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.

项目摘要（参见说明）： 肾移植的巨大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（一种 CD28-B7 共刺激途径抑制剂）已被批准使用，大量证据表明它可以预防肾排斥，且发病率较低，并且可能作为耐受方案的核心药物。然而，尽管贝拉西普似乎能很好地控制初始免疫反应，并且很少引起脱靶副作用，但其对记忆 T 细胞 (TM) 反应的控制不如预期那么强大，而且其使用与 Epstein-Barr 病毒相关的显着发病率有关（EBV）。该项目将利用丰富的研究者经验和广泛的初步数据来开发可与belatacept配对的逻辑辅助疗法。特别是，它将研究整合素粘附分子表达的改变，作为识别可能导致贝拉西普耐药排斥的 TMS 的一种手段，并测试四种新型生物制剂在恒河猴肾移植模型中改善贝拉西普抗排斥作用而不引起排斥反应的能力。与现有标准免疫抑制药物相关的副作用。最终目标是开发一种或多种可转化的方案，可以介导持久、耐受性良好、抗原特异性免疫调节，以防止同种异体移植排斥。有 3 个具体目标。 1) 确定白细胞功能抗原 (LFA)-I 定向治疗作为基于贝拉西普的维持免疫抑制的佐剂的效果。我们将测试两种新型 LFA-1 特异性单克隆抗体 (Mab)，它们具有相同的特异性但不同的同种型 loGI 或 IgG4，以了解它们在预防贝拉西普耐药排斥反应方面的功效，并评估它们对保护性免疫的影响，特别是针对 EBV 同源物，淋巴隐病毒（LCV）。 2) 确定激活诱导的 LFA-1 构象修饰在介导排斥反应中的作用，并测试新型构象特异性抗 LFA-1 单克隆抗体 AL-57。作为贝拉西普的佐剂。我们将定义恒河猴异种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 特异性疗法作为贝拉西普佐剂的效果。我们将测试 VLA-4- 特异性 Mab 那他珠单抗预防或逆转贝拉西普耐药排斥反应的功效，并评估其对保护性免疫的影响。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药物，同时提供关于整合素在病毒和同种免疫中的作用的新见解。