At present,there is no cure for type 1A diabetes(T1D),a T cell-mediated autoim-mune disease.Monoclonal antibodies(mAbs)are used to treat a wide number of diseases.For treating T1D,mAbs that target major immune cell subsets show considerable promise,but so far,when used at doses that do not cause unac-ceptable adverse reactions,have only been able to delay,but not prevent,dis-ease progression.As a potentially safer alternative or adjunct,we have been in-vestigating the utility of mAbs targeting defined peptide-major histocompatibility complex(MHC)II complexes that are the ligands for disease-relevant CD4+T cells.Alleles within the MHC class II locus con-fer the greatest genetic risk for T1D,and activation of pathogenic CD4+T cells by antigen-presenting cells(APCs)express-ing these ligands is central to disease eti-ology.Consequently,selective disruption of these critical interactions should arrest autoimmunity without causing global im-munosuppression.Here,we review stud-ies using an mAb targeting a key pathogenic epitope from insulin to treat a spontaneous mouse model of T1D and discuss the translational potential of ther-apies based on this approach.