Delayed Tolerance Induction in Living Related Donor Renal Transplant Recipients

与生活相关的供体肾移植受者的延迟耐受诱导

• 批准号: 8252790
• 负责人: SUZANNE T ILDSTAD
• 金额: $ 29.97万
• 依托单位: REGENEREX, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-21 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252790
• 关键词: Achievement; Address; Allografting; Autoimmune Diseases; Biomedical Engineering; Bone Marrow; Bone Marrow Stem Cell; Bone Marrow Transplantation; CD8B1 gene; CSF3 gene; Cells; Chimerism; Clinic; Clinical; Data; Dependence; Diabetes Mellitus; Engraftment; Genetic; Goals; Graft Rejection; Graft Survival; Hematopoietic; Hematopoietic stem cells; Hemoglobinopathies; Human; Hypertension; Immunosuppression; Immunosuppressive Agents; Individual; Infusion procedures; Inherited; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Kidney Transplantation; Life; Living Donors; Maintenance; Malignant Neoplasms; Metabolic Diseases; Metachromatic Leukodystrophy; Morbidity - disease rate; Opportunistic Infections; Organ; Organ Donor; Organ Transplantation; Outpatients; Pharmaceutical Preparations; Phase; Postoperative Period; Process; Protocols documentation; Renal function; Risk; Safety; Sickle Cell Anemia; Solid; Staging; Stem cell transplant; Stem cells; Technology; Testing; Tissues; Toxic effect; Translating; Transplant Recipients; Transplantation; Transplantation Tolerance; Transplanted tissue; United States; Withdrawal; Work; base; clinical application; commercialization; conditioning; graft vs host disease; kidney allograft; nephrotoxicity; novel strategies; optimism; prevent; success

DESCRIPTION (provided by applicant): We have developed a protocol that reproducibly induces transplantation tolerance in individuals undergoing a living related donor kidney transplant. Three subjects have been off all immunosuppression for 10 months, 2 months, and 1 month respectively and have remained chimeric with stable renal function. Two additional chimeric subjects are in various stages of withdrawal from immunosuppression. The goal of this proposal is to expand this protocol to individuals who have already been transplanted and have a living donor that could subsequently provide a bone marrow stem cell product for their recipient (delayed tolerance). This work is important because solid organ, vascularized composite tissue, and islet transplantation currently require nonspecific immunosuppressive agents indefinitely for graft maintenance. These agents have significant toxicities, including nephrotoxicity, opportunistic infections, increased rate of malignancy, diabetes, and hypertension. It has been known for over 50 years that bone marrow chimerism induces tolerance to transplanted organs, cells, and tissues. However, the requirement for close HLA matching and toxicity of ablative bone marrow transplantation has limited the widespread application of this approach. The induction of donor-specific tolerance through durable chimerism in mismatched recipients while avoiding graft-versus-host disease (GVHD) would impact organ and tissue recipients as well as for individuals with hemoglobinopathies, inherited metabolic disorders, and autoimmune disorders. We have strong preliminary data in 8 living donor kidney hematopoietic stem cell transplant (HSCT) recipients, 1 metachromatic leukodystrophy recipient, and 1 sickle cell disease transplant recipient that we can safely establish durable chimerism in highly mismatched donor/recipient pairs. We have successfully established high levels of donor chimerism without GVHD in up to 1/6 HLA matched unrelated donor/recipient pairs. Seven of the eight renal transplant recipients were transplanted with cryopreserved G-CSF mobilized HSCT processed to remove GVHD-producing cells and retain tolerogenic CD8+/TCR- graft facilitating cells (the FCRx). Unfortunately, this successful "simultaneous" stem cell/kidney approach does not address individuals who have already received a transplanted organ and who have a living donor willing to donate bone marrow. This proposal modifies this approach to accommodate induction of "delayed tolerance" in a phase I/II protocol. The findings from this study will directly translate to deceased donor organ transplantation. This is of high priority because most organ donors are deceased. Therefore, this novel approach to expand the FCRx technology to delayed tolerance will represent a major milestone in potential commercialization. PUBLIC HEALTH RELEVANCE: Dependence upon anti-rejection drugs in clinical transplantation is expensive and results in significant morbidity and limitation in graft survival. Donor specific transplant tolerance would eliminate the need for drug- based immunosuppression, but has been an elusive goal in the clinic for over a half century. We have developed a potentially transformative approach to achieving transplant tolerance in solid organ transplant recipients based upon a rationally bioengineered stem cell product, termed FCRx. This proposal will determine the safety and efficacy of FCRx for delayed tolerance induction in kidney transplant recipients and will also be directly applicable also to deceased donor organ allograft recipients which comprise the majority of organ transplants.

描述（由申请人提供）：我们已经开发了一种方案，可在接受活体亲属供体肾移植的个体中可重复地诱导移植耐受。3名受试者已分别停用所有免疫抑制10个月、2个月和1个月，并保持嵌合，肾功能稳定。另外两名嵌合受试者正处于不同的免疫抑制退出阶段。该提案的目标是将该方案扩展到已经移植的个体，并且有一个活体供体，随后可以为其受体提供骨髓干细胞产品（延迟耐受）。这项工作很重要，因为实体器官、血管化复合组织和胰岛移植目前需要非特异性免疫抑制剂来维持移植物。这些药物具有显著的毒性，包括肾毒性、机会性感染、恶性肿瘤、糖尿病和高血压的发生率增加。50多年来，骨髓嵌合诱导对移植器官、细胞和组织的耐受性已经为人所知。然而，对HLA紧密匹配的要求和消融骨髓移植的毒性限制了该方法的广泛应用。在不匹配受体中通过持久嵌合诱导供体特异性耐受，同时避免移植物抗宿主病（GVHD），将影响器官和组织受体以及患有血红蛋白病、遗传性代谢紊乱和自身免疫性疾病的个体。我们在8例活体供体肾造血干细胞移植（HSCT）受者、1例异色性白质营养不良受者和1例镰状细胞病移植受者中有强有力的初步数据，我们可以安全地建立高度不匹配的供体/受体对的持久嵌合。我们已经成功地建立了高水平的无GVHD的供体嵌合，多达1/6的HLA匹配不相关的供体/受体对。8名肾移植受者中有7名移植了冷冻保存的G-CSF动员的HSCT，处理后去除产生gvhd的细胞，保留耐受性CD8+/TCR-移植物促进细胞（FCRx）。不幸的是，这种成功的“同时”干细胞/肾脏移植方法并不适用于那些已经接受了移植器官和有活体捐赠者愿意捐献骨髓的人。本提案对该方法进行了修改，以适应I/II阶段协议中“延迟容忍”的诱导。这项研究的结果将直接转化为死者供体器官移植。这是当务之急，因为大多数器官捐献者都已去世。因此，这种将FCRx技术扩展到延迟容限的新方法将是潜在商业化的一个重要里程碑。