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Objectives B and T lymphocyte attenuator (BTLA) and Herpesvirus entry mediator (HVEM) are a pair of receptors that together form an inhibitory immune checkpoint. While immune checkpoints have seen great success as targets in the treatment of various cancers, their therapeutic potential in autoimmune diseases remains to be investigated. Here, we present the effect of peptides targeting the BTLA-HVEM checkpoint on PBMCs from SLE patients.Methods PBMCs were isolated from blood samples of SLE patients. The cells were activated in vitro using an anti-CD3 antibody and cultured for 72h and 120h. Two peptides whose sequences are based on the BTLA’s region, BTLA 35-43 and BTLA 33-64, were evaluated. Activation markers of T cells (CD69, CD25, HLA-DR), dendritic cells (CD80, CD86), as well as changes in apoptosis were measured with flow cytometry. These results were compared to those from the healthy controls. Data was analyzed with FlowJo, and statistical analysis was performed with GraphPad Prism 10.Results An overall decrease in expression of several activation markers was observed across different immune cell populations treated with the BTLA 33-64 peptide. A decrease in one of the T cell activation markers – HLA-DR was observed at 72h and 120h post-activation in cells cultured with the BTLA 33-64 peptide. A decrease was present in the percentage of HLA-DR positive cells as well as the number of molecules present on the cell surface (measured with MFI). No changes in CD25 and CD69 levels were observed.Conclusions The peptides reduced the extent of the immune response, as measured by expression of activation markers. These results support the rationale of targeting immune checkpoints in autoimmune diseases.