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）：我们已经开发了一项方案，该方案可重复诱导接受生活相关的供体肾脏移植的个体的移植耐受性。所有免疫抑制的三名受试者分别为10个月，2个月和1个月，并保持嵌合具有稳定的肾功能。另外两个嵌合受试者处于从免疫抑制退出的各个阶段。该提案的目的是将该方案扩展到已经被移植并拥有活捐赠者的个体，随后可以为其接受者提供骨髓干细胞产品（延迟公差）。 这项工作很重要，因为目前，固体器官，血管化复合组织和胰岛移植需要非特异性免疫抑制剂，以无限期地维持移植物。这些药物具有显着的毒性，包括肾毒性，机会性感染，恶性肿瘤，糖尿病和高血压率提高。已有50多年的历史，骨髓嵌合体诱导对移植器官，细胞和组织的耐受性。然而，对烧蚀性骨髓移植的紧密HLA匹配和毒性的要求限制了这种方法的广泛应用。通过不匹配的接受者中持久的嵌合诱导供体特异性的耐受性，同时避免移植物抗宿主病（GVHD）会影响器官和组织受体以及血红蛋白疾病，遗传性代谢疾病和自身免疫性疾病的人。我们在8个活着的肾脏造血干细胞移植（HSCT）接受者，1个过正常白细胞营养不良的受体和1个镰状细胞疾病移植受者中拥有强大的初步数据，我们可以安全地在高度不匹配的捐赠者/成对的捐赠者中建立耐用的杂物。在高达1/6 HLA匹配的无关供体/接受者对中，我们已经成功地建立了高水平的供体嵌合主义，而没有GVHD。在八个肾移植受者中，有七个用冷冻保存的G-CSF动员的HSCT移植，以去除产生GVHD的细胞，并保留耐受性CD8+/TCR-GRAFT促进细胞（FCRX）。 不幸的是，这种成功的“同时”干细胞/肾脏方法并不是针对已经收到移植器官并且有一个愿意捐赠骨髓的捐赠者的人。该提案修改了这种方法，以适应I/II期协议中“延迟公差”的诱导。这项研究的发现将直接转化为已故的供体器官移植。这是优先考虑的，因为大多数器官捐赠者已死亡。因此，这种将FCRX技术扩展到延迟公差的新颖方法将代表潜在商业化的主要里程碑。 公共卫生相关性：依赖临床移植中抗拒绝药物的依赖是昂贵的，并且导致移植物存活的显着发病率和局限性。 特定于供体的移植耐受将消除对毒品的免疫抑制的需求，但半个多世纪以来一直是诊所中难以捉摸的目标。我们已经开发了一种潜在的变革方法，以基于理性生物工程的干细胞产物（称为FCRX）在固体器官移植受体中实现移植耐受性。该建议将确定FCRX对肾脏移植受者延迟耐受诱导的安全性和功效，并且还将直接适用于已故的供体器官同种异体移植物受体，这些受体包括大多数器官移植。