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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：
7790541
负责人：
SIMON C. ROBSON
金额：
$ 33.48万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-09-15 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7790541
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 Inflammation Mediators 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 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 primate development 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.

一旦了解了排斥反应的机制并进行移植，异种移植可能在临床上是可行的