- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02609932
Effect of IFN-γ on Innate Immune Cells
February 11, 2019 updated by: University of Colorado, Denver
Effect of Interferon-gamma 1-b on Innate Immune Cells
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.
Study Overview
Status
Completed
Conditions
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Actual)
20
Phase
- Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
-
Colorado
-
Aurora, Colorado, United States, 80045
- University of Colorado Denver, Anschutz Medical Campus
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years to 60 years (Adult)
Accepts Healthy Volunteers
Yes
Genders Eligible for Study
All
Description
Inclusion Criteria:
- 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.
Exclusion Criteria:
- Pregnancy.
- History of current infection;
- Two weeks from most recent intercurrent infection;
- History of recurrent infections or immunodeficiency.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: 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.
|
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 Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Neutrophil Nox2 activity.
Time Frame: 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.
|
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.
Time Frame: 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.
|
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.
Time Frame: 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.
|
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
Time Frame: 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
|
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 Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Neutrophil Function studies.
Time Frame: Determine the change in neutrophil function at baseline compared to results on Day 8 after the 4th dose of IFN.
|
Neutrophil chemotaxis, bactericidal activity,ingestion, degranulation, f-Actin expression, CD11b/18 expression, Nox2 activity to a variety of agonists.
|
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.
Time Frame: Determine the change in IFN antibody at baseline compared to results for 7-10 da. and 30 da. after IFN.
|
Anti-drug antibody to be determined by standard assay.
|
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.
Time Frame: Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.
|
Monocyte chemotaxis, bactericidal activity,ingestion, Expression of monocyte specific surface determinants, CD11b/18 expression, Nox2 activity to a variety of agonists, cell content of specific proteins, and antibody dependent cellular cytotoxicity.
|
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.
Time Frame: Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.
|
RNA will be extracted and gene expression will be determined by Affimetrix Gene Chip assay.
|
Determine the change in monocyte function at baseline compared to results on Day 8 after the 4th dose of IFN.
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- 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.
- 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.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start
July 1, 2016
Primary Completion (Actual)
August 1, 2018
Study Completion (Actual)
February 1, 2019
Study Registration Dates
First Submitted
November 11, 2015
First Submitted That Met QC Criteria
November 17, 2015
First Posted (Estimate)
November 20, 2015
Study Record Updates
Last Update Posted (Actual)
February 15, 2019
Last Update Submitted That Met QC Criteria
February 11, 2019
Last Verified
February 1, 2019
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Immunologic Deficiency Syndromes
- Immune System Diseases
- Hematologic Diseases
- Genetic Diseases, Inborn
- Genetic Diseases, X-Linked
- Leukocyte Disorders
- Phagocyte Bactericidal Dysfunction
- Granulomatous Disease, Chronic
- Anti-Infective Agents
- Antiviral Agents
- Antineoplastic Agents
- Interferons
- Interferon-gamma
Other Study ID Numbers
- 15-1643
- UL1TR001082 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
NO
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Chronic Granulomatous Disease
-
National Institute of Allergy and Infectious Diseases...Enrolling by invitationChronic Granulomatous Disease (CGD) | X-Linked Chronic Granulomatous DiseaseUnited States
-
University of California, Los AngelesNational Heart, Lung, and Blood Institute (NHLBI); Boston Children's Hospital; California Institute for Regenerative Medicine (CIRM) and other collaboratorsRecruitingGranulomatous Disease, Chronic, X-linkedUnited States
-
National Institute of Allergy and Infectious Diseases...Active, not recruitingChronic Granulomatous Disease TransplantUnited States
-
GenethonActive, not recruitingX-Linked Chronic Granulomatous DiseaseFrance
-
Children's Hospital of Fudan UniversityRecruitingBCG | Vitamin D3 | Chronic-granulomatous DiseaseChina
-
Great Ormond Street Hospital for Children NHS Foundation...WithdrawnGranulomatous Disease, Chronic, X-linked, VariantUnited Kingdom
-
National Institute of Allergy and Infectious Diseases...RecruitingChronic Granulomatous Disease-associated ColitisUnited States
-
GenethonActive, not recruitingX-Linked Chronic Granulomatous DiseaseUnited Kingdom
-
National Institute of Allergy and Infectious Diseases...Rare Diseases Clinical Research Network; Primary Immune Deficiency Treatment...Enrolling by invitationGranulomatous Disease, ChronicUnited States, Canada
-
Hubert Serve, Prof., MDUnknown
Clinical Trials on Administration of drug (Interferon-gamma 1-b) subcutaneously
-
National Eye Institute (NEI)Completed
-
French National Agency for Research on AIDS and...Hoffmann-La Roche; InterMuneCompletedHepatitis C, ChronicFrance
-
National Cancer Institute (NCI)CompletedRecurrent Mycosis Fungoides and Sezary Syndrome | Refractory Mycosis Fungoides and Sezary Syndrome | Stage IB Mycosis Fungoides and Sezary Syndrome AJCC v7 | Stage IIA Mycosis Fungoides and Sezary Syndrome AJCC v7 | Stage IIB Mycosis Fungoides and Sezary Syndrome AJCC v7 | Stage IIIA Mycosis... and other conditionsUnited States
-
InterMuneCompletedChronic Hepatitis CUnited States
-
Abramson Cancer Center of the University of PennsylvaniaNational Cancer Institute (NCI)CompletedMalignant Pleural MesotheliomaUnited States
-
Accelerated Community Oncology Research NetworkInterMuneCompleted
-
Georgetown UniversityCangene CorporationCompletedHepatitis BUnited States
-
Northwestern UniversityFoundation for Sarcoidosis ResearchRecruitingSARS-CoV2 Infection | Sarcoidosis | Vaccine Response ImpairedUnited States
-
Beijing Biostar Pharmaceuticals Co., Ltd.RecruitingAdvanced Solid TumorChina
-
Fred Hutchinson Cancer CenterNational Cancer Institute (NCI); Affini-T Therapeutics, Inc.Active, not recruiting