GalT-KO Vascularized Thymic Transplantation for Xenograft Tolerance

GalT-KO 血管化胸腺移植以提高异种移植耐受性

基本信息

批准号：
8190111
负责人：
KAZUHIKO YAMADA
金额：
$ 37.5万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8190111
关键词：
Address Adjuvant Allogenic Allografting Animals Antibodies Antigens Australia Biopsy Blood Vessels CD80 gene CD8B1 gene Candida Caring Cell physiology Cessation of life Chronic Clinic Clinical Collaborations Complement Activation Complication Cytomegalovirus Data Development Dinitrochlorobenzene Disease Education Evaluation Excision Excretory function Family suidae Healthcare Hemostatic function Hepatitis C Homeostasis Human Immune Tolerance Immunity Immunocompetence Immunologics Immunosuppression In Vitro Infection Infection prevention Injury Kidney Kidney Diseases Knock-out Laboratories Lead Life Maintenance Measurement Medical Miniature Swine Modeling Molecular Natural Killer Cells Nephrotic Syndrome Organ Organ Donor Papio Patients Pharmaceutical Preparations Postoperative Period Prevention strategy Proteinuria Protocols documentation Reaction Recurrent disease Regimen Regulatory T-Lymphocyte Research Role Staging Steroids Streptococcus pneumoniae T-Cell Depletion T-Lymphocyte TNFSF5 gene Testing Therapeutic immunosuppression Thrombomodulin Thymic Tissue Thymus Gland Transferase Transgenes Transplantation Transplantation Tolerance Trichophyton Weaning Whole-Body Irradiation Xenograft procedure base clinical application cost design effective therapy graft failure graft function implantation improved in vitro Assay in vivo innovation irradiation kidney xenograft nonhuman primate novel podocyte prevent research study response success urinary

项目摘要

The shortage of available donor allografts continues to provoke a health care crisis and provides the rationale for continued xenotransplantation research. We are attempting to address these issues by inducing transplantation tolerance across discordant xenogeneic barriers in non-human primates. Our strategy utilizes composite vascularized thymic-renal grafts from GalT-KO swine. During the most recent project period (late 2004-2008), we markedly decreased the complication rate in the induction period with a "modified regimen," which eliminated steroids and whole body irradiation. Our most significant findings are (1) Extended average survival of life-supporting kidney xenograft recipients to greater than 50 days under the modified immunosuppression regimen as compared to 33 days under the original protocol; (2) Reproducible in vitro evidence for donor-specific tolerance; and (3) Demonstration of CD4/CD8 double positive baboon xenothymocytes in transplanted pig thymic grafts, indicating baboon thymopoiesis, which had otherwise not been achieved in a large animal xenotransplant model. To our knowledge, these results represent the longest average survival of life-supporting xenografts and also provide novel in vitro evidence for tolerance in large animals. In order to make this approach more clinically applicable, this proposal will address remaining crucial concerns of tolerance induction, immune suppression, and issues with renal xenograft function in baboons that may be caused by molecular incompatibilities across species. In Aim 1, we will first confirm immunologic tolerance induced by xenogeneic porcine vascularized thymic grafts and eliminate maintenance immunosuppression using our most successful regimen. We will also attempt to achieve tolerance with a T-cell depletion based regimen in order to remove anfi-CD154 mAb and myelosuppressive drugs. In Aim 2, we will assess in-vitro parameters of xenogeneic immunity before and after transplantation of vascularized thymic tissue. We will examine the fundamental cellular processes involved in the development and maintenance of tolerance. In Aim 3, we will evaluate the cause of xenograft kidney proteinuria and develop preventive strategies. We will explore: 1) the utility of anti-non-Gal antibody removal prior to graft implantation; 2) pharmacologic adjuvant vascular protective therapies shown to be clinically effective for treatment of vascular injury/proteinuria; and 3) the use of kidneys from GalT-KO pigs with additional transgenes, including hDAF, hCD39 and thrombomodulin. The success of a clinically applicable strategy would provide not only a limitless supply of donor organs but also opportunities for transplantation in patients unable to receive a transplant because of presensitization to allogeneic human donors.

可用同种异体移植供体的短缺继续引发医疗保健危机，并提供了理由继续进行异种移植研究。我们正在尝试通过诱导来解决这些问题非人类灵长类动物跨不一致异种障碍的移植耐受性。我们的策略利用来自 GalT-KO 猪的复合血管化胸腺肾移植物。在最近的项目期间（后期 2004-2008），我们通过“改良方案”显着降低了诱导期的并发症发生率，消除了类固醇和全身辐射。我们最重要的发现是 (1) 扩展平均值修改后的支持生命的肾异种移植受者的生存期超过 50 天与原方案下的 33 天免疫抑制方案相比； (2) 体外重复性好供体特异性耐受性的证据；（3）CD4/CD8双阳性狒狒示范移植的猪胸腺移植物中存在异胸腺细胞，表明狒狒具有胸腺生成功能，而在其他情况下，狒狒没有胸腺生成功能已在大型动物异种移植模型中实现。据我们所知，这些结果代表维持生命的异种移植物的平均存活时间最长，并为耐受性提供了新的体外证据在大型动物中。为了使该方法在临床上更适用，该提案将解决耐受诱导、免疫抑制和肾异种移植问题仍然是关键问题狒狒的功能可能是由物种间分子不相容引起的。在目标 1 中，我们首先确认异种猪血管化胸腺移植物诱导的免疫耐受并消除使用我们最成功的方案维持免疫抑制。我们也将努力实现耐受基于 T 细胞消除的方案，以消除抗 CD154 mAb 和骨髓抑制药物。在目标2中，我们将评估移植前后异种免疫的体外参数血管化胸腺组织。我们将研究参与的基本细胞过程耐受性的发展和维持。在目标 3 中，我们将评估异种移植肾的原因蛋白尿并制定预防策略。我们将探讨：1）抗非Gal抗体去除的效用移植物植入前； 2）临床证明有效的药物辅助血管保护治疗有效治疗血管损伤/蛋白尿； 3) 使用 GalT-KO 猪的肾脏其他转基因，包括 hDAF、hCD39 和血栓调节蛋白。临床应用的成功该战略不仅将提供无限的供体器官供应，而且还将提供移植机会由于对同种异体人类捐赠者预敏而无法接受移植的患者。