Effect of IFN-γ on Innate Immune Cells

NCT02609932 | Completed Phase 1

• 2 other identifiers: 15-1643UL1TR001082
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Granulomatous Disease

Keywords

Interferon-gamma; innate immunity

Outcome Measures

Primary Outcomes (4)

• Change in Neutrophil Nox2 activity.

  Nox2 activity will be measured by DHR oxidation or Sod inhibitable cytochrome c reduction.

  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.

• Change in Plasma IL-10 and Neuropterin concentration.

  IL-10nd Neuropterin will be measured by ELISA.

  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.

• Change in Neutrophil Gene Expression Analysis.

  RNA will be extracted and gene expression will be determined by Affimetrix Gene Chip assay.

  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.

• Change in IFN concentration and detection of anti-IFN antibody

  IFN levels and anti-drug antibody will be completed by standard assays.

  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 (4)

• Change in Neutrophil Function studies.

  Determine the change in neutrophil function at baseline compared to results on Day 8 after the 4th dose of IFN.

• Change in Anti-IFN antibody.

  Determine the change in IFN antibody at baseline compared to results for 7-10 da. and 30 da. after IFN.

• Change in Monocyte function studies.

  Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.

• Change in Neutrophil and Monocyte Gene Expression Analysis.

  Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.

Study Arms (1)

SD or SS

OTHER

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.

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

Interventions

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

Also known as: Actimmune

SD or SS

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adults over the age of 18 years up to 60 years.
• At time of screening subject is well and healthy;
• Acute infections resolved;
• Subject off treatment medications;
• 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.
• Non-prescription medications for mild inter-current illnesses will be allowed at the discretion of the principal investigator.

You may not qualify if:

• Pregnancy.
• History of current infection;
• Two weeks from most recent intercurrent infection;
• History of recurrent infections or immunodeficiency.

Sponsors & Collaborators

• University of Colorado, Denver: lead

Study Sites (1)

University of Colorado Denver, Anschutz Medical Campus

Aurora, Colorado, 80045, United States

Location

Related Publications (2)

• 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.

  PMID: 26317224 BACKGROUND

• 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.

  PMID: 35113934 DERIVED

MeSH Terms

Conditions

Granulomatous Disease, Chronic

Interventions

Interferon-gamma; interferon gamma-1b

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Macrophage-Activating Factors; Lymphokines; Proteins; Biological Factors

Study Officials

• Daniel R. Ambruso, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 11, 2015
• First Posted: November 20, 2015
• Study Start: July 1, 2016
• Primary Completion: August 1, 2018
• Study Completion: February 1, 2019
• Last Updated: February 15, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)