Role of B cell interactions in CNS autoimmune demyelination
Role of B cell interactions in CNS autoimmune demyelination
批准号:
10369672
负责人:
Alexander Boyden
金额:
$23.18万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-03-10 至 2024-02-29
关键词:
Adoptive TransferAffectAmericanAmino Acid Sequence HomologyAntibodiesAntigen-Antibody ComplexAntigen-Presenting CellsAntigensAutoimmuneAutoimmune DiseasesAutoimmunityB-Cell ActivationB-LymphocytesBiochemicalBiologyBlindnessCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCNS Demyelinating Autoimmune DiseasesCNS autoimmunityCell CommunicationCell physiologyCellsCellular biologyClinical TrialsCognitive deficitsConsumptionDemyelinating DiseasesDemyelinationsDependenceDevelopmentDiagnosisDiseaseExhibitsExperimental Autoimmune EncephalomyelitisExtracellular DomainFinancial HardshipFlow CytometryFreund&aposs AdjuvantHealthHealthcareHistologicHumanImmuneImmunizationImmunizeInflammatoryInvestigationKineticsLengthLifeLinkMHC Class I GenesMeasuresMediatingMethodologyMinorModelingMultiple SclerosisMusMyelinMyelin ProteinsMyelin Proteolipid ProteinMyelin SheathNatureNerve DegenerationNeural ConductionNeuraxisNeuronsPainParalysedPathogenesisPathogenicityPathologyPatientsPeptidesPeripheral Blood Mononuclear CellPlayProcessProductionProteinsProteolipidsReagentRecombinantsRegulationRelapseReportingResearch PersonnelRodentRoleStructureStructure of germinal center of lymph nodeT-Lymphocyte SubsetsTestingTimeTissuesWorkautoreactivitycell typecentral nervous system demyelinating disordercytokinedesignhuman diseasein vivoinsightinterestmouse modelmultiple sclerosis patientnovelnovel therapeuticsoligodendrocyte-myelin glycoproteinprotein aminoacid sequencerecruitresponsesuccesstositumomab
中文摘要
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英文摘要
PRJOECT ABSTRACT
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous
system (CNS) whereby infiltrating autoreactive clones, with additional pro-inflammatory cell types
they recruit and support, work to destroy the protective myelin sheaths surrounding neurons. This
results in compromised nerve conduction and myriad pathologies including pain, vision loss,
cognitive deficits, and eventual paralysis. It is currently incurable. Due to its early life onset
(typically in the third or fourth decade) and that it progressively worsens over time, an MS
diagnosis tragically sentences patients to a prolonged battle, representing a significant health and
financial burden for nearly 1 million Americans. Understanding the complex immune cell interplay
governing pathogenesis and regulation of disease is critical for the discovery of novel therapeutics
for patients. The MS mouse model experimental autoimmune encephalomyelitis (EAE) has
provided great insights into these processes, and has focused on CD4 T cells (CD4s), which can
adoptively transfer paralysis to healthy mice. The role of B cells and CD8 T cells (CD8s) have
been understudied in comparison. Targeted B cell-depletion success in recent MS clinical trials
has renewed intense interest in the role these cells play in demyelinating disease. However, most
EAE models do not account for pathogenic B cells, where myelin peptide-induced models (eg.
MOG35-55) exhibit EAE in B-less mice. Full-length recombinant human MOG (hMOG) protein
induces B cell-dependent EAE but its production is biochemically cumbersome, time-consuming,
and expensive, representing a barrier of access to efficient investigation of B cells in EAE.
Additionally, MOG is a minor component and buried within the myelin structure and rodent MOG
has residue differences with human MOG that render its induced EAE B cell-independent. Myelin
proteolipid protein (PLP) in contrast is the most abundant myelin protein and shares 100% amino
acid sequence homology between mouse and human. However, like MOG35-55, PLP178-191 induces
B cell-independent EAE. We therefore designed a novel peptide encompassing the extracellular
domains of PLP and have found that it drives a robust B cell-dependent EAE. Our group has
demonstrated that myelin-specific CD8s in human PBMC have regulatory function and are
defective at inhibiting CD4s in MS patients. Further, PLP178-191-specific CD8s suppress EAE and
even eliminate paralysis in mice. Thus, B cell interactions with pathogenic CD4s and regulatory
CD8s (direct or through TFH cells) can be studied in our novel model. This PLP-driven, B cell-
dependent murine model of MS will be developed in the proposed work, and will not only advance
the field’s technical capability, but serve as a much-needed arena for investigating B cells in EAE.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
Proteolipid Protein-Induced Mouse Model of Multiple Sclerosis Requires B Cell-Mediated Antigen Presentation.
蛋白脂质蛋白诱导的多发性硬化症小鼠模型需要 B 细胞介导的抗原呈递。
DOI:
10.4049/jimmunol.2200721
发表时间:
2023
期刊:
Journal of immunology (Baltimore, Md. : 1950)
影响因子:
--
作者:
[Wilhelm,ConnorR, Upadhye,MohitA, Eschbacher,KathrynL, Karandikar,NitinJ, Boyden,AlexanderW]
通讯作者:
Boyden,AlexanderW
Pathogenic B cell:CD4 T cell interactions in a novel B cell-dependent EAE mouse model of multiple sclerosis
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批准号:10718277
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项目类别:
-
资助金额:$47.24万
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财政年份:2023
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负责人:Alexander Boyden
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依托单位:
海外基金