REGULATION DIFFERENCES IN SUBSETS OF ANTIDNA ANTIBODIES

抗体亚类的监管差异

• 批准号: 2769526
• 负责人: LINDA Ann SPATZ
• 金额: $ 10.83万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2769526
• 关键词: B lymphocyte; antibody formation; antinuclear autoantibody; biological signal transduction; gene expression; genetic library; genetically modified animals; hybridomas; immune tolerance /unresponsiveness; immunoglobulin G; immunoglobulin M; immunoglobulin genes; laboratory mouse; polymerase chain reaction

DESCRIPTION (Adapted from the Applicant's abstract): In mice transgenic for the R4A gamma2b heavy chain of an anti-double stranded (ds) DNA antibody, the transgenic heavy chain can pair with a variety of endogenous light chains to produce anti-dsDNA antibodies of different affinities and fine specificities. We have demonstrated that B-cells producing high affinity transgenic anti-dsDNA antibodies are regulated by anergy and deletion in non-autoimmune transgenic mice, whereas in the NZB/W F1 mouse strain, high affinity transgene encoded anti-dsDNA antibody is present in the serum. B-cell hybridomas have been generated from spleen and bone marrow cells of non-autoimmune and autoimmune transgenic mice. Initial results suggest that there are three subsets of transgenic anti-dsDNA secreting B-cells. One subset secretes a high affinity anti-dsDNA antibody that utilizes a Vk1 light chain and is targeted for anergy. These B-cells display a lack of allelic exclusion. Another subset secretes high affinity anti-dsDNA antibody encoded by non Vk1 light chains. These are targeted for deletion. A third subset secretes low affinity anti-dsDNA antibodies which escape regulation. These cells display intact allelic exclusion. We would like to confirm these results by obtaining additional hybridomas from bone marrow and spleen cells derived from non autoimmune transgenic mice. We would also like to determine why these populations of B-cells are regulated differently and we propose to identify affinity and fine specificity differences among these subsets. We will see if bcl-2 can rescue one or both of the subsets of B-cells secreting high affinity anti-dsDNA antibody. We recently generated mice transgenic for the R4Amu heavy chain transgene. We would like to compare the regulation of B-cells secreting transgenic IgM anti-dsDNA antibody with those secreting transgenic IgG2b anti-dsDNA antibody to determine if signaling mechanisms affecting tolerance induction differ between these two isotypes.

描述（改编自申请人的摘要）：在转基因小鼠中， 抗双链（ds）DNA抗体的R4 A γ 2b重链， 转基因重链可以与多种内源性轻链配对 链，以产生不同亲和力和精细的抗dsDNA抗体 特殊性 我们已经证明，产生高亲和力的B细胞 转基因抗双链DNA抗体是由无反应性和缺失调控的， 非自身免疫转基因小鼠，而在NZB/W F1小鼠品系中， 亲和转基因编码的抗dsDNA抗体存在于血清中。 B细胞杂交瘤已经从小鼠的脾和骨髓细胞中产生， 非自身免疫和自身免疫转基因小鼠。 初步结果表明， 有三种分泌转基因抗dsDNA的B细胞亚群。 一 亚群分泌高亲和力抗dsDNA抗体，其利用Vk 1 轻链，并针对无反应性。 这些B细胞缺乏 等位基因排斥 另一个亚群分泌高亲和力抗dsDNA 由非Vk 1轻链编码的抗体。 这些是要删除的。 第三个亚群分泌低亲和力抗dsDNA抗体， 调控 这些细胞显示完整的等位基因排斥。 我们想 通过从骨髓中获得另外的杂交瘤来证实这些结果 和来自非自身免疫转基因小鼠的脾细胞。 我们还 我想知道为什么这些B细胞群的调节方式不同 我们建议确定亲和力和精细特异性之间的差异， 这些子集。 我们将观察bcl-2是否能挽救一个或两个亚群 B细胞分泌高亲和力抗dsDNA抗体。 我们最近 产生R4 Amu重链转基因的转基因小鼠。 我们 我喜欢比较B细胞分泌转基因IgM的调节 抗dsDNA抗体与分泌转基因IgG 2b抗dsDNA抗体 抗体，以确定是否影响耐受诱导的信号传导机制 这两种同种型之间的差异。