TSLP AND LYMPHOPOIESIS

胸腺和骨髓的基质细胞在 淋巴细胞发育通过涉及细胞接触和 细胞因子的提炼。一种新的细胞因子，称为胸腺基质- 衍生淋巴生成素(TSLP)及其相应的受体 细胞因子的确定基于TSLP促进B细胞的能力 体外淋巴生成。本申请中提出的研究将提供 关于这部小说的几个相关方面的基本信息 细胞因子。首先，关于TSLP的细胞来源的新信息 以及该细胞因子受体在不同人群中的分布 将会产生大量的淋巴样细胞。第二，几种分析方法 将用于确定特定人群的响应性 未成熟B、T细胞对外源性TSLP的影响 外源性TSP或TSLP剥夺对T、B淋巴细胞体外和体外培养的影响 活着。第三，因为初步数据表明IL7R 对功能性TSLP受体的贡献，即假设 在胸腺中高表达的TSLP的作用可能有 将测试与IL7的功能重叠。这样的关系可以 解释IL7-/-中观察到的症状严重程度的差异 和IL7R-/-小鼠与B、T淋巴细胞分化敏感性的关系 缺乏白介素7。第四，基于人类自身免疫表型。 过度表达TSLP的转基因小鼠，他们假设改变了水平 TSLP的缺失可能会导致正常维持自我调节的机制被破坏 容忍度将接受测试。关于TSLP生产的基本信息， 靶细胞对该细胞因子的反应及其功能后果 TSLP水平改变对淋巴细胞发育和功能的影响可能会导致 用于人类同源物的鉴定，并可能用于临床 关联性。这些研究可能最终导致治疗方式的出现 这可能有益于逆转初级或获得性的影响 免疫缺陷会影响淋巴细胞的产生，并可能对 设计延缓与年龄相关的淋巴细胞生成下降的方法。 理解TSLP过度表达导致细胞死亡的机制(S) 自身免疫症状的发展可能导致一种新的范式来研究 自身免疫的发病机制。

Stromal cells of the thymus and bone marrow play important roles in lymphocyte development through mechanisms that involve cell contact and the elaboration of cytokines. A novel cytokine, termed thymic stroma- derived lymphopoietin (TSLP), and a corresponding receptor for this cytokine have been identified based on the ability of TSLP to promote B lymphopoiesis in vitro. Studies proposed in this application will provide basic information regarding several related aspects of this novel cytokine. First, new information regarding the cellular sources of TSLP and the distribution of receptors for this cytokine among different populations of lymphoid cells will be generated. Second, several assays will be used to determine the responsiveness of defined populations of immature B and T cells to exogenous TSLP and examine the effect of exogenous TSP or TSLP deprivation on T and B lymphopoiesis in vitro and in vivo. Third, because of preliminary data indicating that the IL7R contributes to the functional TSLP receptor, the hypothesis that the action of TSLP, which is highly expressed in the thymus, may have functional overlap with IL7 will be tested. Such a relationship may account for the disparities in the severity of symptoms observed in IL7-/- and IL7R-/- mice and the differential sensitivity of B and T lymphopoiesis to the lack of IL7. Fourth, based on the autoimmune phenotype exhibited by transgenic mice over-expressing TSLP, they hypothesis that altered levels of TSLP may lead to disruption of mechanisms that normally maintain self- tolerance will be tested. The basic information regarding TSLP production, target cells responding to this cytokine, and the functional consequences of altered levels of TSLP on lymphocyte development and function may lead to the identification of the human homologue and may be of clinical relevance. These studies could ultimately lead to therapeutic modalities that may be beneficial in reversing the effects of primary or acquired immunodeficiencies affecting lymphocyte production and may be useful in designing approaches to retard age-related decline of lymphopoiesis. Understanding the mechanism(s) whereby overexpression of TSLP leads to the development of autoimmune symptoms may lead to a new paradigm to study the pathogenesis of autoimmunity.