Functional and histological evaluation of transplanted pancreatic islets immunoprotected by PEGylation and cyclosporine for 1 year.

Abstract

Pancreatic islet transplantation is one of the most promising strategies for patients suffering from type 1 diabetes mellitus, but several therapeutic immunosuppressive medications must be administered simultaneously to protect transplanted islets in the long-term, and these expose patients to the risk of serious complications. Thus, we developed chemically modified islets with a protective poly(ethylene glycol) (PEG) layer, which reduces immunogenicity by preventing cellular immune reactions. We report here that PEG-based chemical immunomodulation can provide a semi-permanent effective therapy that protects transplanted islets at least for 1 year when accompanied by cyclosporine. Moreover, this combinatorial approach appears to avoid the toxicities associated with immunosuppressive medications because of the reduced amounts of medication required. Also, the conjugated PEG molecules were found to be continuously present at the transplanted islets. However, unmodified islets (control) were completely eliminated within 2 weeks even when CsA was administered. These results strongly suggest that this new combinatorial therapy provides a semi-permanent, effective clinical means of attenuating transplanted islet immunogenicity for a long time, whilst avoiding the toxicities associated with therapeutic levels of immunosuppressants owing to the minimized immunosuppressant.