Authors
Praveen Krishna Veerasubramanian, Wenlan Zang, Vijaya Amancha, Thomas A Wynn, Jie Quan, Fridrik J Karlsson
Published in
Frontiers in immunology. Volume 17. Pages 1867995. Epub Jul 23, 2026.
Abstract
The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise 47 proteins that regulate immune signaling and T cell costimulation. While TNF inhibitors are established therapies for immune-mediated inflammatory diseases (IMIDs), their efficacy is limited by primary non-response and secondary loss of efficacy. Preclinical data suggest that the TNF/TNFR members exhibit redundant and synergistic signaling, motivating combination targeting strategies.
We have systematically evaluated TNF/TNFR combinations as potential immunotolerance targets using integrated computational and experimental approaches. We applied a gene prioritization framework incorporating transcriptomics, genetics, druggability, and pathway regulation data to derive disease association scores for the TNF/TNFR genes in rheumatoid arthritis and inflammatory bowel disease. Based on these scores and T cell expression profiling, ten targets were prioritized for a combinatorial screen using clinical-stage and preclinical pharmacological inhibitors in a mixed lymphocyte reaction (MLR) assay. The effects of the most promising combinations were further characterized by RNA sequencing.
The combinatorial screen identified four drug combinations that significantly suppressed T cell production of IL-2 and IFN-γ: TNF+CD40L, TNF+OX40L, CD40L+OX40L, and CD40L+LTβ/LIGHT. Transcriptional profiling revealed that these combinations broadly downregulated genes associated with T cell activation, proliferation, differentiation, and cytokine production that were induced during the allogeneic response. Notably, the co-inhibition of TNF and CD40L (Adalimumab+Dapirolizumab) produced the most robust suppression, uniquely downregulating 337 genes enriched for key T cell activation pathways, including NF-κB and ERK1/2.
These findings demonstrate that the combinatorial antagonism of TNF/TNFR superfamily members can potently suppress allogeneic T cell responses, with the TNF+CD40L combination showing particularly strong and broad effects. The results support the continued preclinical evaluation of combinatorial TNF/TNFR inhibition as a potential tolerance-inducing therapeutic strategy for patients with refractory IMIDs.
PMID:
42564165
Bibliographic data and abstract were imported from PubMed on 07 Aug 2026.
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