B-cell repertoires in chronic lymphocytic leukemia

慢性淋巴细胞白血病的 B 细胞库

• 批准号: 7585135
• 负责人: Nicholas Chiorazzi
• 金额: $ 32.08万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7585135
• 关键词: Address; Affect; Affinity; Aggressive course; Antibodies; Antigen Receptors; Antigens; Apoptosis; Apoptotic; Autoantigens; Autoimmune Process; Autoimmunity; Avidity; B cell repertoire; B-Lymphocyte Epitopes; B-Lymphocytes; Back; Bacteria; Binding; Biology; Blood; Blood Circulation; Cell Communication; Cell Survival; Cells; Cellular biology; Chronic Lymphocytic Leukemia; Clinical; Code; Data; Development; Diagnosis; Disease; Disease Outcome; Elements; Epitopes; Etiology; Evolution; Fruit; Funding; Future; Generic Drugs; Genes; Genotype; Health system; Healthcare Systems; Immune; Immune response; Immune system; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Indium; Individual; Interdisciplinary Study; Invaded; Lead; Leukemic Cell; Libraries; Life; Ligands; Mediating; Memory; Microbe; Modeling; Molecular; Mono-S; Mutate; Nature; Nucleic Acids; Oligonucleotides; Organism; Outcome; Oxidative Stress; Pathway interactions; Patients; Pattern; Peptide Phage Display Library; Peptides; Phage Display; Physiological; Positioning Attribute; Process; Progress Reports; RNA; Receptors, Antigen, B-Cell; Recruitment Activity; Research Personnel; Sampling; Signal Pathway; Signal Transduction; Solid; Somatic Mutation; Sorting - Cell Movement; Source; Specificity; Structure; Subgroup; Surface; T-Lymphocyte; TLR9 gene; Testing; Therapeutic Studies; Tissues; To autoantigen; Upper arm; Variant; Western World; Work; antigen binding; autoreactive B cell; autoreactivity; base; chemokine; crosslink; cytokine; differentiated B cell; experience; functional outcomes; in vivo; leukemia; lymphoid neoplasm; member; microorganism antigen; middle age; mimetics; novel therapeutics; oligo(U); pre-clinical; preclinical study; public health relevance; receptor; response; trafficking

DESCRIPTION (provided by applicant): B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in the US, is an incurable disease of unknown etiology affecting middle-aged and older individuals. Patients with CLL have variable clinical courses: some live for decades without therapy, whereas others succumb in a few years after diagnosis despite treatment. Our data indicate that CLL is a monoclonal disease of autoreactive B cells with receptors for antigen (BCRs) of very restricted structure. BCR structure relates to disease outcome because patients with BCRs without IgVH somatic mutations (U-CLL) have a much more aggressive course than patients with BCRs with somatic mutations (M-CLL). The principles governing the biology of CLL cells are similar to those of systemic autoimmunity. Autoantigens cull susceptible B cells out of the normal repertoire and into the disease process; this autoantigen selection is probably aided by intermittent stimulation by microbes. Autoantigenic drive does not appear to stop at leukemic transformation, and we believe this factor is the most important in determining the fate of CLL cells and also of the patient. For these reasons, defining the specific immunoreactive epitopes of the autoantigens that drive the leukemic process is critical. In our studies we will focus on autoantigens that emerge during cellular apoptosis; these autoantigens can be of native structure or chemically modified during the apoptotic process. The autoantigenic epitopes as well as mimetic epitopes from phage-display libraries will be delineated, key residues involved in epitope-BCR affinity scrutinized, and then altered to obtain variants with greater or lesser binding constants (Aim 1). Because the consequences of autoantigen binding determine leukemic cell fate, it is pivotal to determine these and establish the parameters that decide cell fate. CLL cells will be stimulated with surrogate antigens and native or mimetic epitopes that vary in form (soluble vs. insoluble), valency (monomeric vs. multimeric), and affinity (low, intermediate, and high) for the BCR. Initials studies will focus on the mechanisms whereby low-affinity BCR engagement leads to CLL cell apoptosis (Aim 2). Since in vivo B lymphocytes receive signals from several sources and through multiple pathways, we will look for synergy or antagonism between BCR-mediated signals and those delivered through intracellular Toll- like receptor 9 (Aim 3). The results of these studies will provide a structural and mechanistic understanding of the relevant autoantigens in this disease and how these autoantigens stimulate CLL cells, ultimately impacting on patient survival. They will lay the groundwork for future pre-clinical studies targeting the BCRs and the antigens bound in this incurable disease. PUBLIC HEALTH RELEVANCE B-cell chronic lymphocytic leukemia is a common, incurable disease, affecting middle-aged and older individuals when they could be enjoying the fruits of their working years. The results of our studies will provide an understanding of how this type of leukemia cell is stimulated to grow. The studies lay the groundwork for future therapies which will target the stimulants or the molecules on the leukemia cells that the stimulants bind.

描述（由申请人提供）：B细胞慢性淋巴细胞白血病（CLL）是美国最常见的白血病，是一种影响中老年人的病因不明的不治之症。 CLL 患者的临床病程各不相同：有些患者无需治疗即可存活数十年，而另一些患者尽管接受治疗，但仍会在诊断后几年内死亡。我们的数据表明，CLL 是一种自身反应性 B 细胞的单克隆疾病，其抗原受体 (BCR) 的结构非常有限。 BCR 结构与疾病结果相关，因为没有 IgVH 体细胞突变 (U-CLL) 的 BCR 患者比有体细胞突变 (M-CLL) 的 BCR 患者具有更具侵袭性的病程。 CLL 细胞的生物学原理与系统性自身免疫相似。自身抗原将易感 B 细胞剔除出正常库并进入疾病过程；这种自身抗原的选择可能是通过微生物的间歇性刺激来帮助的。自身抗原驱动似乎并没有在白血病转化时停止，我们相信这个因素在决定 CLL 细胞以及患者的命运方面是最重要的。由于这些原因，确定驱动白血病过程的自身抗原的特异性免疫反应表位至关重要。在我们的研究中，我们将重点关注细胞凋亡过程中出现的自身抗原；这些自身抗原可以是天然结构或在细胞凋亡过程中经过化学修饰。将描绘来自噬菌体展示文库的自身抗原表位以及模拟表位，仔细检查表位-BCR亲和力涉及的关键残基，然后进行改变以获得具有更大或更少结合常数的变体（目标1）。由于自身抗原结合的结果决定了白血病细胞的命运，因此确定这些并建立决定细胞命运的参数至关重要。 CLL 细胞将用替代抗原和天然或模拟表位刺激，这些表位的形式（可溶性与不溶性）、化合价（单体与多聚体）以及对 BCR 的亲和力（低、中和高）各不相同。初步研究将重点关注低亲和力 BCR 参与导致 CLL 细胞凋亡的机制（目标 2）。由于体内 B 淋巴细胞通过多种途径接收来自多个来源的信号，因此我们将寻找 BCR 介导的信号与通过细胞内 Toll 样受体 9 传递的信号之间的协同或拮抗作用（目标 3）。这些研究的结果将提供对这种疾病中相关自身抗原的结构和机制的理解，以及这些自身抗原如何刺激 CLL 细胞，最终影响患者的生存。他们将为未来针对这种不治之症的 BCR 和抗原的临床前研究奠定基础。 公共卫生相关性 B 细胞慢性淋巴细胞白血病是一种常见的、无法治愈的疾病，影响着本可以享受工作成果的中老年人。我们的研究结果将有助于了解如何刺激这种类型的白血病细胞生长。这些研究为未来的治疗奠定了基础，这些治疗将针对兴奋剂或兴奋剂结合的白血病细胞上的分子。