Retro-inverso D-peptides as a novel targeted immunotherapy for Type 1 diabetes
Autor: | Mihaly Mezei, Yaron Tomer, Erlinda Concepcion, Roman Osman, Hanane Arib, Angela Lombardi, Hanxi Hou |
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Rok vydání: | 2020 |
Předmět: |
CD4-Positive T-Lymphocytes
Male 0301 basic medicine endocrine system Immunology Antigen presentation Mice Transgenic Peptide Lymphocyte proliferation Molecular Dynamics Simulation Lymphocyte Activation Article Cell Line Mice 03 medical and health sciences 0302 clinical medicine Antigen In vivo HLA-DQ Antigens Insulin-Secreting Cells Animals Humans Immunology and Allergy Receptor 030203 arthritis & rheumatology chemistry.chemical_classification Antigen Presentation B-Lymphocytes Chemistry nutritional and metabolic diseases Recombinant Proteins Diabetes Mellitus Type 1 030104 developmental biology Cancer research Female Beta cell Peptides Ex vivo |
Zdroj: | J Autoimmun |
ISSN: | 0896-8411 |
Popis: | Over the past four decades, the number of people with Type 1 Diabetes (T1D) has increased by 4% per year, making it an important public health challenge. Currently, no curative therapy exists for T1D and the only available treatment is insulin replacement. HLA-DQ8 has been shown to present antigenic islet peptides driving the activation of CD4+ T-cells in T1D patients. Specifically, the insulin peptide InsB:9-23 activates self-reactive CD4+ T-cells, causing pancreatic beta cell destruction. The aim of the current study was to identify retro-inverso-D-amino acid based peptides (RI-D-peptides) that can suppress T-cell activation by blocking the presentation of InsB:9-23 peptide within HLA-DQ8 pocket. We identified a RI-D-peptide (RI-EXT) that inhibited InsB:9-23 binding to recombinant HLA-DQ8 molecule, as well as its binding to DQ8 expressed on human B-cells. RI-EXT prevented T-cell activation in a cellular antigen presentation assay containing human DQ8 cells loaded with InsB:9-23 peptide and murine T-cells expressing a human T-cell receptor specific for the InsB:9-23–DQ8 complex. Moreover, RI-EXT blocked T-cell activation by InsB:9-23 in a humanized DQ8 mice both ex vivo and in vivo, as shown by decreased production of IL-2 and IFN-γ and reduced lymphocyte proliferation. Interestingly, RI-EXT also blocked lymphocyte activation and proliferation by InsB:9-23 in PBMCs isolated from recent onset DQ8-T1D patients. In summary, we discovered a RI-D-peptide that blocks InsB:9-23 binding to HLA-DQ8 and its presentation to T-cells in T1D. These findings set the stage for using our approach as a novel therapy for patients with T1D and potentially other autoimmune diseases. |
Databáze: | OpenAIRE |
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