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Description

Juvenile diabetes or insulin-dependent diabetes mellitus (IDDM) is considered as an autoimmune disease where islet infiltration of T cells, B cells, macrophages, and dendritic cells leads to their progressive destruction. It is reported that non-obese diabetic mice (NOD) express a single MHC class II molecule, IAg7, which is shown to be essential for the development of IDDM. It is shown that the major T cell insulin epitope resides with in amino acids 9-23 of the beta chain (B:9-23) and this peptide can bind to IAg7 in multiple positions (registers). Pathogenic CD4 T cells can recognize beta 9-23:I Ag7 complex when the insulin peptide is bound in register 3 (R3), which places amino acids 14-22 of the beta chain in the core P1 to P9 position and places arginine at P9 position, which is highly unfavored for the IAg7 pocket. The binding motifs of IAg7 are degenerate and contain small hydrophobic residues at P4 and P6 position. This monoclonal antibody (clone mAb287) selectively binds to B:9-23 when presented by IAg7 only in R3. It blocks the binding of IAg7-B:10-23 R3 tetramers to cognate T cells and impedes T cell responses to soluble B:9-23 peptides, but does not affect recognition of any other peptide bound to IAg7. This antibody is also shown to diminish T cell infiltration in NOD mice, delay the development of IDDM and overt hyperglycemia. (Ref.: Stratmann, T., et al. (2000). J Immunol. 165(6), 3214-3225, Zhang, L., et al. (2014). Proc. Natl. Acad. Sci. USA. 111 (7), 2656-2661).