Induction of Donor Tolerance in Renal Transplants

肾移植中诱导供体耐受

• 批准号: 8333414
• 负责人: SUZANNE T ILDSTAD
• 金额: $ 173.34万
• 依托单位: REGENEREX, LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-03 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8333414
• 关键词: Address; Aplastic Anemia; Autoimmunity; Biological Assay; Biomedical Engineering; Biopsy; Blood; Bone Marrow; Bone Marrow Cells; Businesses; CD8B1 gene; Cell Transplants; Cells; Childhood; Chimerism; Chronic; Chronic Granulomatous Disease; Collection; Creatinine; Cyclophosphamide; Data; Diabetes Mellitus; Disease; Dose; Engineering; Engraftment; Enrollment; FDA approved; Face; Generations; Goals; Grant; Hand; Health; Heart; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemoglobinopathies; Immune; Immune Tolerance; Immune system; Immunologic Monitoring; Immunosuppression; Immunosuppressive Agents; Inherited; Islets of Langerhans; Kidney; Kidney Failure; Kidney Transplantation; Laboratories; Lead; Legal patent; Life; Liver; Living Donors; Lupus; Macular degeneration; Malignant Neoplasms; Metabolic Diseases; Modeling; Morbidity - disease rate; Mucopolysaccharidosis II; Multiple Sclerosis; Myocardial Infarction; Natural regeneration; Opportunistic Infections; Organ; Organ Transplantation; Organ failure; Patients; Pharmaceutical Preparations; Phase; Population; Preparation; Procedures; Process; Prograf; Property; Protocols documentation; Psoriasis; Regimen; Regulatory T-Lymphocyte; Renal function; Reproducibility; Rheumatoid Arthritis; Safety; Serum; Shipping; Ships; Sickle Cell Anemia; Solid; Stem cell transplant; Stem cells; T-Lymphocyte; Technology; Testing; Thalassemia; Therapeutic; Therapeutic immunosuppression; Tissues; Toxic effect; Transplant Recipients; Transplantation; Universities; Weaning; base; commercialization; conditioning; cost; experience; fludarabine; follow-up; graft vs host disease; in vitro Assay; in vivo; islet; kidney allograft; large bowel Crohn' s disease; leukemia; leukodystrophy; meetings; mortality; mouse model; nephrotoxicity; novel; prevent; quality assurance; regenerative; repaired; stem

DESCRIPTION: Renal transplantation is the preferred therapeutic approach for end organ failure. However, the chronic use of immunosuppressive agents is critical to prevent rejection. The drugs are costly ($15,000-25,000/year) and have significant toxicities including opportunistic infection, an increased rate of malignancy, nephrotoxicity, and other end organ damage. The induction of donor-specific tolerance would address these limitations. Bone marrow chimerism induces tolerance to transplanted organs. However, the toxicity and complications associated with conventional hematopoietic stem cell transplants (HSCT), primarily graft-versus-host disease (GVHD) and the need for a matched donor, has limited the therapeutic application of HSCT to tolerance induction. We have identified and patented a novel tolerogenic bone marrow cell population of CD8+/TCR- facilitating cells (FC) that enhances engraftment of stem cells in mismatched recipients without causing GVHD. The discovery of FC opens the door to employing HSCT as a viable cell-based approach for tolerance induction. The product, FCRx, addresses the major challenges preventing the widespread use of HSCT for tolerance induction. FCRx is a bioengineered bone marrow product that includes hematopoietic stem cells (HSC) and FC, but avoids GVHD in mismatched recipients. In phase I of this proposal, we achieved our proposed milestones, demonstrating that we could reliably produce and transport FCRx and safely infuse it into nonmyeloablatively conditioned renal transplant recipients. We demonstrated that the proprietary FCRx procedure can routinely produce a graft with defined 12-TCR+ T cell composition and enriched for HSC and engraftment-enhancing FC. The ultimate goal is the induction of immune tolerance and the elimination of or reduction in the need for expensive and harmful immunosuppressive drugs. We have developed a nonmyeloablative conditioning regimen with 200 cGy TBI/fludarabine/cyclophosphamide/MMF/prograf to avoid the toxicity of conditioning. Since completing Phase I, we have addressed a major concern expressed by the reviewers regarding our ability to enroll subjects and have now successfully transplanted 6 living donor kidney patients, all of whom demonstrated donor chimerism at one month post-transplant. The approaches for collection, shipping, and FCRx preparation have also been approved by the FDA. Three patients show laboratory evidence of donor-specific tolerance, and immunosuppression is being weaned. The remaining subjects are early in follow-up. The reproducibility and quality assurance of the FCRx process will lead to its successful commercial launch. In phase II we will increase the pace of transplants and demonstrate that FCRx consistently achieves engraftment of HLA mismatched HSC in nonmyeloablatively conditioned kidney transplant recipients, induces donor-specific tolerance without causing significant GVHD, and reduces or eliminates the need for long-term immunosuppression. A recent meeting with FDA classified our product as Phase II, another milestone that will enhance commercialization.

描述：肾移植是终末器官衰竭的首选治疗方法。然而，长期使用免疫抑制剂对预防排斥反应至关重要。这些药物价格昂贵（15，000 - 25，000美元/年），并且具有显著的毒性，包括机会性感染、恶性肿瘤发生率增加、肾毒性和其他终末器官损伤。诱导供体特异性耐受将解决这些局限性。骨髓嵌合体诱导移植器官耐受。然而，与常规造血干细胞移植（HSCT）相关的毒性和并发症，主要是移植物抗宿主病（GVHD）和对匹配供体的需要，限制了HSCT在耐受诱导方面的治疗应用。我们已经鉴定了一种新型的致耐受性骨髓细胞群CD 8 +/TCR-促进细胞（FC），并获得专利，该细胞群可增强干细胞在不匹配受体中的植入，而不会引起GVHD。FC的发现为采用HSCT作为基于活细胞的耐受诱导方法打开了大门。该产品FCRx解决了阻止广泛使用HSCT诱导耐受的主要挑战。FCRx是一种生物工程骨髓产品，包括造血干细胞（HSC）和FC，但在不匹配的受体中避免GVHD。在该提案的第一阶段，我们实现了我们提出的里程碑，证明我们可以可靠地生产和运输FCRx，并将其安全地输注到非清髓性条件性肾移植受者中。我们证明了专有的FCRx程序可以常规地产生具有确定的12-TCR+ T细胞组成的移植物，并且富含HSC和增强植入的FC。最终目标是诱导免疫耐受，消除或减少对昂贵和有害的免疫抑制药物的需求。我们开发了一种非清髓性预处理方案，采用200 cGy TBI/氟达拉滨/环磷酰胺/MMF/BMF，以避免预处理的毒性。自完成I期研究以来，我们已经解决了评审员对我们招募受试者能力的主要担忧，目前已成功移植了6例活体供肾患者，所有患者均在移植后1个月表现出供体嵌合体。用于收集、运输和FCRx制备的方法也已获得FDA批准。3例患者显示供者特异性耐受的实验室证据，免疫抑制正在解除。其余受试者处于早期随访中。FCRx工艺的重现性和质量保证将使其成功商业化。在第二阶段，我们将加快移植的速度，并证明FCRx在非清髓性条件肾移植受者中始终实现HLA不匹配的HSC的植入，诱导供体特异性耐受而不引起显著的GVHD，并减少或消除对长期免疫抑制的需要。最近与FDA的一次会议将我们的产品归类为II期，这是另一个将促进商业化的里程碑。