Development of a B Cell Therapeutic

B 细胞治疗药物的开发

基本信息

批准号：
10683103
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/10683103
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 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 Proliferating 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 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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Conserved Gammaherpesvirus Protein Kinase Counters the Antiviral Effects of Myeloid Cell-Specific STAT1 Expression To Promote the Establishment of Splenic B Cell Latency.

保守的伽马疱疹病毒蛋白激酶对抗骨髓细胞特异性 STAT1 表达的抗病毒作用，促进脾 B 细胞潜伏期的建立。

DOI：
10.1128/jvi.00859-21
发表时间：
2021
期刊：
Journal of virology
影响因子：
5.4
作者：
Sylvester,PA;Jondle,CN;Stoltz,KP;Lanham,J;Dittel,BN;Tarakanova,VL
通讯作者：
Tarakanova,VL

Targeting transmembrane-domain-less MOG expression to platelets prevents disease development in experimental autoimmune encephalomyelitis.

DOI：
10.3389/fimmu.2022.1029356
发表时间：
2022
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
通讯作者：

Myeloperoxidase as a Marker to Differentiate Mouse Monocyte/Macrophage Subsets.

DOI：
10.3390/ijms23158246
发表时间：
2022-07-26
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Gurski, Cody J.;Dittel, Bonnie N.
通讯作者：
Dittel, Bonnie N.

Myeloperoxidase Inhibition Ameliorates Plaque Psoriasis in Mice.

髓过氧化物酶抑制可改善小鼠斑块状银屑病。

DOI：
10.3390/antiox10091338
发表时间：
2021-08-25
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
0
作者：
Neu SD;Strzepa A;Martin D;Sorci-Thomas MG;Pritchard KA Jr;Dittel BN
通讯作者：
Dittel BN

T Cell-Specific STAT1 Expression Promotes Lytic Replication and Supports the Establishment of Gammaherpesvirus Latent Reservoir in Splenic B Cells.

DOI：
10.1128/mbio.02107-22
发表时间：
2022-08-30
期刊：
MBIO
影响因子：
6.4
作者：
Sylvester, P. A.;Jondle, C. N.;Schmalzriedt, D. L.;Dittel, B. N.;Tarakanova, V. L.
通讯作者：
Tarakanova, V. L.