P0211 Characterization of drug-specific CD4+ T cells in patients with inflammatory bowel diseases

Abstract

Listen

Translate article

Abstract Background Biologicals are commonly used to treat chronic inflammatory diseases. Treatment failure is a major limitation for the efficacy of biologicals, which can be caused by the development of anti-drug antibodies. The formation of high-affinity anti-drug antibodies suggests the involvement of specific CD4+ T cell responses. However, the CD4+ T cell reaction against biologicals remains poorly characterized. Therefore, in this study we analyzed CD4+ T cells specific to various biologicals and investigated potential differences of drug-specific CD4+ T cells in patients with continued remission versus those with secondary nonresponses or allergic reactions. Methods Peripheral blood samples were collected at baseline and at week 6, week 14, week 22, week 30 after biological treatment. Drug-specific CD4+ T cells were analyzed using Antigen-Reactive T cell Enrichment (ARTE) directly ex vivo from human peripheral blood. To detect immunogenic regions, drug-specific CD4+ T cells were expanded and restimulated with individual peptides covering the whole variable chain of the therapeutic antibodies. Additionally, single-cell RNA sequencing was performed to investigate the gene expression profiles of drug-specific CD4+ T cells. Results Of the analyzed biological agents, the chimeric antibody infliximab showed significantly higher activation of reactive CD4+ T cells compared to other humanized or fully human biological agents. Notably, this response was characterized by a highly proliferative Th1 phenotype with evidence of long-term memory. In patients with secondary nonresponses or allergic reactions infliximab-specific CD4+ T cells showed elevated gene and protein expression of TNF-a, IFN-g and IL-21. Restimulation experiments indicated that drug-specific CD4+ T cell responses are driven by small immunodominant peptide regions. Conclusion Infliximab exhibits a higher activation of specific CD4+ T cell reactions compared to other biologicals, characterized by a proliferative Th1 response with long-term memory capabilities. Infliximab is a chimeric antibody consisting of murine variable regions, which likely contributes to its immunogenicity. The increased production of TNF-a, IFN-g and IL-21 in patients experiencing secondary nonresponses or allergic reactions highlights the potential role of drug-specific CD4+ T cells in treatment outcomes and formation of anti-drug antibodies. Overall, our data identifies differences in anti-drug CD4+ T cell reactions for different biologicals as well as different treatment outcomes which may contribute to enhance drug efficacy and improve long-term success with immunogenic biologicals.