Effect of IFN-γ on Innate Immune Cells
Condition: Chronic Granulomatous Disease
MeSH terms: Granulomatous Disease, Chronic
Study type: Interventional
Phase: Phase 1

Summary: 
      The investigators hypothesize that neutrophils and monocytes developed under the influence of
      Interferon- gamma-1b (IFN-γ-1b, Actimmune*) in vivo will display enhanced function across a
      broad range of activities related in large part to the transcriptional activation effects of
      this cytokine. The investigators will evaluate the effects of IFN-γ in healthy human subjects
      in vivo on gene expression, biologic activity markers, and functional activity of myeloid
      cells in single dose studies and in steady state studies.
    

Detailed description: 
      Named for their potent ability to interfere and protect against viral infections, interferons
      (IFNs) have many regulatory effects on the immune system.1 Of the members of the two classes
      of these compounds, IFN-γ has the most diverse and powerful immune effects. Studies have
      mostly evaluated IFN-γ interactions with cells of adaptive immunity, including macrophages
      and lymphocytes. Effects on innate immunity, particularly polymorphonuclear leukocytes or
      neutrophils and monocytes are less well studied. However, investigations have suggested that
      IFN-γ may be involved in signal transduction, gene expression, the respiratory burst and
      neutrophil NADPH oxidase (Nox2) activity, phagocytosis, motility, microbicidal activity, and
      apoptosis. Not all of these functions are enhanced by IFN-γ; but the clinical use of this
      cytokine has been driven, in part by these results. For example, the primary motivation for
      initiating investigation of its beneficial clinical effects in Chronic Granulomatous Disease
      (CGD) was its effects on Nox2 activity.2 Most data in this area was based on studies using
      differentiated neutrophils from peripheral blood.1 However, the phenotype of neutrophils
      developed under the influence of this cytokine, not just changes expressed by exposure of
      differentiated cells to IFN-γ, is critical to understanding the physiologic effects of IFN-γ
      and the broad applications for its use in treatment of a range of human diseases. To expand
      their understanding of the role of IFN-γ in the development and functional integrity of the
      neutrophil, the investigators have completed a series of studies with PLB-985 cells in an in
      vitro culture system of myeloid cells. In this proposal, the investigators will evaluate
      innate immune activation and phagocyte function in healthy adult volunteers who are receiving
      IFN-γ.
    

Intervention name(s): Administration of drug (Interferon-gamma 1-b) subcutaneously
Intervention type(s): Drug
Intervention description(s): SD = group who has received a single dose of IFN-gamma (10, 25, 50, and 100 mcg/m2) given once with subsequent analysis of effects (serum IL-10, Neuropterin, and IFN levels as well as neutrophil Nox2 activity and gene expression by Affimetrics Chip analysis). One month is allowed between doses. SS = administration of four doses (50 mcg/m2) of IFN-gamma given on Monday, Wednesday Friday schedule with neutrophil or monocyte function studies performed before the first and after the fourth dose to determine steady state effects.
Other intervention name(s): Actimmune
Intervention MeSH terms: Interferons; Interferon-gamma
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Interferon-gamma; innate immunity