OPTIMIZING IMMUNOTHERAPY FOR ALLOGENEIC ISLET TRANSPLANTATION IN NHP

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在本报告期间，由于对更理想的免疫抑制方案的渴望，没有进行进一步的胰岛肿块或解剖部位实验。我们之前已经研究了3A8的使用，3A8是一种针对CD40的非耗竭鼠单抗。移植同种异体胰岛并用3A8、巴利昔单抗和西罗莫司治疗的动物移植物存活时间分别为155、312、208、120和45天，证实了阻断CD40途径的可能性。为了寻找一种更具临床意义的免疫抑制方案，我们通过开发重组小鼠抗恒河猴-CD40单抗2C10来阐述3A8的成功。这种抗体的两种形式，2C10R1和2C10R4，是用两种不同的恒河猴免疫球蛋白(分别为IgG1和IgG4)开发的。一只猴子被移植了使用这些同种异体胰岛的每一种类型，以及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，我们还利用T细胞依赖的抗体反应对2C10进行了体内鉴定。我们已经证明，与对照组相比，这两种同种类型的抗体消耗和阻断抗体的产生都是最少的。未来的计划包括继续使用这种重组的抗CD40抗体进行同种异体胰岛移植，以建立转化为临床的临床前数据。

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.