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: 8711225
• 负责人: DAVID KC COOPER
• 金额: $ 62.77万
• 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/8711225
• 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; Euthanasia; Family suidae; Functional disorder; Future; Galactosyltransferases; Genetic; Genetic Engineering; 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; 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-to-nonhuman 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) life-supporting 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) life-supporting 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到非人类的两个相互关联的当前问题