Cell Adhesion and Trafficking as a Therapeutic Target in Allotransplantation

细胞粘附和运输作为同种异体移植的治疗靶点

• 批准号: 8705985
• 负责人: Allan D. Kirk
• 金额: $ 92.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705985
• 关键词: Adjuvant; Adjuvant Therapy; Adverse effects; Allografting; Antigens; CD28 gene; Calcineurin inhibitor; Cardiovascular system; Cell Adhesion; Cell Adhesion Molecules; Cells; Characteristics; Chimeric Proteins; Chronic; Clinical; Clinical Data; Clinical Trials; Data; Drug usage; Epitopes; Goals; Heart failure; Herpesviridae; Homeostasis; Homologous Gene; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; In Vitro; Instruction; Integrin alpha4beta1; Integrins; Kidney; Kidney Failure; Kidney Transplantation; Leukocytes; Liver Failure; Lymphocryptovirus; Lymphocyte; Lymphocyte Activation; Macaca mulatta; Maintenance; Malignant - descriptor; Mediating; Memory; Metabolic; Methods; Modeling; Modification; Molecular; Molecular Conformation; Monoclonal Antibodies; Morbidity - disease rate; Mycophenolate; Organ Transplantation; Organ failure; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Physiology; Polyomavirus; Pre-Clinical Model; Prednisone; Prevalence; Process; Prophylactic treatment; Receptor Signaling; Regimen; Regulation; Research Personnel; Resistance; Role; Specificity; Staging; Steroids; T cell response; T memory cell; T-Cell Receptor; Testing; Therapeutic immunosuppression; Translating; Transplantation; Viral; allograft rejection; base; clinically relevant; conformational alteration; diabetic; directed attention; experience; glucose tolerance; immunoregulation; improved; inhibitor/antagonist; insight; isoimmunity; natalizumab; nonhuman primate; novel; novel strategies; pathogen; pre-clinical; prevent; research study; response; sound; therapeutic target; trafficking

PROJECT SUMMARY (See instructions): Kidney transplantation's considerable benefit is offset by the infectious and metabolic morbidity related to its required immunosuppressive drugs. Recently, belatacept, a CD28-B7 costimulation pathway inhibitor, has been approved for use with substantial evidence suggesting that it can prevent kidney rejection with less morbidity, and perhaps serve as a centerpiece agent for tolerance regimens. However, although belatacept appears to control naive immune responses well and evoke few off-target side effects, its control of memory T cell (TM) responses is less robust than hoped and its use is associated with significant morbidity related to the Epstein-Barr Virus (EBV). This Project will leverage substantial investigator experience and extensive preliminary data to develop logical adjuvant therapies that can be paired with belatacept. In particular, it will study altered integrin adhesion molecule expression as a means of identifying TMS with potential to cause belatacept-resistant rejection, and test four novel biologic agents for their ability to improve belatacept's antirejection effect in a rhesus monkey model of kidney transplantation without evoking the side effects related to existing standard immunosuppressive drugs. The ultimate goal is to develop one or more translatable regimens that can mediate lasting, well-tolerated, antigen-specific immune modulation to prevent allograft rejection. There are 3 Specific Aims. 1) To determine the effects of leukocyte function antigen (LFA)-Idirected therapy as an adjuvant to belatacept-based maintenance immunosuppression. We will test two novel LFA-1-specific monoclonal antibodies (Mabs) with identical specificity but distinct isotype, loGI or lgG4, for their efficacy in preventing belatacept-resistant rejection, and assess their effect on protective immunity, particularly toward the EBV-homologue, lymphocryptovirus (LCV). 2) To determine the role of an activation-induced LFA-1 conformational modification in mediating rejection and test the novel conformation specific, anti-LFA-1 Mab, AL-57. as an adjuvant to belatacept. We will define the AL-57 epitope in rhesus alio- and viral-specific immunity and test AL-57 for its ability to prevent or reverse rejection. 3) To define the effects of very late antigen (VLA)-4-specific therapy as an adjuvant to belatacept. We will test the VLA-4- specific Mab natalizumab for its efficacy in preventing or reversing belatacept-resistant rejection, and assess its effect on protective immunity. From these studies we will examine new approaches toward immunosuppression, using translatable agents in a clinically relevant pre-clinical model while concurrently providing new insights into the role of integrins in viral- and allo-immunity.

项目总结（见说明）： 肾移植的显著益处被与其所需的免疫抑制药物相关的感染和代谢发病率所抵消。最近，belatacept，CD 28-B7共刺激通路抑制剂，已被批准使用大量的证据表明，它可以预防肾排斥反应，发病率较低，并可能作为一个核心的药物耐受方案。然而，尽管贝拉西普似乎很好地控制了初始免疫应答并且引起很少的脱靶副作用，但其对记忆T细胞（TM）应答的控制不如所希望的那么稳健，并且其使用与与EB病毒（EBV）相关的显著发病率相关。该项目将利用大量的研究者经验和广泛的初步数据来开发可以与贝拉西普配对的合理辅助治疗。特别是，它将研究改变整合素粘附分子的表达作为一种手段，确定TMS与潜在的原因belatacept耐药排斥反应，并测试四种新型生物制剂的能力，以提高belatacept的抗排斥反应作用在恒河猴模型的肾移植，而不会引起与现有的标准免疫抑制药物的副作用。最终目标是开发一种或多种可翻译的方案，其可以介导持久的、耐受性良好的抗原特异性免疫调节以防止同种异体移植排斥。有三个具体目标。1)确定白细胞功能抗原（LFA）-I导向疗法作为以贝拉西普为基础的维持性免疫抑制的辅助治疗的效果。我们将测试两种新的LFA-1特异性单克隆抗体（单克隆抗体）具有相同的特异性，但不同的同种型，loGI或IgG 4，其在预防贝拉西普耐药排斥反应的疗效，并评估其对保护性免疫，特别是对EBV同源物，淋巴隐病毒（LCV）的影响。2)确定活化诱导的LFA-1构象修饰在介导排斥反应中的作用，并检测新型构象特异性抗LFA-1单抗AL-57。作为贝拉西普的佐剂我们将定义恒河猴同种异体和病毒特异性免疫中的AL-57表位，并测试AL-57预防或逆转排斥反应的能力。3)确定极晚期抗原（VLA）-4特异性治疗作为贝拉西普辅助治疗的效果。我们将测试VLA-4- 特异性单克隆抗体那他珠单抗在预防或逆转贝拉西普耐药排斥反应中的功效，并评估其对保护性免疫的作用。从这些研究中，我们将研究免疫抑制的新方法，在临床相关的临床前模型中使用可翻译的药物，同时提供整合素在病毒和同种免疫中的作用的新见解。