OPTIMIZING IMMUNOTHERAPY FOR ALLOGENEIC ISLET TRANSPLANTATION IN NHP

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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.