Effect of IFN-γ on Innate Immune Cells

NCT ID: NCT02609932

Last Updated: 2019-02-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-07-31
• Study Completion Date: 2019-02-28

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.

Conditions

Chronic Granulomatous Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

SD or SS

In this study, IFN- γ-1b will be subcutaneously administered a total of 30 subjects in one of two cohorts; Single Dose (SD) or Steady State (SS) dosing. Dosing of IFN- γ-1b will be based upon the time subject became eligible and started study. In this non-randomized, open-label study, subjects will be enrolled on the SD cohort first, and once that cohort has been filled, enrollment to the SS cohort will begin. Although not required, subjects in the SD cohort may also volunteer to participate in the SS cohort if they still meet eligibility criteria. Separate consents will be used for the SD and SS cohorts. In the event not all the SD subjects choose to continue onto the SS cohort, we will plan to recruit new participants from our local campus community.

Group Type: OTHER

Administration of drug (Interferon-gamma 1-b) subcutaneously

Intervention Type: DRUG

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.

Interventions

Administration of drug (Interferon-gamma 1-b) subcutaneously

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.

Intervention Type: DRUG

Other Intervention Names

Actimmune

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Daniel R. Ambruso, MD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 26317224 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35113934 (View on PubMed)

Other Identifiers

UL1TR001082

Identifier Type: NIH

Identifier Source: secondary_id

View Link

15-1643

Identifier Type: -

Identifier Source: org_study_id