Research On The Treatment Of Type 1 Diabetes

Type 1 diabetes mellitus(T1DM)is one type of autoimmune diseases that threatens global health.With research focusing on the pathogenesis of diabetes,many new approaches have been developed for the treatment of T1DM.Islet transplantation,a minimal invasive procedure,is currently the most promising treatment that could restore euglycaemia in patients with T1DM.However,graft survival rate remains low in the early post-transplantational period due to the destruction caused by autoimmune rejection.Encapsulation of pancreatic islet with biomaterials provides a physical barrier for the implanted islets,which can potentially improve the islet transplantation rates and expand the applicability of donors from heterogeneous sources.In addition,since risks of developing T1DM can be predicted by detecting islet autoantibodies before diagnosis,antigen-specific immunotherapy could potentially induce immune tolerance with the advantage of affecting only relevant antigens.As a result,considering the lack of research regarding anti-diabetic vaccine development,it is important to explore the types of antigens used for vaccine development and the routes of vaccine administration.The present project has been divided into the following two parts:In the first part,a strategy for islet surface engineering was proposed using a chelate chondroitin CS-incorporated starPEG nanocoating(CS-PEG).The CS-PEG nanocoating was conjugated to the amine bonds of living islet surface via pseudo-orthogonal chemistry.Our results show that CS-PEG surface engineering leads to enhanced in situ revascularization and protective effect against extracellular matrix destruction.CS-PEG surface-modified islets also exhibited robust cell viability and normal insulin secretory ability to glucose.CS-PEG surface modification can also significantly reduce instant blood mediated inflammatory reaction(IBMIR)by reducing blood coagulation and inflammation-related islet cell death,thus avoiding post-transplantation failure.In the second part,we used a T1DM mouse model(NOD mice)to study the effect of a supramolecular polypeptide vaccine based on key insulin peptide GDFDFDY against diabetes progression.Our results showed that the polypeptide could delay the earliest onset of T1DM in NOD mice from 11 weeks to 17 weeks.Percentage of diabetic mice was also significantly reduced from 70%to 30%.Attempts were made to explore the effects of antigen-specific immunization by oral route of administration,and the incidence of diabetes from the treated groups was significantly lower than that of the non-treated control group.The initial exploration of the therapeutic mechanism suggests that the anti-diabetic impact of GDFDFDY peptide could be associated with an increased ratio of GDFDFDY-induced Treg cell population,which is important for induction of immune tolerance.Our preliminary experimental results show that the GDFDFDY peptide has great potential as a preventive vaccine for autoimmune diabetes.