Rhesus Monkey Dendritic Cells for Transplant Tolerance

恒河猴树突状细胞用于移植耐受

• 批准号: 7914917
• 负责人: Angus W Thomson
• 金额: $ 6.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914917
• 关键词: Adoptive Transfer; Allogenic; Allografting; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Autologous Dendritic Cells; Biological Response Modifiers; Blood; Bone Marrow; CD14 gene; Cell Lineage; Cell Maturation; Cell Transplants; Cells; Chimeric Proteins; Clinical; Clinical Oncology; Clinical Trials; Data; Dendritic Cell Therapy; Dendritic Cell Vaccine; Dendritic Cells; Flu matrix protein; Generations; Graft Survival; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Guanine Nucleotide Dissociation Inhibitors; Hematopoietic; Hematopoietic Cell Growth Factors; Human; Human Volunteers; Immune; Immune response; Immunologic Monitoring; Immunosuppressive Agents; In Vitro; Infectious Diseases Research; Inflammatory; Infusion procedures; Interleukin-10; Keyhole Limpet Hemocyanin; Kidney; Kidney Transplantation; Ligands; Liver; Living Donors; Longitudinal Studies; Lung Transplantation; Lymph; Lymphoid Tissue; Macaca mulatta; Maintenance; Modeling; Monitor; Monoclonal Antibodies; Mus; Myelogenous; Nature; Organ; Organ Transplantation; Outcome; Pathway interactions; Peripheral; Pharmaceutical Preparations; Physiologic pulse; Population; Primates; Procedures; Protocols documentation; Publishing; Regulation; Reporting; Research Personnel; Resistance; Rodent; Rodent Model; Role; Secondary to; Sirolimus; Site; Stimulus; Surface; T-Lymphocyte; Therapeutic; Therapeutic Agents; Tissues; Transfusion; Transplantation; Transplantation Immunology; Universities; Vaccine Therapy; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-1; Vitamins; comparative efficacy; conditioning; experience; in vivo; innovation; kidney allograft; monocyte; nonhuman primate; novel; progenitor; prospective; receptor; response

DESCRIPTION (provided by applicant): We hypothesize that stably-immature dendritic cells (DC) can be employed in tolerance-enhancing strategies to promote donor-specific tolerance to renal allografts in the rhesus macaque. In our own and others' recent small animal studies, indefinite organ graft survival enabled by 'DC therapy', is associated with the absence of transplant vasculopathy and the generation of T regulatory cells (Treg) that infiltrate the graft and confer resistance to rejection in naive recipients. In human volunteers, as few as 2.106 immature, autologous DC promote T cell tolerance to model Ags. We have generated 'negative DC vaccines' that resemble tolerogenic DC in humans and rodents by propagating rhesus monocyte-derived DC in vitamin DC and IL-10. Allogeneic recipients infused systemically with these DC in combination with T cell costimulation blockade, develop T cell hyporesponsiveness to donor, with the emergence of CD4+ IL-10+T cells (putative regulatory T cells). Our rodent studies show that combination of similar, stably-immature DC with costimulation blockade or a sub-therapeutic course of rapamycin results in indefinite graft survival. We have 3 specific aims: AIM I: TO COMPARE THE ABILITY OF MATURATION-RESISTANT, DONOR VERSUS RECIPIENT RHESUS DC TO REGULATE ALLOIMMUNE RESPONSES. We will seek to elucidate both in vitro and in vivo how stably-immature DC regulate alloreactive T cells responses, in particular the role of Treg, and ascertain the comparative efficacy of donor-versus-recipient DC.AIM II:TO ASCERTAIN THE EFFICACY OF TOLEROGENIC DC IN RHESUS RENAL TRANSPLANTATION AND THEIR IMPACT ON MECHANISMS UNDERLYING IMMUNE REGULATION. Donor and recipient-derived DC will be compared for their ability to prolong renal allograft survival and regulate anti-donor responses in graft recipients. AIM III: TO DETERMINE THE EXTENT TO WHICH CD40-CD154 PATHWAY BLOCKADE AND RAPAMYCIN AUGMENT THE POTENTIAL OF IMMATURE DC TO PROMOTE LONG-TERM, REJECTION-FREE, RENAL ALLOGRAFT SURVIVAL. We will establish the capacity of anti-GDI 54 mAb and the "tolerance-sparing" drug rapamycin to enhance DC tolerogenicity and their potential to promote donor-specific tolerance in the renal transplant model. Excellent facilities and extensive expertise in NHP organ transplantation, post-transplant monitoring (including immunologic monitoring) and experience with relevant therapeutic agents in primates are available to enable and sustain these studies. In clinical transplantation, pre-emptive conditioning of the prospective graft recipient by infusion of in vitro-expanded "tolerogenic" DC (either donor-derived DC or donor allo-Ag-pulsed, recipient DC) is clearly feasible in relation to live donor renal, liver or lung transplantation and may result in donor-specific tolerance.

描述（由申请人提供）：我们假设稳定未成熟的树突状细胞（DC）可用于增强耐受性的策略，以促进恒河猴对同种异体肾移植物的供体特异性耐受性。在我们自己和其他人最近的小动物研究中，“DC 疗法”实现的无限期器官移植存活与移植血管病变的缺失以及浸润移植物并赋予移植物抗排斥性的 T 调节细胞 (Treg) 的产生有关。天真的接收者。在人类志愿者中，少至 2.106 个未成熟的自体 DC 促进 T 细胞对模型 Ag 的耐受。我们通过在维生素 DC 和 IL-10 中繁殖恒河猴单核细胞衍生的 DC，生产出类似于人类和啮齿动物的耐受性 DC 的“阴性 DC 疫苗”。同种异体受体全身注射这些 DC 并结合 T 细胞共刺激阻断，会出现 T 细胞对供体的低反应性，并出现 CD4+ IL-10+T 细胞（假定的调节性 T 细胞）。我们的啮齿动物研究表明，类似的、稳定未成熟的 DC 与共刺激阻断或雷帕霉素亚治疗疗程的组合会导致无限期的移植物存活。我们有 3 个具体目标： 目标 I：比较抗成熟供体和受体恒河猴 DC 调节同种免疫反应的能力。我们将寻求在体外和体内阐明稳定未成熟 DC 如何调节同种异体反应性 T 细胞反应，特别是 Treg 的作用，并确定供体与受体 DC 的比较功效。恒河猴肾移植中的耐受性 DC 及其对免疫调节机制的影响。将比较供体和受体来源的 DC 延长肾同种异体移植物存活和调节移植物受体抗供体反应的能力。目标 III：确定 CD40-CD154 通路阻断和雷帕霉素增强未成熟 DC 促进长期、无排斥、肾同种异体移植物存活的潜力的程度。我们将建立抗 GDI 54 mAb 和“耐受耐受”药物雷帕霉素增强 DC 耐受原性的能力及其在肾移植模型中促进供体特异性耐受的潜力。在 NHP 器官移植、移植后监测（包括免疫学监测）方面拥有优良的设施和广泛的专业知识，以及灵长类动物相关治疗药物的经验，可以支持和维持这些研究。在临床移植中，通过输注体外扩增的“耐受性”DC（供体来源的 DC 或供体同种异体抗原脉冲的受体 DC）对预期移植受者进行预先调节对于活体供体肾来说显然是可行的、肝或肺移植，并可能导致供体特异性耐受。