OPTIMIZING IMMUNOTHERAPY FOR ALLOGENEIC ISLET TRANSPLANTATION IN NHP

优化 NHP 异体胰岛移植的免疫治疗

• 批准号: 8357444
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 4.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357444
• 关键词: Allogenic; Anatomic Sites; Animals; Antibodies; Antibody Formation; Blocking Antibodies; Clinic; Data; Funding; Future; Graft Survival; Grant; IgG1; IgG4; Immunoglobulins; Immunosuppressive Agents; Immunotherapy; Islets of Langerhans Transplantation; Macaca mulatta; Monkeys; Monoclonal Antibodies; Mus; National Center for Research Resources; Pathway interactions; Primates; Principal Investigator; Reaction; Recombinants; Regimen; Reporting; Research; Research Infrastructure; Resources; Sirolimus; Source; T-Lymphocyte; TNFRSF5 gene; Translations; Transplantation; United States National Institutes of Health; basiliximab; clinically relevant; cost; in vivo; islet; pre-clinical; research study; success

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In this report period no further islet mass or anatomic site experiments have been done due to the desire for a more optimal immunosuppressive regimen. We have previously investigated the use of 3A8, a non-depleting mouse monoclonal antibody targeting CD40. Animals that were transplanted with allogeneic islets and treated with 3A8, basiliximab and sirolimus had graft survivals of 155, 312, 208, 120 and 45 days, establishing the potential of blocking the CD40 pathway. In search of a more clinically relevant immunosuppressive regimen, we have elaborated on the success of 3A8 by developing 2C10, a recombinant mouse anti-rhesus-CD40 monoclonal antibody. Two forms of this antibody, 2C10R1 and 2C10R4, were developed using two different rhesus immunoglobulins (IgG1 and IgG4, respectively). One monkey has been transplanted with allogeneic islets using each of these isotypes along with basiliximab and sirolimus resulting in graft survival of 220 and 258 days, respectively. In addition we have performed an in vivo characterization of 2C10 using a T cell dependent antibody reaction. We have shown that both isotypes are minimally depleting and block antibody production when compared to controls. Future plans include continued allogeneic islet transplants using this recombinant anti-CD40 antibody to establish preclinical data for translation into the clinic.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在本报告期间，由于需要更佳的免疫抑制方案，未进行进一步的胰岛质量或解剖部位实验。我们之前已经研究了3A 8的使用，3A 8是一种靶向CD 40的非消耗性小鼠单克隆抗体。用同种异体胰岛移植并用3A 8、巴利昔单抗和西罗莫司处理的动物具有155、312、208、120和45天的移植物存活，建立了阻断CD 40途径的潜力。为了寻找更临床相关的免疫抑制方案，我们通过开发2C 10（一种重组小鼠抗恒河猴CD 40单克隆抗体）详细阐述了3A 8的成功。使用两种不同的恒河猴免疫球蛋白（分别为IgG 1和IgG 4）开发了两种形式的该抗体2C 10 R1和2C 10 R4。一只猴子已经移植了同种异体胰岛，使用这些同种型中的每一种沿着巴利昔单抗和西罗莫司，导致移植物存活分别为220天和258天。此外，我们已经使用T细胞依赖性抗体反应进行了2C 10的体内表征。我们已经表明，当与对照相比时，两种同种型都最低限度地消耗和阻断抗体产生。未来的计划包括使用这种重组抗CD 40抗体继续进行同种异体胰岛移植，以建立临床前数据用于临床。