Development of a B Cell Therapeutic

B 细胞治疗药物的开发

基本信息

批准号：
10458133
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
项目类别：
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/10458133
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 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 innovation insight migration novel overexpression receptor side effect suicide gene therapeutic target virtual

项目摘要

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.

自身免疫是由于免疫耐受性崩溃而发生，导致适应性免疫失控针对自体组织的反应。据估计有 5000 万美国人患有自身免疫性疾病，其中包括 100 多种不同的疾病，它们几乎共同影响每个器官和组织。和 2001 年，约 16% 的美国人口患有自身免疫性疾病，每年估计治疗费用经计算，总金额超过1000亿美元。虽然每种自身免疫性疾病都与免疫相关调节失调，不存在通用的治疗方法。该提案旨在产生一种新颖的、具有成本效益的、通用的现成的过继细胞疗法（ACT）可通过增强细胞免疫功能来治疗自身免疫性疾病免疫耐受。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，从而抑制对自身组织的免疫反应。 Treg抑制免疫介导的炎症反应使其成为治疗以下疾病的强大治疗靶点自身免疫和其他炎症性疾病。在临床试验中，Treg 数量短暂增加被认为是安全的并显示出一定的功效。然而，Treg细胞疗法面临着许多挑战需要克服。为此，我们建议利用我们最近发现的新 B 细胞子集诱导Treg增殖。这些 B 细胞被命名为 B 细胞 IgDlow/- (BDL)，因为它们表达低/阴性 IgD 是用于纯化和研究的决定性特征。 BDL 与所有其他 B 不同细胞亚群并在 Treg 稳态中发挥重要作用。我们进行了概念验证研究 BDL 可以通过基因工程来长期增强和维持 Treg 数量，从而减弱炎症的严重程度。该提案概述了开发首个 ACT 治疗的策略利用 BDL 调节机制的自身免疫。我们的 ACT 设计为现成的，并且能够普遍适用于任何可以从 Treg 诱导的耐受性增加中受益的患者。这不会仅改变自身免疫的治疗方式，反而会大大降低治疗费用。