Eosinophils and Eosinophil Activation in the Pathogenesis of Human Disease

National Institute Of Allergy And Infectious Diseases

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Abstract

Using a cohort of more than 200 subjects with a wide variety of eosinophilic disorders, ranging from benign eosinophilia to eosinophilic leukemia, we have continued to look for new markers that distinguish between variants of hypereosinophilic syndrome. Assessment of serum and surface IL-5 receptor levels in a large cohort of patients with eosinophilia and/or mastocytosis suggests that regulation of this receptor occurs in vivo. This may have important implications in the setting of recently developed therapeutic agents targeting IL-5 and its receptor. We have developed an assay to examine the effects of such agents on IL-5 receptor bearing cells in the bone marrow using colony forming assays and flow cytometry. We have previously described a family with an autosomal dominant variant of hypereosinophilic syndrome that maps to chromosome 5q31-33. Exhaustive attempts to identify the gene responsible for this condition, including candidate gene sequencing, array CGHY, expression analysis, 454 sequencing of the region upstream of IL-5, in collaboration with John Rioux and Jan Cools, have been unsuccessful to date. High-throughput sequencing of the target region is planned. Fibrosis is one of the most severe complications of eosinophilia and is particularly prevalent in patients with untreated FIP1L1/PDGFRA-positive disease. We have recently completed microarray analysis using eosinophil RNA from FIP1L1/PDGFRA-positive patients before and after imatinib treatment in an effort to identify the factors responsible for the increased prevalence of fibrosis in this condition. Analysis is ongoing. We have continued to study the effects of novel therapies for the treatment of hypereosinophilic syndromes, including monoclonal antibodies to IL-5 and the tyrosine kinase inhibitor, imatinib. We have also begun to explore new therapeutic approaches for the treatment of refractory L-HES in collaboration with Drs. Janik and Morris (NCI). Additionally, we have expanded our studies of monoclonal antibodies targeting IL-5 to explore the role of eosinophilia in post-treatment reactions in the filarial infection, loiasis, since we have previously demonstrated an association between eosinophilia and side effects of DEC treatment in these patients.