Effect of Genetic Modifications on Pig Heart and Kidney Graft Survival in Baboons

基因改造对狒狒猪心和肾移植物存活的影响

• 批准号: 8309413
• 负责人: DAVID KC COOPER
• 金额: $ 51.99万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/8309413
• 关键词: Acute; Adrenal Cortex Hormones; Antibodies; Antithymoglobulin; B-Lymphocytes; Blood Coagulation Disorders; Blood Platelets; CD46 Antigen; CTLA4 gene; Coagulation Process; Complement; Data; Development; Endothelial Cells; Engineering; Euthanasia; Family suidae; Functional disorder; Future; Galactosyltransferases; Genetic; Graft Survival; Heart; Heart Transplantation; Heterogeneity; Human; Immune response; Immunity; Immunosuppressive Agents; Instruction; Investigation; Kidney; Kidney Transplantation; Life; Light; Maintenance; Modification; Molecular; Natural Immunity; Natural Killer Cells; Neoadjuvant Therapy; Organ; Organ Transplantation; Papio; Platelet Activation; Play; Prevention; Primates; Protocols documentation; Regimen; Role; Source; T-Lymphocyte; Thrombocytopenia; Thrombomodulin; Thrombosis; Transgenic Organisms; Vascular Endothelium; Vascular Graft; Xenograft procedure; activated protein C receptor; adaptive immunity; genetic regulatory protein; graft failure; immunosuppressed; knock-down; knockout gene; macrophage; mutant; mycophenolate mofetil; nonhuman primate; novel; prevent; response; success

The proposed studies are directed towards resolving two inter-related current problems in pig-tononhuman primate (NHP) organ xenotransplantation using GTKO.CD46.CD55 pigs (designated GE pigs) (i) to identify a clinically-applicable regimen that prevents an adaptive immune response, and (ii) to identify a means of preventing coagulation dysfunction - in the form of thrombocytopenia and/or consumptive coagulopathy (CC) with associated thrombotic microangiopathy. The immune response may influence the development of coagulation disorders, and coagulation dysregulation may influence the immune response. The exact causative factors of CC remain uncertain, but (i) heightened innate immunity (antibody, complement, platelets, macrophages, NK cells), (ii) the adaptive immune response (T and B cells), and (iii) molecular incompatibilities between pig and NHP, may all play roles. Graft vascular heterogeneity may also be evident as CC and thrombocytopenia occur more rapidly in NHPs with pig kidney rather than heart grafts. We propose that genetic modifications in pigs and novel therapies may protect against these factors. We shall use CIITA mutant pigs (with knock-down of SLA Class II) and other pigs transgenic for human thromboregulatory factors on the GTKO background. Aim 1: To investigate the efficacy in baboons of a clinically-applicable immunosuppressive regimen in preventing the innate and adaptive immune responses after heterotopic heart Tx from (A) GE pigs (n=6) and (B) GE.CIITA pigs (n=6), and to determine whether prevention of elicited xenogeneic immunity correlates with delay in" the onset or prevention of coagulation dysfunction. Aim 2: To investigate the coagulation disorders that develop after (A) heterotopic heart Tx (n=6) or (B) lifesupporting kidney Tx (n=6) from GE.CIITA pigs additionally transgenic for human TBM in baboons immunosuppressed with a clinically-applicable regimen, and to determine the causes of graft failure and coagulation dysfunction. Aim 3: To investigate the coagulation disorders that develop after (A) heterotopic heart Tx (n=6) or (B) lifesupporting kidney Tx (n=6) from GE.CIITA.TBM pigs additionally transgenic for human EPCR in baboons immunosuppressed with a clinically-applicable regimen, and to determine the causes of graft failure and coagulation dysfunction.

拟议的研究旨在解决猪和人之间两个相互关联的当前问题。 用GTKO.CD46.CD55猪(简称GE猪)进行灵长类(NHP)器官异种移植 确定防止适应性免疫反应的临床适用方案，以及(Ii)确定 预防凝血功能障碍的手段--以血小板减少和/或消耗性形式出现 凝固性疾病(CC)伴发血栓性微血管病变。免疫反应可能会影响 凝血功能紊乱和凝血功能失调可能会影响免疫反应。 CC的确切致病因素尚不清楚，但(I)天然免疫增强(抗体， 补体、血小板、巨噬细胞、NK细胞)，(Ii)适应性免疫反应(T和B细胞)，以及(Iii) 猪和NHP之间的分子不亲和性，可能都起到了作用。移植物血管异质性也可能 显然，与心脏移植相比，移植猪肾的NHP更容易发生CC和血小板减少症。 我们认为，对猪的基因改造和新的治疗方法可能对这些因素具有保护作用。我们 应使用CIITA突变猪(SLA II级击倒)和其他人用转基因猪 GTKO背景下的血栓调节因子。 目的1：研究一种临床适用的免疫抑制方案对狒狒的疗效。 预防(A)GE猪(n=6)异位心脏移植后的先天和获得性免疫反应 (B)GE.CIITA猪(n=6)，并确定预防引起的异种免疫是否与 延迟“凝血功能障碍的发生或预防”。 目的2：研究(A)异位心脏移植(n=6)或(B)生命支持后发生的凝血功能障碍 GE.ciita猪肾脏TX(n=6)附加转人TBM基因的狒狒 用临床适用的方案进行免疫抑制，并确定移植失败的原因和 凝血功能障碍。 目的3：研究(A)异位心脏移植(n=6)或(B)生命支持后发生的凝血功能障碍 GE.ciita.tbm猪肾脏TX(n=6)附加转人EPCR基因在狒狒体内的研究 用临床适用的方案进行免疫抑制，并确定移植失败的原因和 凝血功能障碍。