Desensitization of Human Mast Cells and Basophils: Mechanisms and Potential Utili
人类肥大细胞和嗜碱性粒细胞的脱敏:机制和潜在用途
基本信息
- 批准号:8375530
- 负责人:
- 金额:$ 38.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至 2014-03-31
- 项目状态:已结题
- 来源:
- 关键词:2,4-DinitrophenolAllergensAllergic DiseaseAnaphylaxisAntigen-Antibody ComplexAntigensApoptosisAsthmaBasophilsBronchoalveolar Lavage FluidCarboxypeptidaseCathepsin GCell DegranulationCellsCharacteristicsChymaseClinicalClinical MarkersClinical ResearchCollaborationsDataDevelopmentDiseaseDoseEffector CellEvaluationEventHealthHeterophile AntigensHexosaminidasesHourHumanIgEImmunoassayImmunoglobulin GImmunotherapyIn VitroIndividualInflammatoryInsect StingInterleukin-4LungMediatingPathway interactionsPenicillinsPeptide HydrolasesPhenotypePhosphorylation SitePhosphotransferasesPhysiciansProtein Tyrosine KinaseResearch PersonnelSPHK1 enzymeSecretory VesiclesSerumSeveritiesSignal TransductionSkinSkin Test End-Point TitrationSmall Interfering RNAStimulusSurfaceSystemic MastocytosisT-LymphocyteTestingTractionTranslatingTryptaseWorkairborne allergenanti-IgEantigen desensitizationasthmatic airwaybasebeta-n-acetylhexosaminidasedesensitizationhuman SYK proteinhuman subjectin vivomast cellperipheral bloodpreventreceptorreceptor internalizationsphingosine kinasesrc-Family Kinases
项目摘要
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 (MC{T} and MC{TC}) 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 MC{TC} 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 FceRI and FcvRlla. Indeed, preliminary data suggest that when mast cells of the MC{TC} 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 cross-desensitization 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.
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IgE介导的人类速发型超敏反应的主要效应细胞。参与项目1的研究人员先前的工作包括开发类胰蛋白酶作为肥大细胞活化的临床标志物;发现哮喘气道和全身过敏反应期间肥大细胞的活化;鉴定两种类型的人类肥大细胞。(MC{T}和MC{TC}),基于其分泌颗粒的蛋白酶含量和CD 88的表面表达;发现Fc γ RII的活化形式,CD 32a,在细胞表面组成型表达,
皮肤MC{TC}细胞的表面;并在体外抗原脱敏后在具有非活化表型的嗜碱性粒细胞和肥大细胞中发现Syk缺陷。本项目的三个具体目标是:
1.检验人肥大细胞和嗜碱性粒细胞在体外经历对不同抗原的交叉脱敏和通过FceRI和FcvRIIa的异源脱敏的假设。事实上,初步数据表明,当MC{TC}型肥大细胞是IgE抗DNP致敏的,然后用低剂量的DNP-BSA脱敏时,发生交叉脱敏和异源脱敏。
2.体外探索Src和/或Syk酪氨酸激酶对人肥大细胞脱敏的机制。虽然Syk耗尽似乎是可能的,但林恩和/或Fyn的参与是不确定的。 此外,亚细胞区室化的信号转导不同的脱敏和激活的可能性将被检查。与项目3合作研究林恩激酶参与脱敏,与项目4合作研究鞘氨醇激酶-1参与人类肥大细胞和嗜碱性粒细胞脱敏,促进了这些机制研究。
3.确定人类受试者体内青霉素脱敏是否产生肥大细胞和嗜碱性粒细胞的抗原交叉脱敏,并从外周血嗜碱性粒细胞中清除Syk。这项临床研究将开始将我们的体外发现转化为体内情况。
脱敏引起的临床耐受性与免疫治疗引起的临床耐受性的区别在于,一旦过敏原给药停止,脱敏引起的临床耐受性可快速诱导(数小时)和短暂持续(数天)。我们假设脱敏主要针对肥大细胞和嗜碱性粒细胞。更准确地理解脱敏的特征和机制将使医生能够更好地利用这种方法来减少肥大细胞/嗜碱性粒细胞介导的哮喘和过敏性疾病的贡献。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lawrence B. Schwartz其他文献
Tryptase from human mast cells: biochemistry, biology and clinical utility.
- DOI:
- 发表时间:
1990 - 期刊:
- 影响因子:0
- 作者:
Lawrence B. Schwartz - 通讯作者:
Lawrence B. Schwartz
Human Mast Cells Derived From Fetal Liver Cells Cultured With Stem Cell Factor Express a Functional CD51/CD61 (αvβ3) Integrin
- DOI:
10.1182/blood.v86.3.930.930 - 发表时间:
1995-08-01 - 期刊:
- 影响因子:
- 作者:
Yuji Shimizu;Anne-Marie A. Irani;Eric J. Brown;Leonie K. Ashman;Lawrence B. Schwartz - 通讯作者:
Lawrence B. Schwartz
Isolation and Partial Characterization of the Multiple Forms of Deoxyribonucleic Acid-dependent Ribonucleic Acid Polymerase in the Mouse Myeloma, MOPC 315
- DOI:
10.1016/s0021-9258(20)79902-3 - 发表时间:
1974-09-01 - 期刊:
- 影响因子:
- 作者:
Lawrence B. Schwartz;Virgil E.F. Sklar;Judith A. Jaehning;Roberto Weinmann;Robert G. Roeder - 通讯作者:
Robert G. Roeder
Serum tryptase and the laboratory diagnosis of systemic mastocytosis.
血清类胰蛋白酶和系统性肥大细胞增多症的实验室诊断。
- DOI:
10.1016/s0889-8588(05)70300-2 - 发表时间:
2000 - 期刊:
- 影响因子:0
- 作者:
Lawrence B. Schwartz;Anne - 通讯作者:
Anne
Harmonization of Diagnostic Criteria in Mastocytosis for Use in Clinical Practice: WHO vs ICC vs AIM/ECNM
肥大细胞增多症诊断标准在临床实践中的统一:世界卫生组织(WHO)标准、国际肥大细胞增多症研究小组(ICC)标准与美国医学研究所/欧洲神经肌肉疾病中心(AIM/ECNM)标准之比较
- DOI:
10.1016/j.jaip.2024.08.044 - 发表时间:
2024-12-01 - 期刊:
- 影响因子:6.600
- 作者:
Peter Valent;Karin Hartmann;Gregor Hoermann;Andreas Reiter;Iván Alvarez-Twose;Knut Brockow;Patrizia Bonadonna;Olivier Hermine;Marek Niedoszytko;Melody C. Carter;Joseph H. Butterfield;Frank Siebenhaar;Roberta Zanotti;Deepti H. Radia;Mariana Castells;Wolfgang R. Sperr;Sigurd Broesby-Olsen;Massimo Triggiani;Lawrence B. Schwartz;Tracy I. George;Cem Akin - 通讯作者:
Cem Akin
Lawrence B. Schwartz的其他文献
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{{ truncateString('Lawrence B. Schwartz', 18)}}的其他基金
Cellular & Inflammatory Pathways in Ashtma & Allergic Diseases: From IgE to Cells
蜂窝网络
- 批准号:
7896937 - 财政年份:2009
- 资助金额:
$ 38.68万 - 项目类别:
Cellular & Inflammatory Pathways in Ashtma & Allergic Diseases: From IgE to Cells
蜂窝网络
- 批准号:
7426004 - 财政年份:2008
- 资助金额:
$ 38.68万 - 项目类别:
Desensitization of Human Mast Cells and Basophils: Mechanisms and Potential Utili
人类肥大细胞和嗜碱性粒细胞的脱敏:机制和潜在用途
- 批准号:
7476200 - 财政年份:2008
- 资助金额:
$ 38.68万 - 项目类别:
Cellular & Inflammatory Pathways in Ashtma & Allergic Diseases: From IgE to Cells
蜂窝网络
- 批准号:
8066999 - 财政年份:2008
- 资助金额:
$ 38.68万 - 项目类别:
Cellular & Inflammatory Pathways in Ashtma & Allergic Diseases: From IgE to Cells
蜂窝网络
- 批准号:
7792232 - 财政年份:2008
- 资助金额:
$ 38.68万 - 项目类别:
Cellular & Inflammatory Pathways in Ashtma & Allergic Diseases: From IgE to Cells
蜂窝网络
- 批准号:
7597155 - 财政年份:2008
- 资助金额:
$ 38.68万 - 项目类别:
Cellular & Inflammatory Pathways in Ashtma & Allergic Diseases: From IgE to Cells
蜂窝网络
- 批准号:
8243656 - 财政年份:2008
- 资助金额:
$ 38.68万 - 项目类别:
EVALUATION OF BASOPHIL INVOLVEMENT IN HUMAN DISEASE
嗜碱性粒细胞参与人类疾病的评估
- 批准号:
6055696 - 财政年份:1998
- 资助金额:
$ 38.68万 - 项目类别:
EVALUATION OF BASOPHIL INVOLVEMENT IN HUMAN DISEASE
嗜碱性粒细胞参与人类疾病的评估
- 批准号:
6171142 - 财政年份:1998
- 资助金额:
$ 38.68万 - 项目类别:
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