Clinical Trial: Improving the Diagnosis of Common Variable Immune Deficiency

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Observational

Official Title: Improving the Diagnosis of CVID by Analysis of Innate and Adaptive Signaling Pathways

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.

Detailed Summary:

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 finger
Sponsor: Stanford University

Current Primary Outcome: 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

Original Secondary Outcome:

Information By: Stanford University

Dates:
Date Received: February 8, 2016
Date Started: February 2016
Date Completion: July 2018
Last Updated: February 10, 2016
Last Verified: February 2016