attenuating the HMGB1 activity by islet surface modification with glycyrrhizin linked chitosan

Abstract

A type 1 diabetes mellitus (T1D), an auto immune disease that results from the destruction of the beta cell in the pancreas, requires an insulin therapy to control normal blood glucose level and attenuate serious complications. Pancreatic islet transplantation has been emerged as the most potential therapy for the treatment of T1D. However, islet transplantation has been limited by poor islet graft survival and function due to immune response after islet implantation. Recently, a high-mobility group box 1 (HMGB1) protein has been demonstrated to play crucial roles in host’s immune response after islet transplantation. After islet transplantation, damaged islets secreted HMGB1 proteins to extracellular space and then secreted HMGB1 proteins induced inflammatory responses by transduction of cellular signals through its receptor, such as TLR2, TLR4, and receptor for advanced glycation end product (RAGE). Importantly, HMGB1 proteins are abundant in pancreas compared with other organs. Therefore, attenuation of HMGB1 activity can strongly contribute to successful islet transplantation. A Glycyrrhizin, a glycoconjugated triterpene produced by the licorice plant, has HMGB1 inhibition effect by directly binding to HMG boxes. Thus, we modified the islet surface with glycyrrhizin to modulate the release of HMGB1 protein. Glycol chitosan was conjugated with glycyrrhizin to introduce more abundant glycyrrhizin onto the islet surface. Glycyrrhizin-glycol chitosan conjugates were coated onto the surface of islets via polyethylene glycol (PEG) molecule as a linker. Surface modification of islet successfully captured HMGB1 and attenuated the HMGB1 protein activity, thereby enhancing the islet graft survival. Collectively, this novel surface modification technique would be effective therapy for successful outcome of islet transplantation.