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. 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 (MCs) derived from peripheral mononuclear cells are being cultured and examined for MC growth and activation studies in comparison to MCs from healthy volunteers. Patients with IA have been shown to have enhanced growth of MCs derived from peripheral CD34+ cells and these MCs demonstrated hyperresponsiveness with higher release of granule contents. These data provide a reason for continued exploration of the variability in human MC-dependent responses related to a specific phenotype. 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. To explore the contribution of TRPC1 in MC-driven allergic reactions, we examined antigen-mediated anaphylaxis in Trpc1-/- and WT mice, and TRPC1 involvement in the activation of MCs cultured from the bone marrow (BMMCs) of these mice. In vivo, we observed a similar induction of passive systemic anaphylaxis in the Trpc1-/ - mice compared to WT controls, with a delay in recovery from this response in Trpc1-/- mice. In vitro, Trpc1-/- BMMCs responded to antigen with enhanced calcium signalling but with little defect in degranulation. In contrast, antigen-mediated production of TNF-alpha and other cytokines was enhanced in the Trpc1-/- BMMCs. Further, circulating levels of TNF-alpha in response to antigen were preferentially elevated in the Trpc1-/-mice, and administration of an anti-TNF-alpha antibody blocked the delay in recovery from anaphylaxis in these mice. These data thus provide evidence that TRPC1 promotes recovery from the anaphylactic response by repressing antigen-mediated TNF-alpha release from MCs.
|Gotlib, Jason; Pardanani, Animesh; Akin, Cem et al. (2013) International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. Blood 121:2393-401|