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Thromboregulatory Barriers to Xenotransplantation

异种移植的血栓调节障碍

基本信息

批准号：
7549248
负责人：
SIMON C. ROBSON
金额：
$ 27.33万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7549248
关键词：
Abbreviations Acute Address Agonist Anti-Inflammatory Agents Antibodies Anticoagulants Antithrombin III Antithrombins Area Blood Coagulation Factor Blood Platelets Blood Vessels Bone Marrow Bone Marrow Cells Bone Marrow Transplantation CD31 Antigens Cells Chimerism Clinical Coagulation Process Consumption Cyclophosphamide Cyclosporine Cyclosporins Data Development Disease Endothelial Cells Engraftment Excision Family suidae Fibroblasts Genes Genetic Goals Graft Survival Heterophile Antigens Human Humoral Immunities Inflammatory Infusion procedures Injury Intervention Kidney Kinetics Link MALDI-TOF Mass Spectrometry Mediating Mediator of activation protein Miniature Swine Modality Modeling Molecular Molecular Profiling Mus Nature Organ Outcome Papio Pathway interactions Phenotype Platelet Activating Factor Platelet Activation Platelet Glycoproteins Prevention Primates Principal Investigator Process Proteins Proteomics Purinergic P1 Receptors Reaction Reagent Research Resistance Role SolCD39 Sus scrofa TFPI Testing Therapeutic Thrombocytopenia Thrombomodulin Thromboplastin Thrombotic Thrombocytopenic Purpura Thymic Tissue Time Toxic effect Transgenic Mice Transgenic Organisms Umbilical vein Up-Regulation Viral Proteins Xenograft procedure antithrombin III-protease complex clinically relevant gene therapy implantation in vivo kidney xenograft novel nuclear transfer nucleoside triphosphate protein expression research study response therapeutic gene vascular inflammation vector von Willebrand Factor

项目摘要

Xenotransplantation may be clinically feasible once the mechanisms of rejection are understood and graft survival can be achieved without compromising the recipient to the extent that systemic toxicity is encountered. Thrombotic and inflammatory reactions to porcine bone marrow (BM)-derived cells and vasculature are linked to difficulties in establishing mixed discordant chimerism in primates and the development of thrombotic microangiopathy in vascularized grafts. These responses may be associated with humoral immunity to xenogeneic grafts and intrinsic molecular barriers between the discordant species. The development of the GalT-KO pig and removal of the dominant xenoantigen has been a major advance in this area. However, there are still problems in inducing tolerance by generating mixed chimerism, either by vascularized thymic tissues or the bone marrow BM-derived cell approach; limited xenograft survival times and graft injury are still a concern. The goals of this project are directed at delineating mechanisms of the thrombotic sequelae associated with the GalT-KO pig-to-baboon xenotransplant model. We will identify and characterize porcine antigenic targets of both natural and elicited xenoreactive antibodies directed against Gal negative xenografts in vivo by MALDI-TOF Mass Spectrometry. Vascular markers of thrombotic injury will be also determined by porcine gene mini-arrays. Protein expression profiling will be undertaken to validate these vascular markers of xenograft rejection. The role of antithrombotic interventions will be determined addressing both pharmacological and genetic modalities. Antithrombin agents will be administered to baboon recipients of porcine cell infusions and renal grafts, as dual anti-thrombotic and anti- inflammatory agents, at the time of graft implantation and with rejection episodes. We will also study treatment with solCD39 (an ectonucleotidase) and ATL146e (an adenosine receptor A2a agonist), in combination with this antithrombin strategy. Gene therapeutic vectors will be employed to over-express CD39, thrombomodulin and tissue factor pathway inhibitor in GalT-KO BM-derived cells, prior to their infusion into baboons. Outcomes with respect to inflammatory or thrombotic sequelae and engraftment will be examined. We will finally evaluate transgenic approaches to over-express CD39 and the natural human anticoagulant factors in mice and pigs. Our studies will be judged successful if novel and clinically relevant antithrombotic strategies can be then developed and applied.

一旦了解了排斥的机制并移植，异种移植可能在临床上是可行的。可以在不损害接受者的情况下实现存活，因为全身毒性是遇到了。对猪骨髓来源细胞的血栓和炎症反应在灵长类动物中建立混合的不协调嵌合体的困难与血管形成有关血管化移植物中血栓性微血管病变的发展。这些响应可能与对异种移植物的体液免疫和不和谐物种之间的内在分子屏障。这个 Galt-KO猪的发展和优势异种抗原的去除是这方面的一个重大进展区域。然而，通过产生混合嵌合体来诱导耐受性仍然存在问题，要么是通过血管胸腺组织或骨髓来源细胞方法；有限的异种移植存活时间和移植物损伤仍然是一个令人担忧的问题。这一项目的目标是描述与Galt-KO猪到狒狒异种移植模型相关的血栓后遗症。我们将确定和猪天然和诱导的异种反应性抗体的抗原靶的鉴定 MALDI-TOF质谱法测定体内GAL阴性异种移植瘤血栓性损伤的血管标志物也将由猪基因微阵列确定。将进行蛋白质表达谱分析以验证这些异种移植排斥反应的血管标志物。抗血栓干预的作用将是确定同时解决药理和遗传方式问题。抗凝血酶药物将是应用于接受猪细胞输注和肾移植的狒狒，作为双重抗血栓和抗移植物植入时和发生排斥反应时的炎性物质。我们还将研究用solCD39(一种胞外核苷酸酶)和ATL146e(一种腺苷A2a受体激动剂)治疗与这种抗凝血酶策略相结合。基因治疗载体将被用来过度表达 CD39、血栓调节蛋白和组织因子途径抑制物在GALT-KO BM来源的细胞中的表达给狒狒输液。炎症性或血栓后遗症和植入物的结果将接受检查。我们将最终评估过表达CD39和自然人的转基因方法小鼠和猪的抗凝血因子。如果我们的研究具有新颖性和临床相关性，我们的研究将被认为是成功的然后可以开发和应用抗血栓策略。