Preserving Renal Function & Protective Immunity Via Anti-LFA1-Based CNI Avoidance

保护肾功能

• 批准号: 8523752
• 负责人: KENNETH A. NEWELL
• 金额: $ 197.81万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523752
• 关键词: Acute; Allografting; Antibodies; Antigens; Atrophic; Biological Assay; Biological Markers; Biological Preservation; Biopsy; Calcineurin inhibitor; Cells; Clinical; Data; Diabetes Mellitus; Dialysis procedure; Disease; Dyslipidemias; Early Diagnosis; Etiology; Fibrosis; Gene Expression; Glomerular Filtration Rate; Goals; Graft Survival; Homeostasis; Hospitals; Human; Humoral Immunities; Hypertension; Immune; Immune response; Immunity; Immunobiology; Immunosuppression; Immunosuppressive Agents; Incidence; Infection; Injury; Kidney; Kidney Transplantation; Lymphocyte; Maintenance; Measures; Mediating; Outcome; Outcome Measure; Pancreas; Patient Care; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Postoperative Period; Prevalence; Prevention; Proteomics; Protocols documentation; Publishing; Randomized Controlled Trials; Recruitment Activity; Regimen; Relative (related person); Renal function; Research Personnel; Safety; Structure; T memory cell; T-Lymphocyte; Tacrolimus; Time; Translating; Transplant Recipients; Transplantation; Tubular formation; Viral; Virus; base; cardiovascular risk factor; clinically relevant; delayed graft function; efalizumab; experience; immune function; improved; improved functioning; insight; interstitial; liver transplantation; programs; prospective; tool

DESCRIPTION (provided by applicant): Despite continued reductions in short-term rejection rates, long-term outcomes have not significantly improved in the past decade. In the face of this the pressing unmet need, there have been no fundamentally new immunosuppressive agents that have been approved in the new millennium. Our Collaborative will investigate efalizumab as an alternative to CNI-based immunosuppression (IS) in kidney and liver transplantation. Clinical endpoints include efficacy and safety and the trial will systematically assess whether avoidance of CNI-based maintenance IS with efalizumab provides superior preservation of renal structure and function and lower rates of PTDM, hypertension, and dyslipidemia relative to a tacrolimus-based regimen. The studies will be heavily leveraged to gain mechanistic insight regarding the etiology of native renal injury and IFTA and to develop proteomic or gene expression biomarkers of progressive renal injury. We will develop clinically relevant, mechanistically based, non-invasive assays for the early detection of renal injury with the goal of translating our findings into practical tools aiding the clinician in patient care. We will acquire important data on the impact of efalizumab and tacrolimus on protective immunity by systematically defining the type and pattern of viral reactivation observed with each regimen, as well as assessing the impact on peripheral lymphocyte homeostasis and the phenotype and function of virus-specific memory T cells. We will determine whether ongoing exposure of the recipient to donor-antigens under the sustained blockade of LFA-1 with efalizumab while avoiding CNI will result in alterations in anti-donor T cell and/or humoral immunity or an Increased Incidence of recently described tolerance signatures. Given the prevalence of renal injury (native and allograft) and centrality of immune function across all transplant settings regardless of IS regimen, we anticipate broad applicability of these goals. We have aligned three high volume transplant hospitals with extensive experience in clinical transplant studies and recruited investigators with substantial, published experience in human transplant immunobiology to insure that our studies will yield clinically meaningful and mechanistically important results. RELEVANCE: Despite reductions in short-term rejection rates, long-term outcomes have not significantly improved in the past decade and there have been no fundamentally new immunosuppressive agents that have been approved in the new millennium. Our Collaborative will investigate efalizumab as an alternative to CNI-based immunosuppression in kidney and liver transplantation.

描述(由申请人提供)：尽管短期拒绝率持续下降，但长期结果在过去十年中并没有显著改善。面对这一迫切的未得到满足的需求，在新的千年里，没有从根本上批准的新的免疫抑制剂。我们的协作组将研究efalizumab作为肾和肝移植中CNI免疫抑制(IS)的替代方案。临床终点包括有效性和安全性，该试验将系统地评估与基于他克莫司的方案相比，使用efalizumab避免基于CNI的维持是否能更好地保存肾脏结构和功能，并降低PTDM、高血压和血脂异常的发生率。这些研究将被大量利用，以获得关于自然肾损伤和IFTA的病因的机械性见解，并开发进行性肾损伤的蛋白质组或基因表达生物标记物。我们将开发与临床相关的、基于机械的、非侵入性的分析方法，用于早期检测肾脏损伤，目的是将我们的发现转化为实用工具，帮助临床医生进行患者护理。我们将通过系统地定义在每种方案中观察到的病毒重新激活的类型和模式，以及评估对外周淋巴细胞动态平衡和病毒特异性记忆T细胞的表型和功能的影响，获得关于Eefalizumab和他克莫司对保护性免疫的影响的重要数据。我们将确定，在用efalizumab持续阻断LFA-1的情况下，受体持续暴露于供体抗原，同时避免CNI，是否会导致抗供体T细胞和/或体液免疫的改变或最近描述的耐受特征的发生率增加。考虑到肾损伤(自体和同种移植)的盛行率和免疫功能在所有移植环境中的中心性，无论IS方案如何，我们预计这些目标将广泛适用。我们联合了三家在临床移植研究方面拥有丰富经验的大容量移植医院，并招募了在人类移植免疫生物学方面具有丰富已发表经验的研究人员，以确保我们的研究将产生临床上有意义和机械上重要的结果。 相关性：尽管短期排斥率有所下降，但长期效果在过去十年中并没有显著改善，新千年也没有从根本上批准新的免疫抑制剂。我们的协作组将研究efalizumab作为肾和肝移植中基于CNI的免疫抑制的替代方案。

项目成果

Challenges of calcineurin inhibitor withdrawal following combined pancreas and kidney transplantation: Results of a prospective, randomized clinical trial.

• DOI: 10.1111/ajt.15817
• 发表时间: 2020-06
• 期刊: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
• 作者: Stock PG;Mannon RB;Armstrong B;Watson N;Ikle D;Robien MA;Morrison Y;Odorico J;Fridell J;Mehta AK;Newell KA
• 通讯作者: Newell KA