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)： 肾移植的巨大好处被与其所需的免疫抑制药物相关的感染和代谢并发症所抵消。最近，CD28-B7共刺激通路抑制剂belatacept已被批准使用，大量证据表明，它可以预防肾排斥反应，发病率较低，并可能作为耐受方案的核心药物。然而，尽管Belatacept似乎能很好地控制幼稚的免疫反应，并引起很少的非靶标副作用，但它对记忆T细胞(TM)反应的控制不如预期的强大，而且它的使用与与EB病毒(EBV)相关的重大发病率有关。该项目将利用丰富的研究人员经验和广泛的初步数据来开发可与拉帕西汀配对的合理辅助疗法。特别是，它将研究整合素黏附分子表达的变化，以此作为一种手段来鉴定有可能导致抗拉他赛普排斥反应的TMS，并测试四种新型生物制剂在恒河猴肾移植模型中改善拉他赛特抗排斥效果的能力，而不会引起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翻译的方案，能够介导持久的、耐受性良好的、抗原特异性的免疫调节，以防止同种异体移植排斥反应。有三个具体目标。1)探讨白细胞功能抗原(LFA)导向疗法作为贝拉坦维持免疫抑制的辅助治疗效果。我们将测试两种新的LFA-1特异性单抗(MAb)，它们具有相同的特异性但不同的同型，Log1或lgG4，以防止对贝拉西普耐药的排斥反应，并评估它们对保护性免疫的影响，特别是对EBV同源物淋巴腺病毒(LCV)的影响。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，并检测新的构象特异性的抗LFA-1单抗AL-57。作为拉他帕特的佐剂。我们将确定AL-57表位在恒河猴异型和病毒特异性免疫中的作用，并测试AL-57预防或逆转排斥反应的能力。3)明确甚晚抗原(VLA)-4特异性治疗作为贝拉坦的佐剂的疗效。我们将测试VLA-4- 特异性单抗Natalizumab预防或逆转贝拉西普耐药排斥反应的有效性，并评估其对保护性免疫的影响。从这些研究中，我们将检验免疫抑制的新方法，在临床相关的临床前模型中使用可翻译的药物，同时对整合素在病毒和同种免疫中的作用提供新的见解。