STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Widespread application of beta-cell replacement therapy for type 1 diabetes will require a readily accessible source of insulin-producing cells. Xenotransplantation from porcine donors presents an attractive alternative. We have published that neonatal porcine islets transplanted into non-immunosuppressed primates underwent rapid rejection, while administration of a CD28/CD154 costimulation blockade-based regimen resulted in: 1) sustained insulin independence, 2) progressive improvement in glucose tolerance and sustained porcine c-peptide production over time after xenotransplant, and 3) lack of transmission of PERV after xenotransplantation (Cardona et al., Nature Medicine; March 2006). These results were reproduced with the substitution of an anti-CD40 monoclonal antibody for the anti-CD154 monoclonal antibody that was used in the regimen in the studies described above. Despite success with these two similar costimulation blockade-based regimens, the prospect for their clinical use is limited due to associated thromboembolic complications and their early developmental stage in comparison to other more novel agents already FDA approved for psoriasis, an autoimmune skin disorder. In this report year, using an anti-LFA-1 mAb and alefacept-based regimen led to neonatal porcine islet engraftment and survival (60 days) in one of two animals, resulting in promising preliminary data that if reproducible, establishes a potent, clinically relevant immunosuppressive regimen that could serve as a platform for moving neonatal porcine islet transplantation into clinical trials. Thus, representing a potential near-term solution to the critical supply problem in clinical islet transplantation for the millions afflicted with type 1 diabetes.