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Improving the Diagnosis of Common Variable Immune Deficiency

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ClinicalTrials.gov Identifier: NCT02680652
Recruitment Status : Unknown
Verified February 2016 by Manish Butte, Stanford University.
Recruitment status was:  Not yet recruiting
First Posted : February 11, 2016
Last Update Posted : February 12, 2016
Sponsor:
Information provided by (Responsible Party):
Manish Butte, Stanford University

Brief Summary:
This is an observational, case--control study with a single blood draw among two cohorts, patients with CVID and healthy controls. Samples will be analyzed by cytometry (CyTOF) to simultaneously 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
Common Variable Immune Deficiency (CVID)

Detailed Description:

Abstract: An increased susceptibility to bacterial and viral infections is the hallmark of explain the study rationale, primary immunodeficiencies (PID). The most common PID 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 oftentimes 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 monogenic causes for CVID because these methods result in too many "hits" to specifically validate. At the same time, patients with derangements of signaling pathways including STAT1, STAT3, PI3K, and others have CVID, suggesting that by examining the signaling pathways, we could find consistent signs of CVID. The Investigators propose to use a broad, new screen developed by the PI 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 CVID and healthy controls. Methods: Fifty (50) CVID patients (adult and children) will be consented in Dr. Butte's Immunology Clinic at Stanford, and healthy controls (100), at the adult or pediatric primary care clinics at Stanford. There will be one blood draw of 2 mL of blood to analyzed immediately by Stanford's established phospho-CyTOF protocol in the Human Immune Monitoring Core facility at Stanford.

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. Data will be analyzed in FlowJo and CytoBank software, with further statistical analysis in R.

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Study Type : Observational
Estimated Enrollment : 150 participants
Observational Model: Case Control
Time Perspective: Prospective
Official Title: Improving the Diagnosis of CVID by Analysis of Innate and Adaptive Signaling Pathways
Study Start Date : February 2016
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : July 2018


Group/Cohort
CVID
Patients with a diagnosis of Common Variable Immune Deficiency
Healthy Controls
age matched healthy controls



Primary Outcome Measures :
  1. Differences in Immune Cells in CVID and healthy controls. [ Time Frame: 2.5 years ]
    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.


Biospecimen Retention:   Samples With DNA
Whole exome analysis will be performed on all samples


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:   Probability Sample
Study Population
Patients with a diagnosis of CVID and Health controls
Criteria

Inclusion Criteria:

  • Diagnosis of CVID

Exclusion Criteria:

  • none

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): NCT02680652


Contacts
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Contact: Elisabeth Hoyte 650-498-4039 ehoyte@stanford.edu

Sponsors and Collaborators
Stanford University
Investigators
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Principal Investigator: Manish J Butte, MD PhD Stanford University
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Responsible Party: Manish Butte, Assistant Professor, Stanford University
ClinicalTrials.gov Identifier: NCT02680652    
Other Study ID Numbers: BT15-28124
First Posted: February 11, 2016    Key Record Dates
Last Update Posted: February 12, 2016
Last Verified: February 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Keywords provided by Manish Butte, Stanford University:
CVID
Common Variable Immune Deficiency
Additional relevant MeSH terms:
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Immunologic Deficiency Syndromes
Common Variable Immunodeficiency
Immune System Diseases