CC Chemokine-Mediated Differential Immunoregulation by Human Eosinophils

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The Candidate (Dr. Praveen Akuthota) is a member of the Division of Pulmonary, Critical Care, and Sleep Medicine and of the Division of Allergy and Inflammation at Beth Israel Deaconess Medical Center and is an Instructor in Medicine at Harvard Medical School. This K08 Career Development Award will foster his career goal to become an independent investigator in eosinophil immunobiology. During the award period, the career development plan will allow for the honing of his skills as a basic investigator through carrying out the proposed research under the mentorship of Dr. Peter Weller and through a series of didactic experiences. The environment provided by Beth Israel Deaconess Medical Center and Harvard Medical School is ideally suited for the success of both the research and career development components of the award. The research plan focuses on the immunobiology of human eosinophils. Eosinophils have long been regarded to function exclusively as end-effector cells in asthma and other eosinophilic lung disorders, acting through the release of cytotoxic substances. However, mounting evidence has demonstrated that eosinophils have important multipotent immunoregulatory roles. Characterization of differential immunoregulation by eosinophils has lagged behind that of other immune cell types. This lag may be in part responsible for an incomplete understanding of the pathobiology eosinophilic pulmonary diseases, including asthma. The Candidate's previous work has identified the ligands of CCR7 (CCL19 and CCL21) as chemokines whose impacts on eosinophils and their capacity to influence the local immune environment warrant exploration. The proposed studies will address the overall hypothesis that CCR7 receptor-ligand interactions on eosinophils have an integral role in allergic airways disease that promotes resolution of Th2 inflammation and tissue eosinophilia. To address this overall hypothesis, Specific Aims will investigate the mechanism by which: 1) Human Eosinophils Express a Pro-Resolution Phenotype with CCL19 and CCL21 Stimulation; 2) Human Eosinophils Exposed to CCR7 Ligands Prevent Th2 Polarization of Lymphocytes; 3) Allergic Airway Inflammation Is Increased in Mice with CCR7-Deficient Eosinophils. These studies will utilize human eosinophils isolated from the peripheral blood of human donors and murine models of allergic airways inflammation. Specific experimental designs include multiplex-based studies of cytokine secretion, eosinophil gene expression analysis, eosinophil-lymphocyte interaction studies, and murine studies utilizing eosinophil adoptive transfer. The proposed research has the potential to provide insights into differential eosinophil responses to specific chemokine stimuli and lead to improved understanding of the intersection of eosinophilia and pulmonary disease.