Role of Notch signaling during the early priming and activation of alloreactive T cells
Role of Notch signaling during the early priming and activation of alloreactive T cells
批准号:
10510497
负责人:
Ashley Nicole Vanderbeck
金额:
$0.71万
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:
2021-07-01 至 2022-08-31
关键词:
Acute Graft Versus Host DiseaseAlloantigenAllogeneic Bone Marrow TransplantationAntibodiesAntibody TherapyBiological AssayBlocking AntibodiesCell physiologyCellsChromatinChronicClinicalCommunicationComplicationCytokine GeneCytokine SignalingDataDiseaseEpigenetic ProcessFunctional disorderGastrointestinal tract structureGenesGenetic TranscriptionGoalsGraft-Versus-Tumor InductionHomingHourImmuneImmune responseImmune systemImmunobiologyImmunosuppressionImpairmentInflammationInflammatoryInflammatory Response PathwayInjectionsIntegrinsInterleukin-2Intestinal Graft Versus Host DiseaseIntestinesLaboratoriesLifeLigandsMature T-LymphocyteMeasuresMediatingModelingMolecularMonoclonal AntibodiesMorbidity - disease rateMusOrganPathogenesisPathogenicityPathologicPathway interactionsPatientsPeripheralPhasePhysiologic pulsePlayPreventionProductionProphylactic treatmentRegulatory T-LymphocyteRoleScientistShapesSignal PathwaySignal TransductionT cell responseT-Cell ActivationT-LymphocyteTechniquesTestingTimeTissuesTrainingTransplantationTransposaseTropismTumor stageWorkcytokinedimerdisorder controldisorder preventioneffector T cellgastrointestinalgenome-widegraft vs host diseaseimmunoregulationin vivoinfection riskinhibitorinsightisoimmunitymortalitynew therapeutic targetnonhuman primatenotch proteinnovelnucleasepreservationpreventprogramsprophylacticresponsesecondary lymphoid organside effectskillstraffickingtranscriptome sequencingtreatment strategytumor
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Graft-versus-host-disease (GVHD) is the most serious complication of allogeneic bone marrow
transplantation (allo-BMT). GVHD pathogenesis is mediated by alloreactive T cells present in the graft that
recognize alloantigens and damage host tissues. Most GVHD therapies rely on global immunosuppression and
are associated with increased risks of infection and decreased graft-versus-tumor effects. New strategies for
GVHD prevention that protect host tissues while simultaneously preserving the tumor-killing activity of
alloimmune T cells are needed. Our laboratory identified Notch signaling and Delta-like1/4 (Dll1/Dll4) Notch
ligands as critical regulators of the pathogenic allo-T cell response, and attractive new therapeutic targets. In
both mouse and non-human primate models, Notch inhibition in donor T cells leads to long-term protection
from GVHD morbidity and mortality. Short-term in vivo Notch blockade using monoclonal antibodies against
specific Notch receptors or ligands blunts the pathogenicity of alloreactive effector T cells without eliciting
broad immunosuppression, reducing GVT activity, or triggering toxic side effects of chronic Notch inhibition.
While a single injection of anti-Dll1/Dll4 Notch ligand antibodies at the time of transplant was sufficient for long-
term GVHD control, Dll1/Dll4 blockade administered >48 hours after transplant provided no protection against
GVHD. Thus, an early pulse of Notch signaling during the initial stages of T cell activation is critical for
establishing a pathogenic T cell state. However, we do not currently understand how short-term Notch
inhibition exerts long-lasting GVHD protection. Alloreactive T cells rely on two central functions to mediate
disease: trafficking to peripheral target organs and producing proinflammatory cytokines. Our preliminary data
show that Notch inhibition preserves initial T cell IL-2 production and expansion in secondary lymphoid organs
while impairing secretion of multiple inflammatory cytokines and homing to the gastrointestinal tract. Therefore,
I hypothesize that Notch signals delivered to allo-T cells during early stages of T cell priming and activation are
critical for trafficking to the gut and initiating a sustained inflammatory cytokine response. I speculate that these
two key mechanisms explain why short-term Notch inhibition prevents many of the severe, pathological
consequences of GVHD. To explore this hypothesis, I will use MHC-mismatched models of GVHD to
investigate how Notch inhibition influences allo-T cell gut tropism. Moreover, I will use a combination of RNA
sequencing, Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), and Cleave Under
Targets and Release using Nuclease (CUT&RUN) chromatin profiling to provide a genome-wide view of the
transcriptional and epigenetic effects of Notch signaling during early stages of allo-T cell priming/activation.
Altogether, this proposal will elucidate the cellular and molecular mechanisms that underlie the impact of early
Notch signals in shaping the alloimmune response after allo-BMT.
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