As of the date of this report, patients with idiopathic anaphylaxis (IA) 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. 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. The randomized treatment protocol with omalizumab (09-I-0129) is in the patient accrual stage. There have been no serious adverse events contributed to the study drug, in particular drug-induced anaphylaxis. We found a delayed recovery from anaphylaxis inTrpc1-/- mice. Antigen-mediated production of TNF-alpha and other cytokines was enhanced in the Trpc1-/- BMMCs. Additionally, circulating levels of TNF-alpha in response to antigen were preferentially elevated in the Trpc1-/- mice. Administration of an anti-TNF-alpha antibody blocked the delay in recovery from anaphylaxis in these mice. These data thus provided evidence that TRPC1 promoted recovery from the anaphylactic response by repressing antigen-mediated TNF-alpha release from mast cells. A report of these findings has been published. We found that anaphylactic responses were more pronounced in female than in male mice. This enhanced female susceptibility was eliminated after pretreatment with an estrogen receptor antagonist or ovariectomy. Estrogen did not affect mast cell responsiveness or anaphylaxis onset. Instead, it increased tissue expression of endothelial nitric oxide synthase (eNOS). A report detailing these findings is in review
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