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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 在此报告期间，由于渴望更佳的免疫抑制方案，因此没有进行进一步的胰岛质量或解剖部位实验。我们先前已经研究了3A8的使用，3A8是一种靶向CD40的不耗尽的小鼠单克隆抗体。用同种异体胰岛移植并用3A8，巴西里昔单抗和西罗莫司治疗的动物的移植物存活率为155、312、208、120和45天，确定了阻止CD40途径的潜力。为了寻找一种更临床相关的免疫抑制方案，我们通过开发2C10（一种重组小鼠抗逆转CD40单克隆抗体）对3A8的成功进行了阐述。这种抗体的两种形式使用2C10R1和2C10R4，分别使用两种不同的恒河节免疫球蛋白（分别为IgG1和IgG4）开发。一只猴子使用这些同种异体以及大质子症和西洛司司的每一种猴子被移植，分别导致220和258天的移植物存活。此外，我们使用T细胞依赖性抗体反应对2C10进行了体内表征。我们已经表明，与对照组相比，这两种同种型都是最小耗尽和阻断抗体的产生。未来的计划包括使用这种重组抗CD40抗体来建立临床前数据以将其转化为诊所的持续同种异体胰岛移植。