PIDTC Project 6908 CGD ? Abstract Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in any of 5 subunits of the phagocyte NADPH oxidase. Patients are equally affected by infection susceptibility and immune dysregulation both in response to infection and presumed sterile inflammation. This auto-inflammation affects a variety of organ systems, particularly the bowel, lungs and liver. Uncontrolled auto-inflammation can be an indication for hematopoietic cell transplant (HCT) in CGD but retrospective studies suggest that patients with CGD undergoing HCT have a higher incidence of graft versus host disease (GVHD) and mortality if there is active infection or uncontrolled inflammation at the time of transplantation. The exact mechanism of auto- inflammation in CGD is unknown but several in vitro defects have been described. Lastly, studies of HCT indicate associations between GVHD and altered intestinal microbiome alpha diversity. Our prior studies show that 1) HCT can resolve CGD-associated colitis but history of colitis increases risk of GVHD; 2) the intestinal microbiome in CGD patients is altered at baseline with decreased alpha diversity, reduced colonization with anaerobic taxa associated with butyrate production and epithelial barrier protection, and 3) HCT significantly alters the CGD intestinal microbiome signature. We propose to prospectively enroll CGD patients who are planned to undergo HCT or gene therapy. We will longitudinally assess auto-inflammatory symptoms developing an auto-inflammatory disease score. In parallel, blood and stool samples will be assessed for cytokine alterations, metabolomics signatures, and the microbiome. Further, the 6908 protocol will provide opportunity to develop biomarkers of CGD-associated auto-inflammation. The objectives of this proposal are to advance the understanding of diagnosis and management of inflammatory symptoms in CGD in order to define how best to optimize HCT strategy to cure CGD and resolve auto-inflammatory symptoms post allogeneic HCT or gene therapy. With this cohort, we will 1) characterize and quantify auto-inflammatory symptoms that will determine an overall symptom score; 2) assess patient reported outcomes to understand how presence and resolution of auto-inflammation changes quality of life; 3) determine if HCT provides short and/or long term resolution of auto-inflammatory symptoms; 4) determine the optimal HCT strategy and what degree of donor chimerism is necessary to achieve and sustain resolution of auto-inflammatory symptoms; 5) determine biomarkers of CGD-associated auto-inflammation that can be predictive of symptom severity and control, and 6) determine metabolomics and metagenomics data of the stool microbiome in CGD patients and correlate how the biome influences post-HCT outcomes. The impact of the proposed research is that the longitudinal assessment and mechanistic studies we perform will optimize clinician practices and lead to development of clinical trials for CGD patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZTR1)
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University of California San Francisco
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