Antibody V Gene Expression B Cell Lymphocytic Leukemia

抗体 V 基因表达 B 细胞淋巴细胞白血病

• 批准号: 6888453
• 负责人: Thomas J Kipps
• 金额: $ 34.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-21 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6888453
• 关键词: B lymphocyte; CD40 molecule; antigen presenting cell; antitumor antibody; autoantibody; cellular oncology; chronic lymphocytic leukemia; clinical research; disease /disorder model; gene expression; gene frequency; genetically modified animals; human population genetics; human subject; immunoglobulin genes; immunoglobulin structure; laboratory mouse; molecular oncology; neoplasm /cancer genetics; neoplasm /cancer immunotherapy; neoplastic cell; patient oriented research; protein structure function; therapy design /development; tissue /cell culture

We have made significant progress in defining the use of immunoglobulin (Ig) variable region genes (V genes) in chronic lymphocytic leukemia (CLL). Prior studies suggesting restriction in the Ig V gene repertoire have been extended, revealing that the Ig expressed in CLL possibly are selected for their ability to bind multiple self-antigens with low affinity. We generated transgenic mice with B cells that express such polyreactive human IgM and found that these cells can differentiate into marginal zone (MZ), memory-type B cells. Such MZ B cells share gene expression profiles with that of CLL cells. These and other newly developed transgenic mouse models of CLL will allow us to evaluate whether Ig receptor signaling plays a role in leukemogenesis and/or disease progression. Recent studies have revealed that patients with CLL cells expressing mutated Ig have a more indolent clinical course that those with CLL cells that express unmutated Ig genes. Gene expression studies revealed that CLL cells expressing unmutated Ig could be distinguished from the more indolent type through the differential expression of a relatively small subset of genes, one of which encodes ZAP-70. We found that CLL cells that express this protein tyrosine kinase have more proficient signaling via the B cell receptor (BCR) complex than CLL cells that do not express ZAP-70. Transfection studies using adenovirus vectors encoding wild type or mutant forms of ZAP-70 are helping to resolve whether ZAP-70 plays a functional role in BCR signaling that can serve as a therapeutic target in this disease. Finally, work on this project has led to development of strategies for inducing anti-leukemia immune responses via the use of CLL cells that are activated via CD40-ligation. Phase I and early phase II clinical trials using recombinant adenovirus vectors encoding a recombinant CD40-ligand (Ad-CD154) are direct manifestations of work performed on this proposal. Further studies could enable us to refine this approach toward development of truly effective immune therapy for patients with this disease.

免疫球蛋白（IG）可变区基因（V基因）在慢性淋巴细胞白血病（CLL）中的应用研究取得了重大进展。先前的研究表明，限制在IG V基因库已经扩展，揭示了IG在CLL中表达可能是选择他们的能力，结合多种自身抗原的低亲和力。我们用表达这种多反应性人IgM的B细胞产生转基因小鼠，并发现这些细胞可以分化成边缘区（MZ）记忆型B细胞。这种MZ B细胞与CLL细胞共享基因表达谱。这些和其他新开发的CLL转基因小鼠模型将使我们能够评估IG受体信号传导是否在白血病发生和/或疾病进展中起作用。最近的研究已经揭示，具有表达突变的IG的CLL细胞的患者比具有表达未突变的IG基因的CLL细胞的患者具有更惰性的临床过程。基因表达研究揭示，表达未突变的IG的CLL细胞可以通过相对小的基因子集的差异表达（其中之一编码ZAP-70）与更惰性的类型区分开。我们发现，表达这种蛋白酪氨酸激酶的CLL细胞比不表达ZAP-70的CLL细胞具有通过B细胞受体（BCR）复合物的更有效的信号传导。使用编码野生型或突变型ZAP-70的腺病毒载体的转染研究有助于解决ZAP-70是否在BCR信号传导中发挥功能作用，从而可以作为治疗剂。 针对这种疾病。最后，该项目的工作导致了通过使用通过CD 40连接激活的CLL细胞来诱导抗白血病免疫反应的策略的开发。使用编码重组CD 40配体（Ad-CD 154）的重组腺病毒载体进行的I期和早期II期临床试验是本提案工作的直接体现。进一步的研究可以使我们能够改进这种方法，为这种疾病的患者开发真正有效的免疫治疗。