Studies in pig-to-primate cardiac xenotransplantation

猪到灵长类动物心脏异种移植的研究

• 批准号: 8097350
• 负责人: CHRISTOPHER G.A. MCGREGOR
• 金额: $ 104.96万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097350
• 关键词: Achievement; Antibodies; Antibody Formation; Antigen Targeting; Antigens; Binding; Biochemical; Biochemical Markers; Biopsy; Blood Circulation; Bortezomib; Carbohydrates; Cardiac; Cell Transplantation; Chronic; Clinical; Development; Diagnosis; Dissection; Echocardiography; Effectiveness; Electrocardiogram; Endothelial Cells; Engineering; Family suidae; Flow Cytometry; Functional disorder; Funding; Future; Gene Expression; Grant; Heart; Heart Transplantation; Histologic; Histology; Immune response; Immunosuppression; Immunosuppressive Agents; In Situ; Individual; Injury; Intervention; Lasers; Life; Measurement; Mediating; Methods; Modality; Modeling; Monitor; Neoadjuvant Therapy; Organ Donor; Outcome; Patients; Perioperative; Pharmaceutical Preparations; Physiologic Monitoring; Plasma Cells; Plasmapheresis; Primates; Principal Investigator; Procedures; Proteasome Inhibitor; Proteins; Pulmonary Vascular Resistance; RNA; Recombinant Proteins; Recovery; Sampling; Solutions; Surgical Models; Survivors; T-Lymphocyte; Techniques; Testing; Time; Tissues; Transgenic Organisms; Transplantation; Variant; Xenograft procedure; base; cariporide; clinical application; glycosyltransferase; heart preservation; heart xenograft; improved; method development; mycophenolate mofetil; novel; preclinical study; prevent; treatment effect

DESCRIPTION (provided by applicant): The objective of this application is to achieve 90-day median survival of life-supporting cardiac xenotransplantation (CXTx) in the pig-to-primate model using genetically-engineered donors, clinical immunosuppression (IS) and modalities to diagnose and treat delayed xenograft rejection (DXR) leading to preclinical studies of CXTx. Prolonged xenograft survival is now limited by non-Gal antibody-mediated DXR (NGDXR). With improved outcomes for orthotopic (OCXTx), it has emerged that early xenograft function is compromised in up to 50% of cases. We have termed this perioperative cardiac xenograft dysfunction (PCXD). For potential future clinical application of CXTx, it is essential to understand the mechanisms and improve the outcomes of both NGDXR and PCXD. All transplants for Specific Aims (SA) 1-3 will use donors transgenic for CD55 with inactivation of the GGTA-1 glycosyltransferase locus (GTKO:CD55+). In SA 1, to better understand PCXD, plasmapheresis will be used to remove preformed non-Gal antibody (PNGA) and the proteasome inhibitor Bortezomib given to delete plasma cells prior to OCXTx. This therapy will also be combined with cariporide cardiac preservation to mitigate preoperative injury. The impact of PNGA depletion and cariporide treatment on PCXD will be assessed by measurement of cardiac function by echocardiography (ECHO), biochemical markers of cardiac injury, recipient antibody and plasma cell levels, and will be correlated with cardiac gene expression in interim biopsies and explanted hearts. In SA 2, to prevent DXR optimal IS based on induction therapy for B- and T-cells, triple drug IS and Bortezomib will be used to control NGA in OCXTx recipients surviving SA 1. We will further study the mechanism(s) of NGDXR through analysis of antibody responses to GTKO PAECs and novel individual non-Gal carbohydrate and protein target antigens we have identified. Changes in cardiac gene expression will be correlated with DXR. In SA 3, we utilize life-supporting intrathoracic heterotopic CXTx, a currently clinically used heart transplant variant which, as well as being a potential technique for initial clinical application of CXTx, will uniquely allow a) observation of recovery of PCXD by ECHO and b) development of methods for the diagnosis and treatment of DXR without loss of the recipient as the native heart supports the circulation during these periods of xenograft dysfunction. In this aim, plasmapheresis and Bortezomib will be used to treat DXR. The objective of this application, to achieve 3-month median survival of circulation-bearing CXTx, if successful, will lay the groundwork for preclinical studies during this grant period to support clinical application of CXTx. RELEVANCE: Successful xenotransplantation offers a potential clinical solution to alleviate the chronic and increasing shortage of donor organs and cells for transplantation. Our previous studies over 12 years have achieved the longest median survival of heterotopic cardiac xenotransplants and the longest survivors of life-supporting orthotopic cardiac xenotransplants. Achievement of the specific aims of this proposal will bring cardiac xenotransplantation to the threshold of clinical application.

描述（由申请人提供）： 该应用的目的是使用遗传学工程供体，临床免疫抑制（IS）和诊断和治疗延迟延迟的异种移植拒绝（DXR）的临床免疫抑制（IS），实现猪至顶峰模型中的90天中位生存期。现在长时间的异种移植存活率现在受非-GAL抗体介导的DXR（NGDXR）的限制。随着原位（OCXTX）的改善结果，已经出现了早期异种移植功能在多达50％的病例中受到损害。我们称这种围手术期心脏异种移植功能障碍（PCXD）。对于CXTX的未来临床应用，必须了解机制并改善NGDXR和PCXD的结果。所有针对特定目的的移植（SA）1-3将使用供体转基因CD55，而GGTA-1糖基转移酶基因座（GTKO：CD55+）灭活。在SA 1中，为了更好地理解PCXD，将使用血浆置换来去除预制的非GAL抗体（PNGA）和蛋白酶体抑制剂硼替型bortezomib，以删除OCXTX之前删除血浆细胞。该疗法还将与甲状腺肿的心脏保存相结合，以减轻术前损伤。 PNGA耗竭和Cariporide治疗对PCXD的影响将通过超声心动图（ECHO），心脏损伤的生化标志物，受体抗体和浆液性细胞水平的测量来评估，并将与互惠生物的心脏基因表达相关。在SA 2中，为防止DXR最佳是基于B核和T细胞的诱导疗法，将三重药物IS和硼替佐米用于控制Sa 1的OCXTX受体中的NGA。我们将通过分析对GTKO PAECS和Nexp novely nonthny-Gal含有的抗体反应的NGDXR机制进一步研究NGDXR的机制。心脏基因表达的变化将与DXR相关。在SA 3中，我们利用了具有生命支持的静脉内部异位性CXTX，这是一种目前临床使用的心脏移植变体，并且是CXTX初始临床应用的潜在技术，将独特地允许a）允许a）在echo和beverals of dece note de the de the de dxr的损失中恢复PCXD的恢复。异种移植功能障碍。在此目的中，血浆置换和硼替佐米将用于治疗DXR。本应用的目的是实现循环含量CXTX的3个月中位生存期，如果成功的话，将为临床前研究奠定基础，以支持CXTX的临床应用。 相关性：成功的异种移植提供了潜在的临床解决方案，可减轻供体器官和细胞短缺以进行移植。我们以前的12年研究实现了异性心脏异种移植植物的中位生存期最长的中位生存期，并且是生命支持的原位性心脏异种移植植物中最长的生存者。该提案的具体目的的实现将为临床应用的阈值带来心脏异种移植。