Development of a B Cell Therapeutic

B 细胞治疗药物的开发

• 批准号: 10242831
• 负责人: Bonnie N Dittel
• 金额: $ 67.83万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10242831
• 关键词: Adoptive Cell Transfers; Affect; American; Attenuated; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; B Cell Proliferation; B-Lymphocyte Subsets; B-Lymphocytes; BLR1 gene; Biological; Biology; CRISPR/Cas technology; CXCL13 gene; Cell Count; Cell Proliferation; Cell Therapy; Cessation of life; Characteristics; Clinical Trials; Development; Disease; Dose; Engraftment; Ensure; Enterobacteria phage P1 Cre recombinase; FOXP3 gene; Face; Genes; Genetic Engineering; Glucocorticoids; Goals; HLA G antigen; Haplotypes; Homeostasis; Human; Human Herpesvirus 4; Image; Immune; Immune Tolerance; Immune response; Immune system; Immunoglobulin D; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infrastructure; Ligands; LoxP-flanked allele; Lymphocyte; MHC Class I Genes; MS4A1 gene; Mature B-Lymphocyte; Measures; Mediating; Mus; Names; Natural Killer Cells; Organ; Pathogenicity; Patients; Phenotype; Play; Population; Predisposition; Regulatory T-Lymphocyte; Role; Safety; Severities; Specificity; Spleen; Steroids; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Tissues; Treatment Cost; Tumor Necrosis Factor Receptor; War; adaptive immune response; anti-CD20; base; cell killing; chemokine; chemokine receptor; chimeric antigen receptor; cost; cost effective; cost estimate; design; inhibitor/antagonist; innovation; insight; migration; novel; overexpression; receptor; side effect; suicide gene; therapeutic target; virtual

Autoimmunity occurs due to a breakdown in immunological tolerance, leading to uncontrolled adaptive immune responses against self-tissues. There are an estimated 50 million Americans that suffer from autoimmunity, which encompasses 100+ different disorders, which collectively effect virtually every organ and tissue. With ~16% of the US population suffering from autoimmunity, in 2001, annual estimated costs for their treatment calculated were greater than $100 billion. While every autoimmune disease is associated with immune dysregulation, no universal treatments exist. This proposal aims to generate a novel, cost-effective, universal off-the-shelf adoptive cell therapy (ACT) that can be used to treat autoimmune disease by enhancing immunological tolerance. Our strategy is to harness the power of endogenous CD4+Foxp3+ T regulatory cells (Treg) to enhance immune tolerance thereby dampening immune responses to self-tissues. Treg suppress immune-mediated inflammatory responses making them a strong therapeutic target for the treatment of autoimmunity and other inflammatory diseases. In clinical trials, transiently increasing Treg numbers was deemed safe and showed some efficacy. However, Treg cellular therapy faces a number of challenges that need to be overcome. To that end, we propose capitalizing on our recent discovery of a new B cell subset that induces the proliferation of Treg. These B cells were named B cell IgDlow/- (BDL) because their expression of low/neg IgD is the defining characteristic used for their purification and study. BDL are distinct from all other B cells subsets and play an essential role in Treg homeostasis. We have conducted proof-of-concept studies that BDL could be genetically engineered to enhance and sustain Treg numbers long-term thereby attenuating the severity of inflammation. This proposal outlines a strategy to develop a first-of-its-kind ACT for the treatment of autoimmunity utilizing BDL regulatory mechanisms. Our ACT is designed to be off-the-shelf and able to be universally administered to any patient that could benefit from increased Treg-induced tolerance. This will not only transform how autoimmunity is treated, but will greatly reduce the cost of treatment.

自身免疫性由于免疫耐受性破裂而发生，导致不受控制的适应性免疫 反对自我组织的回应。估计有5000万美国人患有自身免疫性， 其中包含100多种不同的疾病，几乎统称每个器官和组织。和 〜2001年，美国自身免疫性遭受自身免疫性的16％，其治疗费用的年度估计费用 计算的大于1000亿美元。而每种自身免疫性疾病都与免疫有关 失调，不存在普遍治疗。该建议旨在产生一种新颖，经济有效的，普遍的 现成的收养细胞疗法（ACT），可通过增强来治疗自身免疫性疾病 免疫耐受性。我们的策略是利用内源性CD4+ FOXP3+ T调节细胞的力量 （Treg）增强免疫耐受性，从而抑制对自我组织的免疫反应。 treg抑制 免疫介导的炎症反应使其成为治疗的强大治疗靶点 自身免疫性和其他炎症性疾病。在临床试验中，瞬时增加Treg数为 被认为是安全的，并显示出一些功效。但是，Treg细胞疗法面临许多挑战 需要克服。为此，我们提议利用我们最近发现的一个新的B细胞子集 诱导Treg的增殖。这些B细胞称为B细胞Igdlow/ - （BDL），因为它们的表达 低/否IgD是用于纯化和研究的定义特征。 BDL与所有其他B不同 细胞子集并在Treg稳态中发挥至关重要的作用。我们已经进行了概念验证研究， BDL可以经过基因设计，以增强和维持TREG数字，从而衰减 炎症的严重程度。该提案概述了制定第一项策略的策略 使用BDL调节机制的自身免疫性。我们的行为旨在现成，能够成为 普遍给予任何可能受益于Treg诱导的公差增加的患者。这不会 只能改变自身免疫的治疗方式，但会大大降低治疗成本。