Clinical trial NCT02609932: Effect of IFN-γ on Innate Immune Cells
Official title: Effect of Interferon-gamma 1-b on Innate Immune Cells
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Granulomatous Disease
Keywords: Interferon-gamma
innate immunity
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
First posted: 2015-11-20
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief 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.

Eligibility criteria: Inclusion Criteria:

1. Healthy adults over the age of 18 years up to 60 years.
2. At time of screening subject is well and healthy;
3. Acute infections resolved;
4. Subject off treatment medications;
5. No diagnosis of chronic conditions or active health care issues for which the subject is actively followed by a health care provider or is on chronic medications.
6. Non-prescription medications for mild inter-current illnesses will be allowed at the discretion of the principal investigator.

Exclusion Criteria:

1. Pregnancy.
2. History of current infection;
3. Two weeks from most recent intercurrent infection;
4. History of recurrent infections or immunodeficiency.

Primary outcomes:
measure: Change in Neutrophil Nox2 activity.
timeFrame: Determine the change in Nox2 activity at baseline compared to results for 8,24,48,72,96 hours after each IFN dose for the SD cohort.
measure: Change in Plasma IL-10 and Neuropterin concentration.
timeFrame: Determine the change in IL-10 and neuropterin concentration at baseline compared to 4, 8, 12, 24, 36, 48, 72, and 96 hours after each IFN dose, SD cohort.
measure: Change in Neutrophil Gene Expression Analysis.
timeFrame: Determine the change in gene expression at baseline compared to 4, 8, 12, 24, 36, 48, 72, and 96 hours after each IFN dose, SD cohort.
measure: Change in IFN concentration and detection of anti-IFN antibody
timeFrame: Determine the change in IFN level at baseline compared to 4, 8, 12, and 24 hours after administration of each dose of IFN-gamma in the SD cohort. Determine the change in IFN antibody at baseline compared to day 7-10 and day 30 after IFN
Secondary outcomes:
measure: Change in Neutrophil Function studies.
timeFrame: Determine the change in neutrophil function at baseline compared to results on Day 8 after the 4th dose of IFN.
measure: Change in Anti-IFN antibody.
timeFrame: Determine the change in IFN antibody at baseline compared to results for 7-10 da. and 30 da. after IFN.
measure: Change in Monocyte function studies.
timeFrame: Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.
measure: Change in Neutrophil and Monocyte Gene Expression Analysis.
timeFrame: Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver, Anschutz Medical Campus
state: Colorado
Study officials:
affiliation: University of Colorado, Denver
name: Daniel R. Ambruso, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ellison MA, Thurman G, Gearheart CM, Seewald RH, Porter CC, Ambruso DR. INF-gamma Enhances Nox2 Activity by Upregulating phox Proteins When Applied to Differentiating PLB-985 Cells but Does Not Induce Nox2 Activity by Itself. PLoS One. 2015 Aug 28;10(8):e0136766. doi: 10.1371/journal.pone.0136766. eCollection 2015.
citation: Ambruso DR, Briones NJ, Baroffio AF, Murphy JR, Tran AD, Gowan K, Sanford B, Ellison M, Jones KL. In vivo interferon-gamma induced changes in gene expression dramatically alter neutrophil phenotype. PLoS One. 2022 Feb 3;17(2):e0263370. doi: 10.1371/journal.pone.0263370. eCollection 2022.