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: 7485793
• 负责人: Thomas J Kipps
• 金额: $ 32.96万
• 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/7485793
• 关键词: Adenovirus Vector; Affinity; Antibodies; Autoantigens; B-Lymphocytes; Binding; Cells; Chronic Lymphocytic Leukemia; Complex; Development; Disease; Disease Progression; Gene Expression; Genes; Human; Immune response; Immunoglobulin Genes; Immunoglobulin Idiotypes; Immunoglobulin M; Immunoglobulins; Immunotherapy; Indolent; Indolent Clinical Course; Ligation; Memory; Molecular Profiling; Mutate; Patients; Phase; Phase II Clinical Trials; Play; Protein Tyrosine Kinase; Receptor Signaling; Receptors, Antigen, B-Cell; Recombinant CD40-Ligand; Recombinants; Role; Signal Transduction; Transfection; Transgenic Mice; Transgenic Organisms; Work; ZAP-70 Gene; leukemia; leukemogenesis; mouse model; mutant; therapeutic target; variable region gene

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.

我们在确定免疫球蛋白(Ig)可变区基因(V基因)在慢性淋巴细胞白血病(CLL)中的应用方面取得了重大进展。先前的研究表明，对Ig V基因谱系的限制已经被扩大，揭示在CLL中表达的Ig可能是因为它们能够以低亲和力结合多种自身抗原而被选择。我们用表达这种多反应的人类IgM的B细胞产生了转基因小鼠，并发现这些细胞可以分化为边缘区(MZ)，即记忆型B细胞。这种MZ B细胞与CLL细胞具有相同的基因表达谱。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受体信号在白血病发生和/或疾病进展中是否发挥作用。最近的研究表明，表达突变免疫球蛋白的CLL细胞的患者比那些表达未突变免疫球蛋白基因的CLL细胞患者的临床病程更缓慢。基因表达研究表明，表达未突变Ig的CLL细胞可以通过相对较小的基因子集的差异表达而与更懒惰的类型区分开来，其中一个基因编码ZAP-70。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细胞通过B细胞受体(BCR)复合体有更熟练的信号传递。使用腺病毒载体编码野生型或突变型ZAP-70的转染研究正在帮助解决ZAP-70是否在bcr信号转导中发挥作用，从而起到治疗作用。 这种疾病的靶点。最后，该项目的工作导致了通过使用通过CD40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CD40配体的重组腺病毒载体(Ad-CD154)进行的I期和早期II期临床试验是对这一建议所做工作的直接表现。进一步的研究可能使我们能够改进这一方法，为这种疾病患者开发真正有效的免疫疗法。