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Improving the Diagnosis of Common Variable Immune Deficiency

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ClinicalTrials.gov Identifier: NCT03335605
Recruitment Status : Active, not recruiting
First Posted : November 8, 2017
Last Update Posted : March 29, 2021
Sponsor:
Collaborator:
Jeffrey Modell Foundation
Information provided by (Responsible Party):
Manish J. Butte, MD PhD, University of California, Los Angeles

Brief Summary:
This is an observational, case-control study with a single blood draw among two cohorts, patients with antibody deficiency (e.g., CVID) and healthy controls. Samples will be analyzed by mass cytometry (CyTOF) to examine the major signaling pathways of all circulating innate and adaptive immune cell types, as well as whole exome sequencing. The goal is to improve our general understanding of the human immune response to infections and the diagnosis of CVID.

Condition or disease
CVI - Common Variable Immunodeficiency

Detailed Description:

An increased susceptibility to bacterial and viral infections is the hallmark primary immunodeficiencies (PIDs). The most common PIDs requiring treatment with Ig replacement (SCIg or IVIg) is Common Variable Immune Deficiency (CVID), which is diagnosed by the presence of hypogammaglobulinemia plus defective responses to vaccine antigens. Prior to diagnosis, CVID patients often develop autoimmunity that requires immunosuppression or cancers that require chemotherapy. Unfortunately, difficulties arise in making the diagnosis of CVID in adults treated with immunosuppressive drugs, steroids, or chemotherapy, preventing the timely use of Ig replacement therapies in these patients. Furthermore, CVID is difficult to diagnose in young children. Exome sequencing and other genetic methods have thus far failed to identify clear monogenic causes for CVID. At the same time, patients with derangements of signaling pathways including STAT1, STAT3, NFKB, PI3K, and others, have clinical antibody deficiency, suggesting that by examining the signaling pathways, the investigators could find signs of CVID. The Investigators propose to use a broad, new screen to study the functional defects of human immune responses in CVID. Using time-of-flight mass cytometry (CyTOF) and phospho-specific antibodies, the investigators will simultaneously examine the major signaling pathways of all circulating innate and adaptive immune cell types at once to identify abnormal phosphorylation of signaling molecules in response to a variety of canonical stimuli. This method is innovative because it identifies signaling defects in the immune response while being insensitive to chemotherapy or immunosuppression, because the signaling responses examined are biologically upstream of immunosuppressed targets. Our approach generates a new "signaling fingerprint" for facilitating the diagnosis of CVID. Our proposal is also impactful, because knowledge gained about functional defects in CVID, when combined with whole exome sequencing, will improve the general understanding of the human immune response to infections.

There are two major aims: 1) studying healthy control subjects across a variety of ages as comparisons to CVID patients, and furthermore to generate new information about how immune signaling responses change with age, which is currently unknown; and 2) studying CVID patients to identify the consistent aberrant signaling responses that will allow the acceleration of diagnosis and treatment.

Design of study: The investigators propose an observational, case-control study with a single blood draw among two cohorts, patients with antibody deficiency (CVID) and healthy controls. Methods: Fifty (50) CVID patients (adult and children) will be consented in the Immunology Clinic at UCLA. Healthy, age- and gender-matched controls will be sought at the same time (100). There will be one blood draw of < 5 mL of blood to be analyzed immediately by phospho-CyTOF at UCLA. Genomic DNA will be prepared from samples and sequences analyzed.

This screen examines phosphorylation of all circulating immune cell types at once (CD4 and CD8 T cells, B cells, NK cells, monocytes, macrophages, neutrophils, eosinophils, and DCs). Whole blood from subjects and from controls will be aliquotted into portions, and each portion will be stimulated with either cytokines, TLR agonists, anti-TCR or anti-BCR antibodies, PMA, or left unstimulated. Treated cells will be surface stained, fixed, permeabilized, and stained intracellularly for 12 signaling phospho-proteins, then analyzed by CyTOF, which enables measurement of over 50 parameters simultaneously.

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Study Type : Observational
Estimated Enrollment : 150 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Improving the Diagnosis of Common Variable Immune Deficiency by Analysis of Innate and Adaptive Signaling Pathways
Actual Study Start Date : May 1, 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : June 1, 2022


Group/Cohort
Antibody deficiency (CVID)
Subjects with antibody deficiency (CVID)
Healthy controls
Age and gender-matched control subjects



Primary Outcome Measures :
  1. Differences in Immune Cells in CVID and healthy controls [ Time Frame: 2 years ]
    Whole blood from subjects and from controls will be aliquotted into portions, and each portion will be stimulated with either cytokines, TLR agonists, anti-TCR or anti-BCR antibodies, PMA, or left unstimulated. Treated cells will be surface stained, fixed, permeabilized, and stained intracellularly for 12 signaling phospho-proteins, then analyzed by CyTOF, which enables measurement of over 50 parameters simultaneously across all circulating immune cell types (CD4 and CD8 T cells, B cells, NK cells, monocytes, macrophages, neutrophils, eosinophils, and DCs). All responses across all cells for all stimuli will be aggregated by principal components analysis to a single metric that will be compared between subjects with antibody deficiency and controls.


Biospecimen Retention:   Samples With DNA
< 5 mL of whole blood


Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Patients with a diagnosis of CVID and Healthy controls
Criteria

Inclusion Criteria:

  • Diagnosis of antibody deficiency (CVID)

Exclusion Criteria:

-


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03335605


Locations
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United States, California
UCLA
Los Angeles, California, United States, 90095
Sponsors and Collaborators
University of California, Los Angeles
Jeffrey Modell Foundation
Investigators
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Principal Investigator: Manish J Butte, MD PhD University of California, Los Angeles
Publications:
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Responsible Party: Manish J. Butte, MD PhD, Associate Professor and Chief, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT03335605    
Other Study ID Numbers: UCLA-IMMUNOLOGY-16-001950
First Posted: November 8, 2017    Key Record Dates
Last Update Posted: March 29, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Manish J. Butte, MD PhD, University of California, Los Angeles:
primary immunodeficiency
Additional relevant MeSH terms:
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Immunologic Deficiency Syndromes
Common Variable Immunodeficiency
Immune System Diseases