Targeting innate immunity in Type 1 diabetes

Targeting innate immunity in Typediabetes AbstractTypediabetesT Dis an autoimmune disease characterized by specific destruction of pancreatic insulin producing beta cellsaccompanied by beta cell directed autoimmunity involving autoreactive T cells and islet autoantibodiesWhile blood glucose levels can be controlled with diet and medicationa cure for the disease remains elusiveand T D cannot be prevented or reversed in humansWhile T D is easy to prevent in the nonobese diabeticNODspontaneous mouse modelreversing T D in mice is more difficultMuch research has focused on autoreactive T cellswith the goal of developing antigen specific immunotherapyWhile some of these approaches have succeeded in the NOD mousedozens of human clinical trials have failedOver the pastyearsthe incidence of T D has increased dramaticallyThehygiene hypothesissuggests that decreased exposure of the innate immune system to environmental immune stimulantse gbacterial products such as Toll like receptorTLRstimulating lipopolysaccharideaffects the adaptive immune system and increases subsequent autoimmunityDuring our investigations into the role of innate immunity in T Dwe have identified TLRantibodies that do not directly stimulate T cells but induce tolerogenic antigen presenting cells that mediate decreased adaptive T cell responsesWe have found that treatment of acute onset T D in NOD mice with these anti TLRMDagonistic antibodies results in a remarkably high rate of disease reversal and demonstrates proof of concept for a novel therapeutic approach in T DDuring this Phase I projectwe will identify a human counterpart to the murine antibodyWe will confirm its activity in vitro in a humanized NSG mouse modelThese studies will provide the basis for translation of this discovery from the murine models to humans to create the first disease modifying treatment for T D NarrativeTypediabetesT Dis an autoimmune disease affecting the ability of pancreatic beta cells to produce insulinThe incidence of T D is increasingThere is no cure for the diseaseand effective treatment requires lifelong monitoring and control of blood glucose levelsWe have identified a monoclonal antibody that reverses T D in a mouse modelWith further developmentthis antibody has the potential to be the first treatment to cure T D