Type 1 diabetes (T1D) is one of the most common chronic diseases of childhood; in fact, its incidence has increased by 4% per year in the last 40 years; every year 30,000 new cases are diagnosed, 50% of whom are children. T1D is caused by an autoimmune destruction of beta cells, resulting in blunted insulin production. There is currently no curative therapy for T1D and the only available treatment is insulin replacement that - although being life-saving – remains problematic and can be associated with often fatal high or low glucose levels. Since T1D results from killing and/or silencing beta cells by various immune effectors mechanisms, several non-targeted immune therapies have been proposed in order to block the immune attack. However, these therapies have unacceptable toxicity, making novel therapies urgently needed. The overall goal of this project is to develop precision-targeted therapies for T1D by blocking presentation of pancreatic antigens to T-cells using an innovative approach. We hypothesized that the presentation of pathogenic pancreatic peptides to T-cells within the HLA-DQ8 pocket is a key trigger in T1D, and that blocking peptide binding to this pocket can be used to treat/prevent the autoimmune response targeting beta cells in T1D. Rationale: In order to block the antigen presentation in T1D we are targeting HLA-DQ8, which has been shown to be crucial in presenting pancreatic peptides, triggering T1D. Additionally, we focus on blocking the interaction between HLA-DQ8 and the insulin B-chain peptide InsB:9-23, since this diabetogenic peptide binds selectively to HLA-DQ8 and is a major T-cell epitope. We propose to block antigen presentation to treat/prevent autoimmunity in T1D using retro-inverso D-amino acid peptides (D-peptides). Their unique properties such as a longer half-life and a lower antigenicity in vivo compared to L-peptides or therapeutic antibodies offer significant advantages over other therapeutic strategies. To test our hypothesis we will use the following tools: human B cells homozygous for HLA-DQ8, transgenic mice expressing human HLA-DQ8, and peripheral blood mononuclear cells (PBMCs) from new onset HLA-DQ8 T1D patients. All of them represent exquisite instruments to evaluate in vitro, ex vivo, and in vivo the functional role of our D-peptides in preventing beta cell destruction.
|Effective start/end date||3/1/20 → 2/28/21|