SCID MICE AND THE CONTROL OF LYMPHOCYTE DIFFERENTIATION

SCID 小鼠和淋巴细胞分化的控制

• 批准号: 3125427
• 负责人: MELVIN J BOSMA
• 金额: $ 24.19万
• 依托单位: INSTITUTE FOR CANCER RESEARCH
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-05-01 至 1991-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3125427
• 关键词: B lymphocyte; T lymphocyte; antibody dependent killer cell; antibody receptor; athymic mouse; binding proteins; genetic manipulation; genetic markers; hybridomas; immunogenetics; immunoglobulin genes; immunoglobulin idiotypes; immunoglobulins; immunoregulation; laboratory mouse; leukocyte activation /transformation; monoclonal antibody; mouse leukemia; neoplasm /cancer immunology; neoplasm /cancer transplantation; radiation immunosuppression; radiotracer; suppressor T lymphocyte; tissue /cell culture

Normal lymphocyte maturation is blocked in mutant C.B-17scid mice; consequently, they lack functional T and B cells. However, some scid mice are "leaky" (approximately 15%); i.e., they spontaneously produced large quantities of immunoglobulin (Ig); preliminary evidence suggests that the B cells responsible are few in number and may all derive from a common B lymphocyte stem cell (B-LSC). We propose to test this possibility in several ways using Igh allotypes and novel Igh gene rearrangements as clonal markers. Assuming that monoclonality will apply to most leaky scid mice, we will evaluate the capacity of B-LSC for lymphocyte generation and replacement (persistence and quantity of Igh allotype levels) and diversity (number and kind of Igh-V genes expressed). This capacity will be compared to that of less committed hematopoietic stem cells (HSC). That is, we will deliberately make scid mice "leaky" by reconstitution with B (and T) lymphocyte progency of a single normal HSC. Reconstitution will be accomplished by co-transfer of limiting numbers of BALB/c (Igh-a) and C.AL-20 (Igh-d) fetal liver cells into C.B-17scid (Igh-b) neonates (and embryos). Igh allotypes will serve as clonal markers. Varying the genotype and age of donors and recipients will enable us to examine both T and B cell lineages and the effect of different microenvironments on stem cell growth and differentiation. The value of the scid mouse model for the proposed study is that it enables us to assay the in vivo potential of stem cells at different stages of development and in the context of a normal developmental progression. Many reconstituted scid mice may show unrestricted lymphoid differentiation; i.e.; both T and B lymphocyte replacement. Leaky scid mice, on the other hand, should enable us to study restricted lymphoid differentiation; i.e., B lymphocyte generation in the absence of T cells and in the absence of recruitment of less committed HSC (functional T cells have not yet been detected in any scid mice).

突变型 C.B-17scid 小鼠中正常淋巴细胞成熟受阻； 因此，它们缺乏功能性 T 细胞和 B 细胞。 然而，有些 scid 小鼠 “泄漏”（约 15%）；也就是说，他们自发地产生了大量的 免疫球蛋白 (Ig) 的量；初步证据表明，B 负责的细胞数量很少，并且可能全部源自共同的 B 淋巴细胞干细胞（B-LSC）。 我们建议测试这种可能性 使用 Igh 同种异型和新颖的 Igh 基因重排的几种方法 克隆标记。 假设单克隆性适用于大多数泄漏 scid 小鼠，我们将评估 B-LSC 生成淋巴细胞的能力和 替代（Igh 同种异型水平的持续性和数量）和多样性 （表达的 Igh-V 基因的数量和种类）。 这个容量将被比较 与定向程度较低的造血干细胞 (HSC) 相比。 也就是说，我们将 通过用 B（和 T）重构故意使 scid 小鼠“渗漏” 单个正常 HSC 的淋巴细胞后代。 重组将是 通过有限数量的 BALB/c (Igh-a) 和 C.AL-20 (Igh-d) 胎儿肝细胞转化为 C.B-17scid (Igh-b) 新生儿（和 胚胎）。 Igh 同种异型将作为克隆标记。 改变 捐赠者和接受者的基因型和年龄将使我们能够检查 T 和B细胞谱系以及不同微环境对干细胞的影响 细胞生长和分化。 scid 小鼠模型对于本研究的价值在于它能够 我们检测干细胞在不同阶段的体内潜力 发育和正常发育进程的背景下。 许多 重组的 scid 小鼠可能表现出不受限制的淋巴分化； IE。; T 和 B 淋巴细胞替代。 另一方面，漏水的 scid 小鼠 另一方面，应该使我们能够研究限制性淋巴分化； IE。， 在缺乏 T 细胞和缺乏 T 细胞的情况下生成 B 淋巴细胞 招募不太投入的 HSC（功能性 T 细胞尚未被 在任何 scid 小鼠中均检测到）。