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Retro-inverso D-peptides as a novel targeted immunotherapy for Type 1 diabetes.

Citation
Lombardi, A., et al. “Retro-Inverso D-Peptides As A Novel Targeted Immunotherapy For Type 1 Diabetes.”. Journal Of Autoimmunity, p. 102543.
Center Albert Einstein College of Medicine
Author Angela Lombardi, Erlinda Concepcion, Hanxi Hou, Hanane Arib, Mihaly Mezei, Roman Osman, Yaron Tomer
Keywords HLA-DQ8, InsB:9-23, RI-D-peptides, type 1 diabetes
Abstract

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.

Year of Publication
2020
Journal
Journal of autoimmunity
Volume
115
Number of Pages
102543
Date Published
12/2020
ISSN Number
1095-9157
DOI
10.1016/j.jaut.2020.102543
Alternate Journal
J Autoimmun
PMID
32951964
PMCID
PMC7683378
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