An Animal Model of Hemophagocytic Lymphohistiocytosis
噬血细胞淋巴组织细胞增多症的动物模型
基本信息
- 批准号:8099560
- 负责人:
- 金额:$ 37.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-08-10 至 2013-06-30
- 项目状态:已结题
- 来源:
- 关键词:Activated LymphocyteAnimal ModelAntigen PresentationAntigensBirdsBloodBone MarrowBone Marrow CellsBone Marrow TransplantationBrainCD8B1 geneCaspaseCell physiologyCellsChildhoodDefectDendritic CellsDiseaseDisease modelEpstein-Barr Virus InfectionsFeverGenesGeneticHemophagocytic LymphohistiocytosesImmuneImmune responseInfectionInterferon Type IIInterferonsLeadLiverLymphocytic choriomeningitis virusMarrowModelingMusMutationNatural Killer CellsPancytopeniaPathogenesisPatientsPhenotypePopulationPopulation DynamicsProcessProductionRegulatory T-LymphocyteRelative (related person)RoleSeriesSplenomegalyStimulusSyndromeT-LymphocyteTestingViralViral AntigensVirusVirus Diseasesbasebonecell typecytotoxicimmune activationimmunoregulationimprovedin vivoinsightkillingsmacrophagemortalitynovelperforinresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): Hemophagocytic lymphohistiocytosis (HLH) is a childhood disorder of excessive and abnormal immune activation, characterized by severe damage to the bone marrow, and a mortality rate approaching 50%. Nearly all patients with HLH have a severe deficiency of cytotoxic killing by T and NK cells, and many of these patients have been found to harbor mutations in the gene encoding perforin. We developed a novel murine model of this disorder, in which perforin deficient (prf) mice are challenged with lymphocytic choriomeningitis virus (LCMV). Following infection, prf mice develop a phenotype that is nearly identical to HLH. Using this model, we have discovered that the HLH phenotype is directly driven by the abnormal overproduction of interferon gamma (IFN-g) by CD8+ T cells. Additionally, we have found that DC's from prf mice harbor increased amounts of viral antigen and acquire increased capacity to stimulate virus-specific T cells after infection. These findings implicate increased antigen presentation by DC populations as the underlying cause of IFN-g overproduction in prf mice, and suggest that perforin normally functions to down modulate antigen presentation. Multiple cell types that express perforin are known to interact with DC's. In order to identify which of these populations would normally down modulate stimulation by DC's, we have performed a series of cell depletion, transfer, and bone marrow transplantation experiments. These studies have revealed that perforin-expressing cell types can influence both DC function and in vivo IFN-g production, and suggest that CD8+ T cells are the most critical cell type exerting this regulatory effect. Based on our preliminary studies, we hypothesize that perforin-dependant cytotoxic killing of selected dendritic cells by CD8+ T cells limits the entry and/or persistence of antigen in DC populations, and thereby limits immune activation. To test our hypothesis, we will pursue the following specific aims: Aim 1.) Define how antigen handling and presentation differ between WT and prf DC subsets after LCMV infection. Aim 2.) Determine whether CD8+ T cells are the principle cell type that suppresses DC stimulatory function via a perforin-dependant mechanism. This project will lead to better understanding of how cytotoxic function regulates the immune response and lead to improved therapies for patients with HLH and perhaps many other immunopathologic disorders.
描述(由申请人提供):淋巴淋巴虫组织细胞增多症(HLH)是一种过度和异常免疫激活的儿童疾病,其特征是对骨髓严重损害,死亡率接近50%。几乎所有HLH患者均严重缺乏T和NK细胞的细胞毒性杀伤,其中许多患者被发现在编码perforin的基因中含有突变。我们开发了一种新型的这种疾病的鼠模型,其中淋巴细胞脉络膜脑膜炎病毒(LCMV)挑战了细胞蛋白缺乏(PRF)小鼠。感染后,PRF小鼠会形成与HLH几乎相同的表型。使用此模型,我们发现HLH表型是由CD8+ T细胞对干扰素伽马(IFN-G)异常产生的直接驱动的。此外,我们发现来自PRF小鼠的DC含有增加的病毒抗原量,并获得了增加感染后刺激病毒特异性T细胞的能力。这些发现表明,DC种群增加了抗原表现,是PRF小鼠IFN-G过量产生的根本原因,并建议穿孔蛋白通常功能降低调节抗原表现。已知多种表达穿孔蛋白的细胞类型与DC相互作用。为了确定这些人群通常会通过DC调节刺激,我们进行了一系列细胞耗竭,转移和骨髓移植实验。这些研究表明,表达性能的细胞类型可以影响直流功能和体内IFN-G产生,并表明CD8+ T细胞是发挥这种调节作用的最关键细胞类型。基于我们的初步研究,我们假设通过CD8+ T细胞对选定的树突状细胞的细胞毒性杀死限制了DC种群中抗原的进入和/或持久性,从而限制了免疫激活。为了检验我们的假设,我们将追求以下特定目的:目标1.)定义LCMV感染后WT和PRF DC子集之间的抗原处理和表现如何不同。目标2.)确定CD8+ T细胞是否是通过依赖穿孔蛋白依赖机制抑制直流刺激功能的原理细胞类型。该项目将更好地了解细胞毒性功能如何调节免疫反应,并改善HLH患者以及许多其他免疫病理疾病的患者的疗法。
项目成果
期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab.
- DOI:10.1002/pbc.24188
- 发表时间:2013-01
- 期刊:
- 影响因子:3.2
- 作者:Marsh, Rebecca A.;Allen, Carl E.;McClain, Kenneth L.;Weinstein, Joanna L.;Kanter, Julie;Skiles, Jodi;Lee, Nadine D.;Khan, Shakila P.;Lawrence, Julia;Mo, Jun Q.;Bleesing, Jack J.;Filipovich, Alexandra H.;Jordan, Michael B.
- 通讯作者:Jordan, Michael B.
Macrophage-Lineage Cells Negatively Regulate the Hematopoietic Stem Cell Pool in Response to Interferon Gamma at Steady State and During Infection.
- DOI:10.1002/stem.2040
- 发表时间:2015-07
- 期刊:
- 影响因子:0
- 作者:McCabe A;Zhang Y;Thai V;Jones M;Jordan MB;MacNamara KC
- 通讯作者:MacNamara KC
Molecular and cellular mechanisms of Mycobacterium avium-induced thymic atrophy.
- DOI:10.4049/jimmunol.1201525
- 发表时间:2012-10-01
- 期刊:
- 影响因子:0
- 作者:Borges M;Barreira-Silva P;Flórido M;Jordan MB;Correia-Neves M;Appelberg R
- 通讯作者:Appelberg R
Reduced-intensity conditioning haematopoietic cell transplantation for haemophagocytic lymphohistiocytosis: an important step forward.
- DOI:10.1111/j.1365-2141.2011.08785.x
- 发表时间:2011-09
- 期刊:
- 影响因子:6.5
- 作者:Marsh RA;Jordan MB;Filipovich AH
- 通讯作者:Filipovich AH
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Michael Jordan其他文献
Michael Jordan的其他文献
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