TSLP AND LYMPHOPOIESIS

胸腺和骨髓的基质细胞在 通过涉及细胞接触的机制进行淋巴细胞发育， 细胞因子的加工。一种新的细胞因子，称为胸腺基质- 衍生的淋巴细胞生成素（TSLP）及其相应的受体 基于TSLP促进B的能力，已经鉴定了细胞因子 体外淋巴细胞生成。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细胞来源的新信息 以及这种细胞因子的受体在不同细胞中的分布 将产生淋巴样细胞群。第二，几种检测方法 将用于确定以下人群的反应性： 未成熟的B和T细胞对外源性TSLP的作用，并检查 外源性TSP或TSLP剥夺对T和B淋巴细胞生成的体外和体内影响 vivo.第三，由于初步数据表明IL 7 R 有助于功能性TSLP受体，这一假说认为， TSLP在胸腺中高度表达，其作用可能 将测试与IL 7的功能重叠。这样的关系可以 解释了在IL 7-/-中观察到的症状严重程度的差异。 和IL 7 R-/-小鼠以及B和T淋巴细胞生成的差异敏感性 缺乏IL 7。第四，基于免疫表型， 转基因小鼠过度表达TSLP，他们假设改变水平 TSLP可能会导致正常维持自我的机制中断， 容忍度将受到考验。关于TSLP生产的基本信息， 靶细胞对这种细胞因子的反应，以及功能性后果 TSLP水平改变对淋巴细胞发育和功能的影响可能导致 人类同源物的鉴定，并可能是临床 本案无关这些研究可能最终导致治疗方式 这可能有助于逆转原发性或后天性 影响淋巴细胞产生的免疫缺陷， 设计方法来延缓与年龄相关的淋巴细胞生成下降。 了解TSLP过度表达导致肿瘤细胞凋亡的机制 自身免疫症状的发展可能会导致一个新的范式来研究 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.