NJH ID: #09-17
Type 1 diabetes (T1D) is an increasingly common, incurable autoimmune disease. It is estimated that about 80,000 children develop the disease each year. The risk of developing T1D is genetically closely-linked in mice, rats and humans to structurally similar MHCII alleles with similar peptide-binding properties. In the non obese diabetic (NOD) mouse model of T1D, the crucial MHCII allele is called, IAg7. Although during the course of T1D in NOD mice CD4 T cells appear in the pancreas specific for IAg7, it is the T cell response to a particular insulin derived peptide (B:9-23) presented by IAg7 that is required for development of the disease. Recent studies by investigators at National Jewish Health (NJH) have unequivocally identified the correct register (register 3) of B:9-23 binding to IAg7 for the vast majority of pathogenic T cells. This binding register had been overlooked in previous studies, because of very weak B:9-23 binding compared to other registers.
Dr. John Kappler’s group at NJH have re-engineered the B:9-23 peptide to bind very strongly to IAg7 in register 3. Using recombinant IAg7/B:9-23 register 3 complexes, they have generated two inhibitorymonoclonal antibodies, 287 and 4D12, directed at the B:9-23 peptide in register 3 to block diabetogenic T cells interaction. These i antibodies will block the interaction between MHC and the pathogenic T cells involved in the initiation/progression of T1D.
These engineered two IAg7/B:9-23 complexes are unique tools for both diagnosis and preventive treatment of T1D.
State of Development
Tetramer-positive T-cell clones isolated from T1D patients that responded to stimulation by B:11-23 peptide and denatured insulin protein were conclusively shown to recognize B:11-23 bound to HLA-DQ8 in the low-affinity register 3. Recently our structural studies showed the B:11-23 is bound to HLA-DQ8 in the fashion as B:11-23 bound to MHC in NOD mice.
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- Crawford F, et al. Proc Natl Acad Sci U S A. 108:16729-34, 2011. PMC3189014. PMID: 21949373
Stadinski BD, et al. Proc. Natl. Acad. Sci. USA 107: 10978-10983, 2010. PMC 2890771. PMID: 20534455
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- US #8,673,300. Other US and international pending.
John Kappler, PhD, Brian Stadinski, PhD, Li Zhang, PhD, and George Eisenbarth, MD
This technology is available for licensing
For Further Information, Contact:
Emmanuel Hilaire, PhD
Technology Transfer Office
National Jewish Health
1400 Jackson St., Room M206b
Denver, CO 80206