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Repertoire selection of AQP4-specific T cells that cause CNS autoimmunedisease

引起中枢神经系统自身免疫性疾病的 AQP4 特异性 T 细胞的库选择

基本信息

批准号：
10520039
负责人：
SCOTT S ZAMVIL
金额：
$ 43.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-24 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10520039
关键词：
Adoptive Transfer Advanced Development Affinity Alleles Amino Acid Sequence Animals Antibodies Antigens Autoantigens Autoimmunity B-Lymphocytes Binding CNS autoimmune disease CNS autoimmunity Cells Cerebrospinal Fluid Clinical Clone Cells Data Defect Development Epitopes Exhibits Experimental Models Foundations Genes Goals HLA-DRB1 Histologic IL17 gene IgG1 Immune response Immunization Immunotherapy Inflammation Inflammatory Lesion Mediating Modeling Multiple Sclerosis Mus Myelin Neuromyelitis Optica Optical Coherence Tomography Organ Model Paralysed Pathogenesis Pathogenicity Pathology Patients Peptides Peripheral Phenotype Proliferating Rattus Regulation Role T cell regulation T cell response T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes T-cell receptor repertoire Testing Thymic epithelial cell Thymus Gland Tissues Transgenic Mice Transgenic Organisms Visual System Wild Type Mouse aquaporin 4 cytokine in vivo insight novel programs response success targeted treatment

项目摘要

PROJECT SUMMARY / ABSTRACT Based upon the observation that aquaporin-4 (AQP4)-specific antibodies are IgG1, a T cell-dependent isotype, it was hypothesized that aquaporin-4 (AQP4)-specific T cells have a key role in neuromyelitis optica (NMO) pathogenesis. AQP4-specific T cells have been identified in NMO patients and, in comparison to healthy controls (HC), AQP4-reactive T cells are expanded and exhibit Th17 polarization, findings that further support the role of Th17 cells in NMO. Unfortunately, it is not feasible to evaluate how AQP4-reactive T cells participate directly in CNS inflammation in NMO patients. Thus, it is important to develop models to evaluate the potential role of AQP4-specific T cells in NMO. Initial attempts in generating an in vivo AQP4-based NMO model in wild-type (WT) mice and rats have not met with success. Recently, it was observed that pathogenic AQP4-specific T cells exist in AQP4-deficient (AQP4-/-) mice. Those T cells recognize two novel determinants. In comparison to other AQP4 determinants identified in WT mice, the novel determinants induce robust proliferation in AQP4-/- mice, but only a weak response in WT mice. Hyper-reactivity is AQP4-specific, but not epitope-specific as we discovered a second AQP4 epitope induced vigorous proliferation in AQP4- /-, but not WT, mice. The T cell receptor (TCR) repertoires used for recognition of these determinants in AQP4-/- and WT mice are distinct. T cells reactive to these determinants isolated from AQP4-/- donor mice induced clinical and histologic CNS autoimmune disease in 100% of recipient WT mice tested. Collectively, these findings represent the first successful induction of clinical AQP4-targeted CNS autoimmunity. Our findings suggest responses to those epitopes in AQP4-/- mice reflect a loss of central T cell tolerance. Findings from studying mice deficient in T cells only or B cells only indicate that peripheral T cell regulation also alters expression of pathogenic AQP4-specific T cells. We propose to test our hypothesis that there is a defect in thymic negative selection of AQP4-specific T cells in mice, a possibility that may be relevant to NMO pathogenesis. We will examine how peripheral T cell regulation may influence pathogenic AQP4-specific immune responses. In Specific Aim 1, by using unique approaches and novel mice, we will characterize the phenotype of pathogenic AQP4-specific T cells and generate AQP4-specific TCR transgenic mice. In Specific Aim 2, we will characterize the repertoire of AQP4-specific T cells in AQP4-/- and WT mice that express HLA- DR17 (DRB1*0301), the MHC II allele most highly associated with NMO. Separately, we will examine AQP4-specific T cell responses in NMO patients to determine if DR17-restricted AQP4-specific T cell epitopes identified those mice correspond to AQP4 T cell epitopes in NMO patients. In preliminary data, using these mice we discovered a novel HLA- DR17-restricted AQP4 determinant, and observed that it is recognized by T cells from HLA-DR17+ NMO patients, findings that support feasibility of this aim. Findings obtained in this program should elucidate mechanisms controlling development of pathogenic AQP4-specific T cells in NMO, provide a foundation advancing development of in vivo NMO models, and may provide insight for development of selective NMO immunotherapy.

项目摘要/摘要根据观察到水通道蛋白4(AQP4)特异性抗体是IgG1，一种T细胞依赖的亚型，它是推测水通道蛋白4(AQP4)特异性T细胞在视神经脊髓炎(NMO)发病机制中起关键作用。已经在NMO患者中发现了AQP4特异性T细胞，与健康对照组(HC)相比，AQP4反应 T细胞扩增并表现出Th17极化，这一发现进一步支持Th17细胞在NMO中的作用。不幸的是，评估AQP4反应性T细胞如何直接参与NMO的中枢神经系统炎症是不可行的病人。因此，重要的是要建立模型来评估AQP4特异性T细胞在NMO中的潜在作用。在野生型(WT)小鼠和大鼠体内建立基于AQP4的NMO模型的初步尝试尚未遇到成功。近年来，研究发现AQP4基因缺陷(AQP4-/-)小鼠体内存在致病的AQP4特异性T细胞。那些T 细胞识别两个新的决定因素。与在WT小鼠中发现的其他AQP4决定因素相比，新的决定簇在AQP4-/-小鼠中诱导强烈的增殖，但在WT小鼠中仅有微弱的反应。高反应性是 AQP4特异的，但不是表位特异的，因为我们发现了第二个AQP4表位诱导AQP4- /-，但不是WT，小鼠。识别AQP4-/-和WT中这些决定因素的T细胞受体(TCR)谱系老鼠是不同的。从AQP4/-供体小鼠分离出对这些决定因素有反应的T细胞，诱导临床和组织学受体WT小鼠中枢神经系统自身免疫性疾病的受试率为100%。总的来说，这些发现代表着第一个成功的诱导临床靶向AQP4的中枢神经系统自身免疫。我们的发现提示AQP4-/-小鼠对这些表位的反应反映了中枢T细胞耐受性的丧失。对只有T细胞或B细胞缺陷的小鼠的研究结果表明，外周T细胞调节也改变了致病的AQP4特异性T细胞的表达。我们建议验证我们的假设，即小鼠胸腺对AQP4特异性T细胞的负选择存在缺陷，这种可能性可能与NMO的发病机制有关。我们将研究外周T细胞调节如何影响致病性AQP4特异性免疫反应。在具体目标1中，通过使用独特的方法和新的老鼠，我们将鉴定致病AQP4特异性T细胞的表型，并产生AQP4特异性TCR转基因小鼠。在……里面特定目标2，我们将描述表达HLA4的AQP4-/-和WT小鼠的AQP4特异性T细胞的谱系。 DR17(DRB1*0301)，与NMO关联最高的MHC II等位基因。另外，我们将研究AQP4特定的T细胞 NMO患者的细胞反应以确定DR17限制性AQP4特异性T细胞表位是否识别这些小鼠与NMO患者的AQP4 T细胞表位相对应。在初步数据中，使用这些小鼠，我们发现了一种新的人类白细胞抗原- DR17限制性的AQP4决定簇，并观察到它被来自HLA-DR17+NMO患者的T细胞识别，支持这一目标的可行性的研究结果。在这个项目中获得的发现应该阐明控制机制 NMO中致病的AQP4特异性T细胞的发展，为促进体内NMO的发展提供了基础模型，并可能为选择性NMO免疫疗法的发展提供见解。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting B Cells to Modify MS, NMOSD, and MOGAD: Part 1.

DOI：
10.1212/nxi.0000000000000918
发表时间：
2021-01
期刊：
Neurology(R) neuroimmunology & neuroinflammation
影响因子：
0
作者：
Graf J;Mares J;Barnett M;Aktas O;Albrecht P;Zamvil SS;Hartung HP
通讯作者：
Hartung HP

Functional characterization of reappearing B cells after anti-CD20 treatment of CNS autoimmune disease.

DOI：
10.1073/pnas.1810470115
发表时间：
2018-09-25
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Häusler D;Häusser-Kinzel S;Feldmann L;Torke S;Lepennetier G;Bernard CCA;Zamvil SS;Brück W;Lehmann-Horn K;Weber MS
通讯作者：
Weber MS

Persistently reduced humoral and sustained cellular immune response from first to third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients.

DOI：
10.1016/j.msard.2022.103729
发表时间：
2022-04
期刊：
Multiple sclerosis and related disorders
影响因子：
4
作者：
Bajwa HM;Novak F;Nilsson AC;Nielsen C;Holm DK;Østergaard K;Witt AH;Byg KE;Johansen IS;Mittl K;Rowles W;Zamvil SS;Bove R;Sabatino JJ;Sejbaek T
通讯作者：
Sejbaek T

Low protection from breakthrough SARS-CoV-2 infection and mild disease course in ocrelizumab-treated patients with multiple sclerosis after three mRNA vaccine doses.