immune cells and both innate and adaptive immune responses. In 1986, early clinical trials of this cytokine began to evaluate its therapeutic potential. The initial studies focused on the tolerability and pharmacology of IFN-gamma and systematically determined its antitumor and anti-infection activities. In the 20-plus years since those first trials, IFN-gamma has been used in a w ...[more]

PMID: 20074276

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Project description:ObjectiveFamilial hemophagocytic lymphohistiocytosis (FHLH) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and natural killer cells incapable of cytolytic killing. In murine models of FHLH, interferon-γ (IFNγ) produced by CD8+ T cells has been identified as a critical mediator of disease, and an IFNγ-blocking antibody (emapalumab) has recently been approved by the Food and Drug Administration. However, development of hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFNγ questions the absolute necessity of IFNγ in driving disease. This study was undertaken to determine the necessity of IFNγ in driving HLH.MethodsIFNγ-/- Prf1-/- mice were infected with lymphocytic choriomeningitis virus (LCMV), and HLH immunopathologic features, including survival, weight loss, cytopenias, cytokine profiles, and immune cell phenotypes, were assessed. Mixed bone marrow chimeras were created to determine the immune cell-intrinsic role of IFNγ receptor signaling. CD8+ T cell depletion and interleukin-33 (IL-33)/ST2 blockade were performed using monoclonal antibodies.ResultsLCMV infection of IFNγ-/- Prf1-/- mice resulted in severe HLH-like disease. CD8+ T cells and the IL-33/ST2 axis remained essential mediators of disease; however, IFNγ-independent HLH immunopathology correlated with a 10-15-fold increase in neutrophilia (P < 0.001) and an altered cytokine milieu dominated by IL-6, IL-1β, and granulocyte-macrophage colony-stimulating factor (GM-CSF) (P < 0.05). Furthermore, IFNγ regulated CD8+ T cell expression of GM-CSF and neutrophil survival.ConclusionIFNγ is not necessary for the development of fulminant HLH, requiring physicians to consider case-by-case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL-33/ST2 signaling, may be more universally applicable treatment options that ameliorate both IFNγ-dependent and -independent manifestations of HLH/MAS.

Dataset Information

Clinical Use of Interferon-gamma.

Publications

Clinical Use of Interferon-gamma.

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