Novel Therapies for Chronic Renal Allograft Dysfunction in Children

儿童慢性同种异体移植肾功能障碍的新疗法

基本信息

批准号：
7452840
负责人：
WILLIAM E. HARMON
金额：
$ 147.98万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7452840
关键词：
Abate Acute Adherence Adolescent Adult Adverse effects Affect Age Alloantigen Allografting Animals Antigen-Presenting Cells Antigens Area B-Lymphocytes Biological Assay Biological Markers Brain Death Calcineurin Calcineurin inhibitor Cardiovascular system Cell Aging Cell Communication Cells Child Childhood Chimeric Proteins Chronic Clinical Clinical Trials Design Collaborations Complex Cosmetics Creatinine Data Data Analyses Development Disease Dose End stage renal failure Endothelial Cells Event Experimental Models Functional disorder Goals Graft Survival Growth Factor Half-Life Human Hyperlipidemia Hypertension Immune response Immunosuppression Immunosuppressive Agents In Vitro Infant Infection Inflammatory Response Injury Interruption Investigation Isoantibodies Kidney Kidney Diseases Kidney Transplantation Laboratories Lead Letters Life Living Donors Lymphoproliferative Disorders Measures Mediating Mediator of activation protein Modeling Molecular Natural History Nature Numbers Operative Surgical Procedures Organ Organ Transplantation Outcome Pathogenesis Pathway interactions Peripheral Pharmaceutical Preparations Pharmacologic Substance Phase I/II Trial Phase II Clinical Trials Phase III Clinical Trials Play Polyomavirus Prevention Prevention therapy Primates Principal Investigator Procedures Process Production Protein Kinase C Protein Kinase C Inhibitor Protocols documentation Purpose Randomized Randomized Clinical Trials Rate Recording of previous events Records Registries Renal function Reperfusion Injury Reporting Research Personnel Risk Role Safety Scientist Secondary to Serum Signal Transduction Smooth Muscle Myocytes Surrogate Markers Survival Rate T-Cell Activation T-Cell Receptor T-Lymphocyte Techniques Testing Therapeutic Intervention Therapeutic immunosuppression Time Toxic effect Translating Transplant Recipients Transplantation Withdrawal age group base demographics experience graft function improved in vivo inhibitor/antagonist innovation intravenous administration kidney allograft macrophage monocyte neoplastic nephrotoxicity novel novel strategies novel therapeutics peripheral blood preclinical study prevent programs response success

项目摘要

DESCRIPTION (provided by applicant): The primary hypothesis of this proposal is that T cell recognition of alloantigen, costimulation and subsequent activation plays a critical role in orchestrating the alloimmune response responsible for initiation and progression of chronic allograft rejection. The corollary hypothesis is that inhibiting T cell activation by T cell costimulatory blockade or by Protein Kinase C inhibition will prevent progression of chronic organ dysfunction following transplantation. The secondary hypothesis is that calcineurin inhibitors (CNI) play an important role in promoting chronic allograft dysfunction because of their nephrotoxicity. Therefore, removing CNIs, along with provision of adequate, safe and non-toxic immunosuppression to inhibit T cell activation should prevent the progression of organ dysfunction, and improve renal function and long-term outcome. The overall goal of this proposal is to develop novel therapies for prevention and interruption of progression of chronic allograft dysfunction in children. We have formed a consortium of six large pediatric kidney transplant programs with proven track records of participation in multi-center collaborative randomized clinical trials of innovative immunosuppression protocols. We also have assembled five mechanistic core laboratories to define the biomarkers of chronic allograft dysfunction and the effects of novel therapeutic interventions. We are proposing two alternative trials: 1 Belatacept Protocol: In this protocol we will test the hypothesis that B7 blockade by belatacept will block ongoing alloimmune responses and allow conversion from CNI in pediatric renal transplant recipients leading to prevention of progression of chronic allograft dysfunction and improvement in renal function. In collaboration with BMS we now propose to initiate belatacept 6-24 months post-transplantation to withdraw CNI and prevent progression of chronic allograft dysfunction in pediatric kidney transplant recipients. Since belatacept is provided as once monthly intravenous infusions, the protocol has the added potential to improve immunosuppression adherence in adolescent transplant. 2 AEB071 Protocol: In this protocol, we will test the hypothesis that Protein Kinase C inhibition will effectively block ongoing alloimmune responses and permit CNI withdrawal in pediatric renal transplant recipients leading to prevention of progression of chronic allograft dysfunction and improvement in renal function. In collaboration with Novartis we now propose to initiate AEB071 6-24 months post-transplantation to withdraw CNI and prevent progression of chronic allograft dysfunction in pediatric kidney transplant recipients. 3 Mechanistic Studies: We will test the hypothesis that inhibition of T cell activation by belatacept or AEB071 will inhibit the effector mechanisms of chronic allograft rejection, including T cell alloreactivity, alloantibody production (B cells), as well as other mediators of the chronic inflammatory response. These effects can be detected by sensitive and specific assays, including peripheral cellular/humoral assays, and peripheral blood and intragraft molecular assays. The main goal of these studies is to understand the mechanisms of action of belatacept/AEB071 and to develop a set of surrogate biomarkers of chronic allograft dysfunction and stability in pediatric kidney transplant recipients.

描述（由申请人提供）：该提案的主要假设是T细胞识别同种抗原，共刺激和随后的激活在策划负责慢性同种异体移植排斥的引发和进展的同种异体免疫反应中起着至关重要的作用。推论假设是，通过T细胞共刺激阻断或蛋白激酶C抑制抑制T细胞激活将防止移植后慢性器官功能障碍的进展。次要假设是钙调神经酶抑制剂（CNI）由于其肾毒性而在促进慢性同种异体移植功能障碍中起重要作用。因此，除去CNIS，并提供足够的，安全和无毒的免疫抑制以抑制T细胞激活，应防止器官功能障碍的进展，并改善肾功能和长期结局。该提案的总体目标是开发用于预防和中断儿童慢性同种异体功能障碍进展的新型疗法。我们组成了一个由六个大型儿科肾脏移植计划组成的财团，并有经过证实的记录参与创新免疫抑制方案的多中心协作随机临床试验。我们还组装了五个机械核心实验室，以定义慢性同种异体功能障碍的生物标志物和新型治疗干预措施的影响。我们提出了两项替代试验：1 Belatacept方案：在此方案中，我们将测试以下假设：Belatacept遭到BLATACEPT的B7封锁将阻止正在进行的同种异体免疫反应，并允许在儿科肾移植受者中CNI从CNI转化，从而导致预防慢性同种异体手术功能和改善肾脏功能的进展。现在，我们建议在移植后6-24个月启动Belatacept，以撤回CNI并防止小儿肾脏移植受者慢性同种异体移植功能障碍的进展。由于BELATACEPT是一次每月一次静脉输注，因此该方案具有改善青少年移植中免疫抑制依从性的额外潜力。 2 AEB071方案：在此方案中，我们将测试以下假设：蛋白激酶C抑制作用将有效阻止正在进行的同种免疫性反应，并允许CNI戒断儿科肾移植受者，从而预防慢性同种异体移植功能障碍和肾功能的改善。现在，我们建议在移植后6-24个月启动AEB071启动AEB071，以撤回CNI，并防止小儿肾脏移植受者中慢性同种异体移植功能障碍的进展。 3机械研究：我们将检验以下假设：Belatacept或AEB071对T细胞激活的抑制作用将抑制慢性同种异体移植排斥的效应机制，包括T细胞同种异体反应性，同种抗体产生（B细胞），以及慢性炎症反应的其他介体。这些效果可以通过敏感和特定的测定法（包括外周细胞/体液测定法）以及外周血和手体内分子测定法检测到。这些研究的主要目的是了解Belatacept/AEB071的作用机理，并开发一组慢性同种异体移植功能障碍和稳定性的替代生物标志物在小儿肾脏移植受者中。