Research Project
10189649
SUMMARY Type 1 diabetes (T1D) is characterized by an inability to achieve normoglycemia due to autoimmune events mistakenly targeting destruction of insulin-producing beta-cells of the pancreas. The major challenge of T1D is the two-fold onslaught whereby (1) chronic autoimmunity destroys beta-cells and (2) recovery is irreversibly lost due to the repeated chronic autoreactive attacks. Although current treatments do temperately reduce hyperglycemia, they can inadvertently lead to significant health complications (i.e. global immunosuppressive drugs impair natural host immunity and deregulate physiological functions and allogenic transplants are met with acute/chronic rejection). The long-term goals of the laboratory are to directly address these challenges of effectively alleviating T1D by developing antigen-specific tolerance to restrain autoimmune-mediated events coupled with insulin restorative strategies to alleviate hyperglycemia. The investigations have two principal aims to tackle this challenge: (1) engineering MHC class II-modified tolerogenic dendritic cell immunotherapies to specifically restrain autoreactive attacks in the beta-cell compartment without impairing natural host immunity (to pathogens or transformed cells), and (2) development of donor-derived MHC class I-matched beta-cells seeded in novel biomaterials to restore insulin production and normalize blood glucose levels. For the first aim, studies will reprogram DC towards tolerogenic states by knocking out key genes responsible for governing immunity. The approach is combined with silencing of endogenous MHC class II and replacing that with a transgene encoding a modified MHC class II that exclusively presents beta-cell autoantigen peptides with high affinity. Results will lead to tolerogenic DC solely presenting MHC class II-restricted beta-cell autoantigens upon adoptive transfer in vivo, leading to restrained autoreactive T cell responses without impairing normal host adaptive immunity. Even with success in stopping repeated autoreactive T cell attacks, tissue damage is often irreversible in mid- and late-stages of T1D. To address this challenge, the second aim will develop a restorative approach using donor-derived MHC class I-matched beta-cells seeded on novel biomaterials to restore insulin production in vivo. Donor-derived beta-cells will be genetically reprogrammed to express MHC class I matched to the recipient's haplotype; the approach will highlight the value in use of donor tissues for restorative applications. These insulin-producing donor-derived MHC class I-matched beta-cells will then be seeded in a novel patented biomaterial prior to implantation in the non-obese diabetic mouse model. Success of the approach will restrain diabetes progression by restoring normoglycemia through glucose- dependent insulin production. Findings generated from these studies will support development of innovative and novel translational and clinical-relevant therapeutic applications for combating T1D.
