Pathogenesis and Treatment of Idiopathic Anaphylaxis

截至本报告日期，特发性速发型过敏反应患者继续入选研究。 大多数患者入住住院部，并接受骨髓程序，试图阐明病因并评估其疾病的发病机制。患者也有研究血液抽取沿着与常规实验室。我们与NIH临床中心的骨髓核心设施合作，根据当前WHO诊断系统性肥大细胞增多症的标准评估所有患者的骨髓抽吸物和活检。 培养来自外周单核细胞的肥大细胞，并与来自健康志愿者的肥大细胞进行比较，以进行肥大细胞生长和活化研究。在研究的一个方面，并在探索与供体相关的人类肥大细胞反应的差异，我们研究了肥大细胞活化的影响PGE 2和选择性PGE 2受体配体。我们观察到大约一半的供体的人肥大细胞对PGE 2和PGE 2 EP 3受体激动剂硫前列酮没有反应。然而，来自剩余供体的肥大细胞和LAD 2人肥大细胞系对PGE 2和硫前列酮作出反应，抗原介导的脱粒和IL-8产生显著增强。EP 2激动剂，布他前列素，未能调节任何类型的肥大细胞中的抗原介导的反应。这些不同的表型不能用EP 2或EP 3表达的差异或PGE 2升高cAMP水平的能力的差异来解释。此外，响应者和非响应者肥大细胞群体表现出类似的磷脂酰肌醇3-激酶和MAP激酶的激活。然而，PLC γ 1易位到细胞膜和相关的钙信号增强，只有在响应人群。这些数据提供了与供体相关的人肥大细胞依赖性应答的变异性的一个原因，以及提供了检查共活化受体在易受过敏性疾病影响的患者中的作用的基础。 奥马珠单抗（09-I-0129）的随机化治疗方案正处于患者招募阶段。

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.