TGF-Beta Regulates B Lymphocyte Development & Function

说明(申请人提供)：转化生长因子-B (转化生长因子-β)是一种有效的体外增殖分化抑制因子， 以及包括B系细胞在内的多种细胞类型的存活。在小鼠身上 通过基因靶向缺乏转化生长因子-β1(转化生长因子-β1-/-)，有一种扩增 B细胞及其浆细胞子代II外周淋巴器官 表型与细胞因子的抗增殖作用一致 相比之下，我们没有观察到B细胞前体细胞在 骨髓，但相反，发现了年龄相关性的减少 转化生长因子-β1-/-小鼠的祖细胞。B的中试研究结果 正常小鼠的造血祖细胞表明，极低剂量的 转化生长因子-β可能促进前B细胞的存活或分化。这些 观察结果导致了一种假设，即转化生长因子-β对B细胞有积极影响 谱系祖细胞在其发育的特定时间点。为了测试这一点 假说，以探索机制，并了解意外的特点 在体内没有转化生长因子-β1的情况下出现的B细胞发育， 提出了具体的目标。目标1：定义表型和分化 转化生长因子-β1-/-B细胞前体细胞的潜能。在这一目标中，对 还将检查祖细胞缺陷的T细胞。目标2：实现 定义正常B细胞发育的转化生长因子-β反应阶段。目标3：TD 研究B细胞发育过程中自分泌转化生长因子-β的必要性 利用嵌合小鼠模型进行体内分化。目标4：在体内创造 B系细胞对转化生长因子-B选择性无反应的模型这些 研究涉及B细胞发育的基本机制及其通过以下方式放松调控 细胞因子缺乏。为这些实验创建的小鼠模型可能会成为 研究自身免疫性疾病和抗转化生长因子β的有价值的工具 恶性肿瘤。

DESCRIPTION (Provided by the Applicant): Transforming Growth Factor-B (TGF-beta) is a potent inhibitor of the in vitro proliferation differentiation, and survival of many cell types including B lineage cells. In mice made deficient in TGF-beta 1 by gene targeting (TGF-B 1-/-), there is an expansion of B-cells and their plasma cell progeny ii peripheral lymphoid organs, a phenotype consistent with the anti-proliferative effects of the cytokine By contrast, we did not observe an equivalent expansion of B-cell progenitors in the bone marrow, but instead have identified an age-dependent reduction in the progenitor cells of the TGF-beta 1-/- mice. Results of pilot studies on B lineage progenitor cells from normal mice indicate that very low doses of TGF-beta may promote the survival or differentiation of pre-B-cells. These observations have led to the hypothesis that TGF-beta positively influences B lineage cell progenitors at specific points in their development. To test this hypothesis, to explore mechanisms, and to understand the unexpected features of B-cell development that arise in the absence of TGF-B 1 in vivo, the following Specific Aims are proposed. Aim 1: To define the phenotype and differentiation potential of TGF-beta 1-/- B cell progenitors. In this aim the requirement for T-cells in the progenitor cell deficiency will also be examined. Aim 2: To define the TGF-beta-responsive stages of normal B-cell development. Aim 3: Td examine the need for autocrine TGF-beta in B-cell development and differentiation in vivo using chimeric mouse models. Aim 4: To create in vivo models in which B lineage cells are selectively unresponsive to TGF-B. These studies address basic mechanisms of B-cell development and its deregulation by cytokine deficiency. The mouse models created for these experiments may become valuable tools for studies of autoimmune diseases and TGF-beta-resistant human malignancies.