Common Variable Immune Deficiency (CVID) Clinical Trial
Official title:
Improving the Diagnosis of CVID by Analysis of Innate and Adaptive Signaling Pathways
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.
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.
;
Observational Model: Case Control, Time Perspective: Prospective
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Enrolling by invitation |
NCT01852370 -
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|
Phase 1/Phase 2 |