Th17 Studies

Th17-based Mucosal Vaccine

We are studying memory Th17 responses using mouse models of Klebsiella pneumoniae.

Our previous work (Chen et. al., Immunity. 2011 Dec 23;35 (6):997-1009.) has demonstrated that immunization-induced Th17 cells provide serotype/antibody independent protection against a variety of strains of K. pneumonia including the recently described multidrug-resistant New Delhi metallo-beta-lactamase strain.

These Th17 cells recognized conserved Klebsiella outer membrane proteins (OMPs) and immunization with OMPs also conferred serotype/antibody independent protection.

Current work includes understanding of the mechanism of generation of these memory Th17 cells and cloning the highly conserved OMPs from K. pneumonia and testing their immunogenicity as Th17 based vaccine candidates.

Successful vaccine strategy can be used not only in prevention of multidrug resistant bacteria outbreaks but also in prophylactic treatment for immunocompromised patients that may lack B cell responses or for patients undergoing anti-CD20 treatment.

Th17-based Mucosal Vaccine

Vaccination generates memory Th17 cells in the lung (shown by flow cytometry) providing protection against bacteria including antibiotic-resistant strains.
Click to view larger image.

The Role of IL-17R Signaling in Cigarette Smoke-induced Emphysema

Cigarette smoke is known to cause several respiratory ailments, including chronic bronchitis, emphysema, chronic obstructive pulmonary disease (COPD) and lung cancer. We are investigating the role of cigarette smoke as a causative factor or modifier of these lung diseases.

Th17 cells are a critical component in chronic inflammatory diseases. Naive T cells differentiate into Th17 cells through co-exposure to IL-6 and TGF-β, both of which are present during COPD. Moreover, the aryl hydrocarbon receptor (AhR), which is activated by cigarette smoke, has a key role in promoting the Th17 response and expression of IL-22.

We are characterizing the role of IL-17R signaling in cigarette smoke-induced emphysema and IL-17 related cytokines as biomarkers in COPD.

The Role of IL-17R Signaling in Cigarette Smoke-induced Emphysema

Lung tissue samples from mouse models exposed to air and cigarette smoke showing IL-17RA-/- mice have significantly less tissue emphysema (D) compared to control mice (C). Click to view larger image.

Role of IL-17 and IL-22 in Chronic Alcoholic Liver Disease 

Chronic alcohol consumption affects virtually all tissues of the body, leading to disorders in multiple organ systems. However, liver inflammation and fibrosis is a major cause of morbidity and mortality.

Although over expression of IL-22 can ameliorate hepatitis and improve hepatocyte survival, the protective mechanisms of IL-22 have not been fully elucidated. We hypothesize that IL-17 is critical for the development of alcoholic hepatitis and that endogenous IL-22 is rendered ineffective due to sequestration by Il-22RA2, an IL-22 binding protein.

Therefore, our current projects are: 1) Determine the cellular sources of IL-17A, IL-17F, and IL-22 in a murine model of alcohol-induced liver inflammation; 2) Investigate the contributions of hepatocyte expression of IL-17 receptors in mediating inflammation in our murine model of alcoholic hepatitis; and 3) Investigate the contributions of hepatocyte expression of IL-22 receptor and soluble IL-22RA2 in mediating inflammation and hepatocyte repair in a murine model of alcohol induced liver inflammation and in patients with alcoholic hepatitis.