Surface camouflage of pancreatic islets using 6-arm-PEG-catechol in combined therapy with tacrolimus and anti-CD154 monoclonal antibody for xenotransplantation

Abstract

This study proposes a new combination method of using 6-arm-PEG-catechol to enhance the PEG effect on one hand and another combination of using low doses of Tacrolimus (FK506) and anti-CD154 mAb (MR1) with PEGylation for effective immunoprotection on the other in a xenogenic islet transplantation model. The surface coverage of PEG, viability and functionality of islets were evaluated in vitro, and the effect of surface camouflage on immunoprotection for transplanted islets was evaluated. In addition, the synergistic effects of surface camouflaged islets with low doses of immunosuppressant drugs, such as FK506 and MR1, were evaluated in the xenotransplantation model. The median survival time (MST) of 6-arm-PEG-catechol grafted islets (12.0 +/- 1.1 days) was not significantly increased, compared to that of unmodified islets (10.5 +/- 1.3 days). However, when 0.2 mg/kg of FK506 was daily administered, the MST of 6-arm-PEG-catechol grafted islet (21.0 +/- 1.9 days) was increased twice, compared to that of unmodified islets treated with 0.2 mg/kg of FK506 (10.0 +/- 0.9 days). Interestingly, when the recipients of 6-arm-PEG-catechol grafted islets were treated with 0.2 mg/kg of FK506 and 0.1 mg/mouse of MR1, normoglycemia was maintained up to 50 days of transplantation without any fluctuation of glucose level. Therefore, a newly developed protocol using 6-arm-PEG-catechol with FK506 and MR1 would certainly be an effective combination therapy for the treatment of type 1 diabetes.