Current Clinical Trials
Principal Investigator: Larry Borish, MD
Immune and Molecular Mechanisms in
Aspirin-Exacerbated Respiratory Disease (AERD)
We are investigating the role of cysteinyl leukotrienes and cytokines in the development of aspirin-exacerbated respiratory disease (AERD). We hypothesize that cysteinyl leukotrienes and other arachidonate metabolites promote eosinophil, fibroblast and fibrocyte proliferation, secretion of proinflammatory cytokines, and the aggressive remodeling characteristic of asthma, sinusitis and nasal polyposis. Concentrations of cysteinyl leukotrienes (CysLTs) and their receptors are significantly higher in tissue obtained from subjects with AERD as compared to aspirin tolerant asthma or the healthy airway. AERD is characterized by upregulation of CysLT synthesis pathways and CysLT receptors, including novel receptors that are targeted by CysLTE4, occurring concomitantly with downregulation of PgE2 synthesis (cox2 and mPGES1) and responsiveness (EP2) pathways. These aberrations are controlled by cytokines including IL-4 and IL-13 acting through the transcription factor pStat6 but AERD is also characterized by prominent expression of IFN-γ. Therapeutic aspirin desensitization functions, at least in part, through blocking gene transcription mediated through diminished expression of pStat6 in the nucleus.
Our current studies emphasize the role of CysLTs acting through this putative CysLTE4 receptor pathway, in particular on eosinophils, as well as aberrant signaling mechanisms involving PgE2. These studies involve transcriptome screening, proteomics, and genome-wide searches to identify unique molecular pathways responsible for the development of aspirin-exacerbated respiratory disease.
CD4+ and CD8+ T Cell Dependent Mechanisms
of RV-induced Asthma Exacerbations
The greatest morbidity associated with asthma is the occurrence of severe, potentially life-threatening exacerbations. Rhinovirus (RV) accounts for ~60-70% of childhood and adolescent asthma exacerbations. Although an exacerbation would be predicted whenever a cytopathic inflammatory response is superimposed upon the asthmatic lung, this is not what is observed – and only RV infections are consistently associated with asthma exacerbations. RV-associated asthma exacerbations are linked to the presence of an increased type 2 cytokine signature (IL-4, IL-5, and IL-13) and one explanation is that these cytokines are being produced by the RV-specific T cells themselves, either CD4+ helper (Th2-like) or CD8+ cytotoxic (Tc2-like) T lymphocytes. It is this inflammatory response produced by T lymphocytes that we propose is harmful to the host. Exacerbations are also linked to the diminished expression of the anti-inflammatory cytokine IL-10. IL-10 may provide a feedback role to control the collateral damage associated with an exuberant T cell response. The source of this IL-10 during infection, we believe, is also likely the effector T cells themselves.
Our studies currently focus on the production of type 2 cytokines and IL 10 by RV-specific effector T-cellsto determine whether there is a correlation between Type 2 Cytokines and /or IL-10 and the development of increased upper and lower airways inflammation following RV infection. We hypothesize that RV-specific T cells from subjects who develop an exacerbation of their upper and lower airway inflammation during RV infection release higher levels of type 2 cytokines and/or lower levels of IL-10. For these studies, we infect asthmatic volunteers with RV and identify circulating RV-specific CD4+ helper and CD8+ cytotoxic T effector lymphocytes.