Biomarker Guided CNI Substitution in Kidney Transplantation
生物标志物引导肾移植中的 CNI 替代
基本信息
- 批准号:9926399
- 负责人:
- 金额:$ 20.71万
- 依托单位:
- 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:2020-09-17 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdverse eventAftercareAllograftingAntibodiesAntibody FormationB cell differentiationB-LymphocytesBiological MarkersBiopsyCalcineurin inhibitorCategoriesCellsChronicClinicalClinical TrialsComplementDataDiagnostic testsEnrollmentExclusion CriteriaFOXP3 geneFailureFibrosisGenerationsGoalsGraft RejectionGrantHLA-DR AntigensHumanImmuneImmune responseImmunosuppressionIndividualInflammationInflammatoryInflammatory ResponseInjuryInstitutional Review BoardsInterleukin-6InterventionKidney TransplantationLinkMaintenanceMediatingMediator of activation proteinMolecularMonitorMonoclonal AntibodiesMonoclonal Antibody TherapyMycophenolateNatural ImmunityObservational StudyOutcomePathogenicityPathway interactionsPatient-Focused OutcomesPatientsPharmaceutical PreparationsPhenotypePlasma CellsPlasmablastPositioning AttributePrednisonePrognostic MarkerProtocols documentationRandomized Controlled TrialsRegulatory T-LymphocyteRenal functionReperfusion InjuryResolutionRiskRisk stratificationSafetyStatistical Data InterpretationT cell differentiationT-LymphocyteTestingTherapeutic AgentsTherapeutic immunosuppressionTimeTransplant RecipientsTransplantationTreatment ProtocolsValidationWithdrawalWorkadaptive immunityarmbaseclinical riskcohortcytokinedesigndiagnostic biomarkerexperienceimprovedimproved outcomeisoimmunitymTOR Inhibitornoninvasive diagnosisnovel markernovel therapeuticsoperationpost-transplantpredictive markerprogramsprospectiverecruitresponseside effectstandard of caresubcutaneousvalidation studies
项目摘要
Abstract
Kidney transplant recipients have suboptimal long-term outcomes on current therapy predominantly due to off-
target effects of calcineurin inhibitor (CNI)-based protocols, and/or their failure to control the immune response
to the graft. Improving patient outcomes will require novel therapeutic agents that inhibit components of the
recipient’s immune response not controlled by CNI-based therapy. Interleukin (IL)-6 is a cytokine that promotes
T cell proinflammatory phenotypes (i.e. Tfh, Th1, Th17 cells) while inhibiting regulatory T cells, as well as
promoting antibody formation by inducing B cell differentiation into plasmablasts. The critical involvement of IL-
6 in these pathways makes it an attractive target for attempts to improve kidney transplant outcomes, especially
in the context of CNI substitution strategies. Additionally, while CNI withdrawal/substitution can improve kidney
function, randomized controlled trials of CNI withdrawal/substitution performed by our group and others, in
clinically “low risk” kidney transplant recipients have failed. Thus, current clinical risk stratification strategies and
available immunosuppressive therapies are inadequate for guiding individualized immunosuppression. The co-
PIs of this proposal have identified that the level of HLA-DR/DQ molecular mismatch (mMM): a) classifies kidney
transplant recipients as high, intermediate or low risk for developing a primary alloimmune response (i.e.
rejection), and b) identifies the low-risk category as those likely to tolerate CNI minimization/withdrawal. Based
on these data the FDA accepted HLA-DR/DQ mMM into its Biomarker Qualification Program with the caveat
that prospective multicenter validation is required. To this end, we propose a prospective observational,
multicenter, HLA mMM validation study (Aim 1) that includes, in a subset of 300 immune quiescence patients,
a randomized controlled trial substituting anti-IL-6 mAb (Clazakizumab [Claza]) for CNI (Aim 2), testing the
impact of the intervention on 2 year outcomes. Mechanistic studies will delineate the pathways by which Claza
impacts outcomes after CNI substitution. Within this framework, we will test the hypothesis that in the absence
of pre-existing DSA, the HLA-DR/DQ mMM score is both a prognostic and predictive biomarker capable of
guiding immunosuppressive therapy in kidney transplantation. In addition, our consortium has identified multiple
non-invasive diagnostic biomarkers of subclinical/clinical rejection. In Aim 3 we will: a) validate the utility of each
biomarker alone and together as non-invasive diagnostic tests for detect rejection in a real-world kidney
transplant cohort, and b) assess the utility of each biomarker to detect resolution of rejection in response to
therapy as determined by a post-treatment biopsy. The goal of this R34 proposal is to complete the study
protocol design, finish designing the mechanistic studies, finalize the statistical analysis plan, and establish the
framework for trial operation and management in order to be in a position to submit an FDA trial IND application,
a final application for IRB approval and a U01 application.
摘要
项目成果
期刊论文数量(0)
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Peter Scott Heeger其他文献
Peter Scott Heeger的其他文献
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{{ truncateString('Peter Scott Heeger', 18)}}的其他基金
Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation
肾移植中生物标志物引导的 CNI 替代评估
- 批准号:
10654057 - 财政年份:2022
- 资助金额:
$ 20.71万 - 项目类别:
Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation
肾移植中生物标志物引导的 CNI 替代评估
- 批准号:
10488428 - 财政年份:2022
- 资助金额:
$ 20.71万 - 项目类别:
Multiparametric mapping of Covid-19 immune responses in Kidney transplant recipients
肾移植受者 Covid-19 免疫反应的多参数绘图
- 批准号:
10241179 - 财政年份:2020
- 资助金额:
$ 20.71万 - 项目类别:
Cell Death Pathways and Heart Transplant Rejection
细胞死亡途径和心脏移植排斥
- 批准号:
10162490 - 财政年份:2017
- 资助金额:
$ 20.71万 - 项目类别:
Targeting factor B to prevent transplant rejection
靶向因子 B 预防移植排斥
- 批准号:
9000104 - 财政年份:2015
- 资助金额:
$ 20.71万 - 项目类别:
Targeting factor B to prevent transplant rejection
靶向因子 B 预防移植排斥
- 批准号:
8873752 - 财政年份:2015
- 资助金额:
$ 20.71万 - 项目类别:
Individualizing Therapy for Kidney and Heart Transplant Recipients
肾脏和心脏移植受者的个体化治疗
- 批准号:
8100584 - 财政年份:2010
- 资助金额:
$ 20.71万 - 项目类别:
Noninvasive Markers and Transplant Outcome in Humans
人类非侵入性标志物和移植结果
- 批准号:
7919132 - 财政年份:2009
- 资助金额:
$ 20.71万 - 项目类别:
Cross-Disciplinary Training Program in Transplant Research
移植研究跨学科培训计划
- 批准号:
8662683 - 财政年份:2008
- 资助金额:
$ 20.71万 - 项目类别:
Cross-Disciplinary Training Program in Transplant Research
移植研究跨学科培训计划
- 批准号:
9284372 - 财政年份:2008
- 资助金额:
$ 20.71万 - 项目类别:
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