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Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease

Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease
转化新型药物靶向生物标志物来治疗移植物抗宿主病
批准号:
10618840
负责人:
Sophie Paczesny
金额:
$31.72万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
未结题
起止时间:
2013-05-03 至 2025-04-30
关键词:
Acute Graft Versus Host DiseaseAddressAllogenicAntibodiesAppearanceBindingBiologicalBiological AssayBiological MarkersBiological ProductsCD28 geneCessation of lifeClinicClinicalClinical ResearchClinical TrialsComplicationCorrelative StudyCytoprotectionDataDendritic CellsDetectionDevelopmentDiseaseDisease modelEffector CellEquilibriumFred Hutchinson Cancer Research CenterFutureGoalsHematologic NeoplasmsHematopoietic Stem Cell TransplantationHumanImmuneIncidenceIndianaInflammationInterleukin-2InterleukinsInterventionIntestinesJournalsLaboratoriesMCAM geneMalignant - descriptorMeasuresMediatingMembraneMolecularMorbidity - disease rateMulticenter StudiesNatural ImmunityNewly DiagnosedPathogenesisPathway interactionsPatientsPeripheral Blood Mononuclear CellPlasmaPopulationPre-Clinical ModelPrognostic MarkerProspective StudiesProteomeProteomicsPublishingRecurrent diseaseRegimenRegulationRegulatory T-LymphocyteResearchRiskSafetySamplingScienceSeverity of illnessSteroidsStromal CellsT-LymphocyteTestingTherapeuticTranslatingTranslational ResearchTransplant RecipientsUniversitiesadaptive immunityantagonistcancer therapyclinical investigationclinically relevantcurative treatmentsdesigndisorder preventioneffector T cellefficacy testinggastrointestinalgraft vs host diseasehematopoietic cell transplantationinnovationinsightmortalityneutralizing antibodynew therapeutic targetnovelnovel strategiesnovel therapeutic interventionnovel therapeuticspatient stratificationpost-transplantpredicting responsepreemptive interventionpreventprophylacticprospectivepublic health relevancereceptorresponserisk stratificationspecific biomarkerssuccesstherapeutic targettherapy resistanttranslational medicinetumor

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英文摘要
PROJECT SUMMARY/ABSTRACT Despite the high rates of acute graft versus host disease (aGVHD) (up to 50%) and their related mortality/morbidity following allogeneic hematopoietic cell transplantation (allo-HCT), there remains a paucity of therapies and biological correlative studies offered. Current therapies are limited to the nonspecific steroidal targeting of effector cells. Our long-term goal is to identify and validate GVHD biomarkers with the potential for risk stratification and therapeutic targeting. In the previous cycle, we discovered that: (1) soluble STimulation-2 (sST2), the interleukin-33 (IL-33) decoy receptor, as a biomarker for risk of therapy-resistant GVHD and death (N. Engl. J. Med, 2013); (2) Mechanistically, we have shown that during GVHD, sST2 was secreted earlier by intestinal stromal cells and later by cytopathic intestinal T effector cells (Teffs) (Science Translational Medicine, 2015); (3) Furthermore, we have shown that sST2 sequesters IL-33, limiting its availability to T cells expressing the transmembrane molecule form of ST2, mostly cytoprotective regulatory T cells (Tregs) (Science Translational Medicine, 2015; Journal of Clinical Investigation Insights, 2019); (4) Through another proteomics discovery comparing samples at 14 days post-transplantation in patients who develop gastrointestinal (GI) GVHD vs not, we found a T-cell population expressing CD146 that is Th17 prone and ICOS (Inducible T-cell COStimulator)-induced (Journal of Clinical Investigation Insights, 2016). Our new hypotheses address gaps remaining and will be tested with three specific aims: 1) Elucidate the cellular and molecular mechanisms of anti-ST2 neutralizing antibody mediated regulation of inflammation; 2) Implement a prospective multicenter study to determine ST2 threshold as a prognostic biomarker of aGVHD for enabling a biomarker-based preemptive trial; and 3) Inhibit the ICOS/ICOSL pathway with a dual ICOS/CD28 antagonist to prevent and treat aGVHD. The proposed research is significant because the impact of these studies will be 1) to risk stratify patients before initiating GVHD treatment, and 2) to develop entirely novel therapeutic strategies while simultaneously providing novel biological insights into a fatal condition, GVHD.
期刊论文(22)
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会议论文
DOI: 10.1007/s12185-013-1406-9
发表时间: 2013-09
期刊: INTERNATIONAL JOURNAL OF HEMATOLOGY
影响因子: 2.1
作者: [Paczesny, Sophie, Raiker, Nisha, Brooks, Sam, Mumaw, Christy]
通讯作者: Mumaw, Christy
DOI: 10.1111/bjh.18300
发表时间: 2022-08
期刊: BRITISH JOURNAL OF HAEMATOLOGY
影响因子: 6.5
作者: [Pratta, Michael, Paczesny, Sophie, Socie, Gerard, Barkey, Natalie, Liu, Hao, Owens, Sherry, Arbushites, Michael C., Schroeder, Mark A., Howell, Michael D.]
通讯作者: Howell, Michael D.
DOI: 10.1182/bloodadvances.2021005420
发表时间: 2022-05-24
期刊: BLOOD ADVANCES
影响因子: 7.5
作者: [DePriest, Brittany Paige, Li, Hong, Bidgoli, Alan, Onstad, Lynn, Couriel, Daniel, Lee, Stephanie J., Paczesny, Sophie]
通讯作者: Paczesny, Sophie
DOI: 10.1016/j.bbmt.2015.07.004
发表时间: 2015-10
期刊: Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子: --
作者: [Akil A, Zhang Q, Mumaw CL, Raiker N, Yu J, Velez de Mendizabal N, Haneline LS, Robertson KA, Skiles J, Diaz-Ricart M, Carreras E, Renbarger J, Hanash S, Bies RR, Paczesny S]
通讯作者: Paczesny S
14
    Chronic Graft-Versus-Host Disease Biomarkers: Prediction of Resistance to Therapy
    Development of first-in-class ST2 inhibitors for treating graft-versus-host disease
    海外基金