Developing controlled release immune complexes to treat multiple sclerosis
开发控释免疫复合物来治疗多发性硬化症
基本信息
- 批准号:10679346
- 负责人:
- 金额:$ 7.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-05 至 2025-03-04
- 项目状态:未结题
- 来源:
- 关键词:Adaptive Immune SystemAddressAminesAntigen-Antibody ComplexAntigen-Presenting CellsAntigensAutoantigensAutoimmune DiseasesAutoimmunityBiocompatible MaterialsCellsCentral Nervous SystemCharacteristicsChargeCuesDataDendritic CellsDiseaseDisease ProgressionDrug Delivery SystemsDrug ModelingsElectrostaticsEnvironmentExhibitsFRAP1 geneGene ExpressionGoalsHigh Pressure Liquid ChromatographyImmuneImmune TargetingImmune ToleranceImmune responseImmune signalingImmune systemImmunocompromised HostImmunohistochemistryImmunologyImmunosuppressionImmunosuppressive AgentsImpairmentIn VitroInfectionInflammationInflammatoryInnate Immune SystemInsulin-Dependent Diabetes MellitusInvestigational TherapiesInvestmentsKineticsLeadLibrariesLinkLipidsLymphocyteMacrophageMeasuresModelingMolecularMorphologyMultiple SclerosisMyelinMyelin SheathNatural ImmunityNatural Killer CellsNeurologicNeuronsOligonucleotidesPathogen detectionPathway interactionsPatientsPatternPharmaceutical PreparationsPlayPolymersPredispositionPropertyQuality of lifeReactionReceptor SignalingRegulatory T-LymphocyteReporterResearchRheumatoid ArthritisRoleSeveritiesSignal PathwaySignal TransductionSirolimusStructureSurfaceT-LymphocyteTechniquesTestingTimeToll-like receptorsTrainingUnited States National Institutes of HealthWorkadaptive immunityantagonistblood-brain barrier crossingcapsulecareercareer developmentcombatcompliance behaviorcontrolled releasecrosslinkcytotoxic CD8 T cellsdensitydesigndraining lymph nodeimmune modulating agentsimmunoregulationimprovedinsightinterestmouse modelmultiple sclerosis patientmultiple sclerosis treatmentnew technologynovel therapeuticspolarized cellpost-doctoral trainingpre-clinicalreceptor functionresponsesecondary lymphoid organself assemblyskillstraffickingtreatment strategyuptake
项目摘要
In autoimmune diseases, the immune system mistakenly identifies “self”-molecules/antigens as foreign, resulting
in an orchestrated attack of the body. In multiple sclerosis (MS), the immune system attack of the protective neuronal sheath
– myelin - results in debilitating neurological impairment and poor quality of life. Current MS therapies are non-curative,
require life-long compliance, and exhibit non-specific effects that increase patient susceptibility to infection. To circumvent
MS treatment challenges, emerging therapies seek to direct myelin self-antigens (MOG) and immunomodulatory cues to
redirect the immune response. Toll-like receptors, which detect pathogen-associated patterns on antigen presenting cells
(APCs) are involved in MS. Recently, TLR9 antagonist, GpG has been shown to downregulate APC activation while
promoting TREGS. Similarly, Rapamycin (Rapa), an immunosuppressant drug has garnered interest because it inhibits major
pathways and promotes regulatory T cells (TREGS). Since coordination between the innate and adaptive immune system in
MS drives disease, the proposed study will target these pathways simultaneously to promote antigen-specific immune
tolerance in MS.
We have previously developed self-assembled carriers built entirely from immune cues – termed immune
polyelectrolyte multilayers (iPEMs) that enable combinatory delivery of multiple cues, controlled loading, and high cargo
densities. iPEMs assembled using MOG and GpG reduce TLR9 signaling while promoting TREGS but show moderate
efficacy in preclinical MS models. Since TREGS play a crucial role in moderating immune responses, the proposed work aims
to load Rapa in the core of MOG/GpG iPEMs to enable co-delivery of MOG to induce antigen-specific immune responses,
GpG to downregulate APC activity, and incorporate cross-links to control Rapa delivery to induce TREGS. In Aim 1, the
hypothesis that cross-link density in MOG/GpG (Rapa) iPEMs is correlated to release intervals will be tested. This will be
accomplished by generating a library of iPEMs from combinations of MOG, control antigen (ANT-CTRL), GpG, inactive
control ODN (ODNCTRL), as well as Rapa with distinct cross-linking conditions to control release. In Aim 2, cross-linked
iPEM release kinetics will be linked to APC activation and T cell polarization. In Aim 3, the efficacy of crosslinked iPEMs
in preclinical MS models will be assessed to test the hypothesis that dual-targeting of innate and adaptive immunity is
necessary to drive antigen-specific TREGS in MS. These studies will show that modulating both innate and adaptive immunity
is necessary to generate robust antigen-specific responses in MS and will provide insight that informs the design of new
therapies to treat MS and other autoimmune diseases. At the same time, new skills and techniques will be acquired
throughout the course of the studies to propel the goal of the trainee to lead an academic research lab focused on developing
immunomodulatory drug delivery systems after postdoctoral training.
在自身免疫性疾病中,免疫系统错误地将“自身”分子/抗原识别为外来物,导致
项目成果
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Marian Adriana Ackun-Farmmer的其他文献
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