TGF-Beta Regulates B Lymphocyte Development & Function

性状（申请人提供）：转化生长因子-B （TGF-β）是体外增殖分化的有效抑制剂， 以及包括B谱系细胞在内的许多细胞类型的存活。在小鼠中， 通过基因靶向（TGF-β 1-/-）， B细胞及其浆细胞后代在外周淋巴器官中的分布， 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细胞祖细胞的等效扩增， 骨髓，但相反，已经确定了一个年龄依赖性的减少， TGF-β 1-/-小鼠的祖细胞。关于B的试点研究结果 来自正常小鼠的谱系祖细胞表明， TGF-β可以促进前B细胞的存活或分化。这些 观察结果导致了TGF-β对B有积极影响的假设 谱系细胞祖细胞在其发育的特定点。为了验证这一 假设，探索机制，并了解意外的特点， 在体内缺乏TGF-β 1的情况下产生的B细胞发育， 提出了具体目标。目的1：确定表型和分化 TGF-β 1-/- B细胞祖细胞的潜力。在这一目标中， 还将检查祖细胞缺陷中的T细胞。目标2： 定义正常B细胞发育的TGF-β反应阶段。目标3：Td 检查B细胞发育中自分泌TGF-β的需要， 使用嵌合小鼠模型进行体内分化。目标4：在体内创造 其中B谱系细胞选择性地对TGF-B无反应的模型。这些 研究通过以下方式阐述了B细胞发育及其失调的基本机制： 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TGF-β人的有价值的工具 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.