Immunodeficiencies that impair lymphocyte survival

损害淋巴细胞存活的免疫缺陷

• 批准号: 7074652
• 负责人: Robert Thomas Woodland
• 金额: $ 39.33万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074652
• 关键词: B lymphocyte; Retroviridae; apoptosis; biological signal transduction; flow cytometry; gene expression; gene targeting; gene therapy; immunodeficiency; immunogenetics; laboratory mouse; ligands; lymphocyte proliferation; protein tyrosine kinase; sex linked trait; transfection /expression vector

DESCRIPTION (provided by applicant): We have recently shown that mature and immature B lymphocytes actively replicate upon transfer into B-cell deficient hosts (Cabatingan et.al. J. Immunol. 2002. 169:6765). This homeostatic B cell proliferation (B cell HP) is dependent on Bruton's tyrosine kinase (BTK), inhibited at high B cell densities, independent of antigen and T cells, active at low levels in normal hosts and distinct from more "conventional" mitogenic responses as replicating cells retain a naive phenotype. New results show B cell HP absolutely requires BLyS (B lymphocyte stimulator) as a costimulator that induces the biochemical changes necessary to support B cell growth and division. BLyS stimulation is BTK-independent and synergizes with BTK-dependent inductive signals to initiate B cell HP. HP in B cells is a unique response to B cell deficit that may be important for maintaining B cell numbers and selectively expanding the naive B cell repertoire. The proposed studies will identify unique components of each of the signal pathways necessary for B cell HP, establish the interdependence of the BCR, the BLyS receptor (BR3) and B cell HP and determine the anatomical sites and cells necessary to support B cell HP. Aim 1 is to determine the mechanism of HP signaling using pharmacological inhibitors to define critical components unique to the BTK-dependent inductive pathway and the BLyS dependent BTK-independent lymphotrophic pathway using separate in vitro assays specific for each process. The functional relevance of the signaling components initially identified in this screen will be confirmed using genetic approaches with in vitro and in vivo analyses. Aim 2 is to determine the interactions between BCR and BR3, the two major nonredundant regulators of B cell homeostasis and B cell HP. Using BCR ablated and monoclonal B cell populations, we will determine if the BCR modulates HP by affectingBR3 expression or function and determine directly if the BCR can provide the BTK-dependent inductive signals required for HP thereby biasing the naive Ig repertoire. Aim 3 is to identify the location and cells in the spleen that deliver the inductive and lymphotrophic signals necessary for B cell HP and to determine if ligands delivering these signals are unique to the spleen. Understanding the mechanism of B cell HP will provide new strategies for effecting immune reconstitution in the aged or immunodeficient or following chemotherapy or recovery from lymphotoxic infections.

描述（由申请人提供）：我们最近表明，成熟和未成熟的B淋巴细胞在转移到B细胞缺陷宿主后会积极复制（Cabatingan等人，J. Immunol. 2002. 169：6765）。这种稳态B细胞增殖（B细胞HP）依赖于布鲁顿酪氨酸激酶（BTK），在高B细胞密度下受到抑制，不依赖于抗原和T细胞，在正常宿主中以低水平活跃，并且与更“常规”的促有丝分裂应答不同，因为复制细胞保留幼稚表型。新的结果表明，B细胞HP绝对需要BLyS（B淋巴细胞刺激因子）作为共刺激因子，诱导支持B细胞生长和分裂所必需的生化变化。BLyS刺激是BTK非依赖性的，并与BTK依赖性诱导信号协同作用以启动B细胞HP。B细胞中的HP是对B细胞缺陷的独特应答，其对于维持B细胞数量和选择性扩增幼稚B细胞库可能是重要的。拟定的研究将确定B细胞HP所需的每种信号通路的独特组分，确定BCR、BLyS受体（BR 3）和B细胞HP的相互依赖性，并确定支持B细胞HP所需的解剖部位和细胞。目的1是使用药理学抑制剂确定HP信号传导的机制，以使用对每个过程特异性的单独体外测定来定义BTK依赖性诱导途径和BLyS依赖性BTK非依赖性淋巴细胞营养途径特有的关键组分。在该筛选中最初鉴定的信号传导组分的功能相关性将使用遗传方法通过体外和体内分析来确认。目的2是确定BCR和BR 3之间的相互作用，这两个主要的非冗余调节B细胞稳态和B细胞HP。使用BCR消融和单克隆B细胞群，我们将确定BCR是否通过影响BR 3表达或功能来调节HP，并直接确定BCR是否可以提供HP所需的BTK依赖性诱导信号，从而使幼稚IG库产生偏倚。目的3是鉴定脾中传递B细胞HP所需的诱导和淋巴细胞信号的位置和细胞，并确定传递这些信号的配体是否是脾所特有的。了解B细胞HP的作用机制，将为老年人、免疫缺陷者、化疗后或慢性光损伤后的免疫重建提供新的策略。