As of the date of this report, patients with idiopathic anaphylaxis continue to be admitted for study. The majority of the patients are admitted to the inpatient unit and undergo a bone marrow procedure in an attempt to elucidate the etiology and evaluate the pathogenesis of their disease. Patients also have research blood drawn along with routine labs. In collaboration with the NIH Clinical Center's myeloid core facility, we assess all the patient bone marrow aspirates and biopsies obtained based on the current WHO criteria to diagnose systemic mastocytosis. Mast cells derived from peripheral mononuclear cells are being cultured and examined for mast cell growth and activation studies in comparison to mast cells from healthy volunteers. In one facet of the study and in exploring differences in human mast cell responses related to donor, we examined mast cell activation as influenced by PGE2 and selective PGE2-receptor ligands. We observed that human mast cells from approximately half of the donors failed to respond to PGE2 and the PGE2 EP3 receptor agonist, sulprostone. However, mast cells from the remaining donors and the LAD2 human mast cell line responded to PGE2 and sulprostone with marked enhancement of antigen-mediated degranulation and IL-8 production. The EP2 agonist, butaprost, failed to modulate antigen-mediated responses in any type of mast cell. These distinct phenotypes could not be explained by differences in EP2 or EP3 expression or by differences in the ability of PGE2 to elevate levels of cAMP. Moreover, both responder and non-responder mast cell populations exhibited similar activation of phosphatidylinositol 3-kinase, and MAP kinases. However, translocation of PLCgamma1 to the cell membrane and the associated calcium signal were enhanced only in the responder population. These data provide one reason for variability in human mast cell-dependent responses related to donor, as well as providing a basis for examining the effects of co-activating receptors in patients susceptible to allergic conditions. The randomized treatment protocol with omalizumab (09-I-0129) is in the patient accrual stage.
Showing the most recent 10 out of 23 publications
