Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody deficient syndrome and is characterized by decreased levels of serum immunoglobulins and recurrent sinopulmonary infections. In addition, up to 50% of patients manifest a non-infectious malabsorption syndrome, also known as CVID enteropathy, that is usually resistant to treatment. The pathogenesis of CVID enteropathy is still unclear, but recent studies have suggested that it results from a complex interaction between the gut microbiota and the intestinal epithelium leading to a hyperactive mucosal immune response characterized by increased production of Interleukin-12 and Interferon-gamma. Further work in a mouse model of this enteropathy demonstrated that in the presence of microbiota but not in germfree animals, intestinal epithelium of immunodeficient hosts upregulates interferon-dependent immune genes at the expense of metabolic genes. In addition, preliminary microarray analysis CVID patient tissue revealed a similar dysregulation of gene expression in human CVID. We propose that selective inhibition of the hyperactive mucosal immune response would correct the gene imbalance and resolve the malabsorption in CVID patients. Ustekinumab is a monoclonal antibody to the p40 subunit of interleukin-12/23. It is approved for the treatment of psoriasis, and is currently being evaluated in Phase III trials fo the treatment of refractory Crohn's disease. We propose to treat CVID enteropathy patients with ustekinumab and assess the effects on clinical and immunologic parameters as well as on gene expression. Response to therapy will be assessed by evaluation of the degree of malabsorption, histological alterations in gut biopsies, cytokine production and global gene expression in blood, gut biopsies and isolated intestinal mononuclear cells. Changes in intestinal microbial composition in gut biopsies will be monitored using metagenomic analysis of shotgun sequencing data and correlated with clinical and immunological parameters to define microbes possibly driving the hyperactive immune response. These studies will therefore provide a unique opportunity to perform an evaluation of a novel therapy of CVID enteropathy while at the same time conducting studies defining the mechanisms underlying CVID enteropathy under dynamic conditions.

Public Health Relevance

In this study we will test the efficacy of a novel medicine (ustekinumab) for enteropathy associated with common variable immunodeficiency. Besides finding a solution for patients who currently do not have efficient treatment, this study will also study key microbial and molecular aspects of this disorder providing insights into host-microbe interaction in the gut and contributing to future successes in management of other gut diseases.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI109695-02
Application #
8726282
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Griffith, Linda M
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Oregon State University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Corvallis
State
OR
Country
United States
Zip Code
97331