Desensitization of Human Mast Cells and Basophils: Mechanisms and Potential Utili

哮喘和过敏性疾病是重要的健康问题，肥大细胞和可能的嗜碱性粒细胞是 人免疫球蛋白E介导的即刻变态反应主要效应细胞调查人员之前的工作 参与项目1包括开发类胰蛋白酶作为肥大细胞激活的临床标志物；发现 哮喘呼吸道和全身过敏反应期间肥大细胞的激活；鉴定两种类型的肥大细胞 人肥大细胞(MCT和MCTC)分泌颗粒和表面的蛋白酶含量 CD88的表达；发现FcyRII的激活形式，CD32a，组成表达在 皮肤MCTC细胞表面；在具有非释放表型的嗜碱性粒细胞中发现Syk缺乏 体外抗原脱敏后的肥大细胞。当前项目的三个具体目标是： 1.验证人体肥大细胞和嗜碱性粒细胞在体外经历交叉脱敏的假设 通过FcsRI和FcvR11a的不同抗原和异源脱敏。事实上，初步的 数据表明，当MCTC型肥大细胞被IgE抗DNP致敏，然后脱敏 在低剂量的DNP-BSA中，交叉脱敏和异源脱敏都会发生。 2.探讨src和/或syk对人肥大细胞脱敏的体外机制(S) 酪氨酸激酶。尽管Syk似乎有可能枯竭，但LYN和/或FYN的参与尚不确定。 此外，信号的亚细胞区隔的可能性对于脱敏和 将检查激活情况。与Project 3合作研究Lyn Kinase在 脱敏，以及与项目4关于鞘氨醇激酶-1参与脱敏。 人类肥大细胞和嗜碱性粒细胞促进了这些机制的研究。 3.确定人体内青霉素脱敏是否产生抗原交叉脱敏 肥大细胞和嗜碱性粒细胞，并从外周血嗜碱性粒细胞中耗尽Syk。这 临床研究将开始将我们的体外研究结果转化为体内情况。 脱敏所致的临床耐受与免疫治疗所致的耐受可因其快速的 一旦停止给药，诱导期(小时)和短期持续期(天)。我们假设 脱敏主要针对肥大细胞和嗜碱性粒细胞。更准确地理解这些特征 脱敏背后的机制(S)将使医生能够更好地利用这种方法来 减少肥大细胞/嗜碱性粒细胞在哮喘和过敏性疾病中的作用。

Asthma and allergic diseases are important health concerns, and mast cells and possibly basophils are the major effector cells of IgE-mediated immediate hypersensitivy in humans. Previous work by the investigators involved in Project 1 includes developing tryptase as a clinical marker for mast cell activation; finding activation of mast cells in the asthmatic airway and during systemic anaphylaxis; identifying two types of human mast cells (MCT and MCTc) based on the protease content of their secretory granules and the surface expression of CD88; discovering the activating form of FcyRII, CD32a, constitutively expressed on the surface of skin MCTC cells; and finding Syk-deficiency in basophils with the non-releaser phenotype and in mast cells after antigen desensitization in vitro. The three specific aims of the current project are to: 1. Test the hypothesis that human mast cells and basophils in vitro undergo cross-desensitization to different antigens and heterologous desensitization through FcsRI and FcvRlla. Indeed, preliminary data suggest that when mast cells of the MCTc type are IgE anti-DNP-sensitized and then desensitized with low doses of DNP-BSA, both cross-desensitization and heterologous desensitization occurs. 2. Explore in vitro the mechanism(s) for desensitization of human mast cells involving Src and/or Syk tyrosine kinases. Although Syk depletion seems likely, the involvement of Lyn and/or Fyn is uncertain. Further, the possibility that subcellular compartmentalization of signaling differs for desensitization and activation will be examined. Collaborations with Project 3 on studies of Lyn kinase involvement in desensitization, and with Project 4 on the involvement of sphingosine kinase-1 in desensitization of human mast cells and basophils facilitate these mechanistic studies. 3. Determine whether penicillin desensitization of human subjects in vivo produces antigen crossdesensitization of mast cells and basophils and depletes Syk from peripheral blood basophils. This clinical study will begin to translate our in vitro findings to the in vivo situation. Clinical tolerance due to desensitization can be distinguished from that due to immunotherapy by its rapid induction (hours) and short persistence (days) once allergen administration ceases. We hypothesize that desensitization targets primarily mast cells and basophils. Understanding more precisely the characteristics of and the mechanism(s) behind desensitization will enable physicians to better utilize this approach to reduce mast cell/basophil-mediated contributions to asthma and allergic diseases.