Insulin Peptide-based Supramolecular Hydrogel Peptide Nap-G~DF~DF~DY For Prevention Of Type 1 Diabetes

In recent years,the incidence of type 1 diabetes(T1D)has increased,substantially especially among children and young adults.Morbidity of T1D also shows a concerning tendency of getting younger.At present,insulin replacement therapy is still the most commonly used clinical method for treating T1D.However,insulin have no effect on preventing the further deterioration of T1D.Extensive studies have reported that antigenspecific immune tolerance induction could be a feasible and effective way to prevent or delay the progression of T1D.Nonetheless,inoculation with single T1D autoantigen had been associated with poor clinical outcome.Supramolecular hydrogel based on peptide can self-assemble into various micro-or nano-structures,and have shown promising potential in vaccine development,controlled drug delivery and immune regulation.Previous reports have elucidated that these peptide nanoclusters have the ability to function both as antigen depot and immune adjuvant.Recent research on cancer immunotherapy development have revealed the therapeutic potential of Nap-GDFDFDY,a naphthylacetic acid modified D-isomer tetrapeptide of glutamate-phenylalanine-phenylalanine-tyrosine(GFFY)hydrogel,as a kind of excellent vaccine adjuvant.Inadvertently,we have found that Nap-GDFDFDY contain conserved peptide sequence,GFFY,of 3 major autoantigens for autoimmune T1D,i.e.insulin,proinsulin,and glutamic acid decarboxylase(GAD).Considering that insulin peptide GFFY-based supramolecular hydrogel may potentially simulate the structure and function of multiple major autoantigens of T1D,this study investigated the possibility of supramolecular hydrogel peptide as a promising treatment of T1D for antigen-specific immune tolerance induction.Subsequently,by using NapGDFDFDY as immune therapy against T1D,our data showed that subcutaneous injection of Nap-GDFDFDY achieved complete protection of nonobese diabetic(NOD)mice from T1D development till the age of 36 weeks.Pancreatic islet morphology was better maintained with minimal immune cell infiltration and significantly alleviated dedifferentiation of islet ? cells in NOD mice treated with Nap-GDFDFDY.Preliminary evidence indicated that the protective role of Nap-GDFDFDY is likely attributable to its positive impact on increased peripheral T regulatory cells(Tregs)population and maintained the function of Tregs including the secretion of TGF-?1,etc.Serum cytokine microarray result further implicated a "buffering" role of Nap-GDFDFDY in systemic inflammatory tone in NOD mice.Our studies on NOD mice that were already hyperglycemia futher demonstrated that Nap-GDFDFDY can effectively delay the increase in blood sugar caused by T1D.These findings indicated positive effects of Nap-GDFDFDY in T1D prevention.We propose that Nap-GDFDFDY could be a novel immune therapeutic intervention strategy for T1D.