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Neuronal antigen surveillance and autoimmunity in CNS demyelinating disease

中枢神经系统脱髓鞘疾病的神经元抗原监测和自身免疫

基本信息

批准号：
10609862
负责人：
Charles Lee Howe
金额：
$ 59.2万
依托单位：
MAYO CLINIC ROCHESTER
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：
2020-07-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609862
关键词：
Acute Address Adoptive Transfer Antigen Presentation Antigen Presentation Pathway Antigen-Presenting Cells Antigens Autoimmunity Autologous Automobile Driving Axon Blood Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Clonal Expansion Coupled Cuprizone Defect Demyelinating Diseases Demyelinations Disease Disease Progression Disease remission Effector Cell Engineering Evolution Exhibits Experimental Autoimmune Encephalomyelitis Fibroblasts Genes Goals Health Histocompatibility Antigens Class I Human Immunization Induced pluripotent stem cell derived neurons Infiltration Inflammation Injury Intervention Ion Channel Knowledge Lymphocyte MHC Class I Genes Measures Mediating Mediator Microfluidics Mission Modeling Molecular Multiple Sclerosis Multiple Sclerosis Lesions Mus National Institute of Neurological Disorders and Stroke Nervous System Physiology Neurons OVA-8 Ovalbumin Pathogenesis Pathogenicity Patients Peptides Peripheral Population Proliferating Public Health Relapse Research Resolution Role Secondary to Specificity Symptoms T cell infiltration T-Lymphocyte Testing Time Toxic effect Transgenic Organisms United States National Institutes of Health Work adeno-associated viral vector axon injury burden of illness cytotoxic CD8 T cells disability experimental study functional disability improved innovation loss of function multiple sclerosis patient neoantigens neuroinflammation novel novel therapeutic intervention oligodendrocyte-myelin glycoprotein prevent recruit remyelination response targeted treatment therapy development trafficking

项目摘要

There is a critical unmet need to identify the pathogenic mechanisms that drive disease progression in patients with multiple sclerosis (MS). Accumulation of axon injury and functional disability in MS are not adequately impacted by current therapies. The long-term goal of this work is to discover new strategies to prevent or reverse disease progression in MS. Despite evidence that CD8+ T cells are associated with axon injury and progression in MS, the functional role for these cells and the relevant mechanisms required for recruitment of these cells to the demyelinated brain are unknown. The antigenic targets of neuron-specific CD8+ T cells are also unknown. The overall objectives of this study are to test the mechanistic role of neuron antigen-specific CD8+ T cells in the injury of demyelinated axons and to determine whether patients with MS have such cells. The rationale is that axon injury is the primary substrate of progression in MS, axonal MHC class I expression is upregulated by inflammation and demyelination, and cytotoxic CD8+ T cells directed against neuron-specific antigens injure demyelinated axons. The central hypothesis of this proposal is that neuron antigen-specific CD8+ T cells injure demyelinated axons. Guided by strong preliminary evidence, the hypothesis will be tested using AAV-mediated transduction of neurons to drive expression of the neoantigen ovalbumin (OVA) within the context of CNS demyelination induced by cuprizone toxicity or immunization against a myelin oligodendrocyte glycoprotein-derived peptide (MOG-EAE) in hosts that have transgenic CD8+ T cells directed against the OVA- derived peptide SIINFEKL (OT-I). The study will also use autologous T cells and fibroblast-derived iPSC- derived neurons grown in microfluidic chambers to determine whether MS patient CD8+ T cells injure their own axons. Three specific aims will be pursued: 1) determine the mechanisms of CD8+ T cell-mediated axon injury in the demyelinated CNS; 2) identify the cellular locus of MHC class I expression required for axon injury and determine how demyelination drives CNS infiltration of neuron antigen-specific CD8+ T cells; 3) determine whether MS patients have neuron-antigen specific CD8+ T cells. This approach is conceptually innovative because of the proposal that demyelination and inflammation induce axonal presentation of self-peptides on MHC class I. The approach is technically innovative based on the use of novel AAV vectors to drive neoantigens in neurons within the demyelinated CNS, selective deletion of brain-resident antigen presenting cells (APCs) vs peripheral APCs, use of multiple host manipulations coupled to adoptive transfer of traceable effector cells to temporally and spatially profile anti-neuronal T cell trafficking, and the use of patient-derived neurons and autologous CD8+ T cells. This work will make a significant, powerful impact on the field by revealing the capacity of CD8+ T cells directed against neuron-specific antigens to injure demyelinated axons and by identifying such T cells in patients with MS.

确定驱动患者疾病进展的致病机制是一个关键的未满足的需求

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peripheral blood mononuclear cell phenotype and function are maintained after overnight shipping of whole blood.

DOI：
10.1038/s41598-022-24550-6
发表时间：
2022-11-19
期刊：
SCIENTIFIC REPORTS
影响因子：
4.6
作者：
Johnson, Renee K.;Overlee, Brittany L.;Sagen, Jessica A.;Howe, Charles L.
通讯作者：
Howe, Charles L.

ISGylation is induced in neurons by demyelination driving ISG15-dependent microglial activation.

DOI：
10.1186/s12974-022-02618-4
发表时间：
2022-10-20
期刊：
Journal of neuroinflammation
影响因子：
9.3
作者：
通讯作者：

CD8+ T cells recognizing a neuron-restricted antigen injure axons in a model of multiple sclerosis.

DOI：
10.1172/jci162788
发表时间：
2023-11-01
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
Clarkson, Benjamin D. S.;Grund, Ethan M.;Standiford, Miranda M.;Mirchia, Kanish;Westphal, Maria S.;Muschler, Liz S.;Howe, Charles L.
通讯作者：
Howe, Charles L.

Septin-5 and -7-IgGs: Neurologic, Serologic, and Pathophysiologic Characteristics.

DOI：
10.1002/ana.26482
发表时间：
2022-12
期刊：
ANNALS OF NEUROLOGY
影响因子：
11.2
作者：
Hinson, Shannon R.;Honorat, Josephe A.;Grund, Ethan M.;Clarkson, Benjamin D.;Miske, Ramona;Scharf, Madeleine;Zivelonghi, Cecilia;Al-Lozi, Muhammad Taher;Bucelli, Robert C.;Budhram, Adrian;Cho, Tracey;Choi, Ellie;Grell, Jacquelyn;Lopez-Chiriboga, Alfonso Sebastian;Levin, Marc;Merati, Melody;Montalvo, Mayra;Pittock, Sean J.;Wilson, Michael R.;Howe, Charles L.;McKeon, Andrew
通讯作者：
McKeon, Andrew

Citrullinated myelin induces microglial TNFα and inhibits endogenous repair in the cuprizone model of demyelination.