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Synergistic Immunomodulatory Combinations Induce Robust Human Tolerogenic Dendritic Cells for Antigen-Specific Treg Generation
Journal article   Open access   Peer reviewed

Synergistic Immunomodulatory Combinations Induce Robust Human Tolerogenic Dendritic Cells for Antigen-Specific Treg Generation

Sihan Jia, Joshua Chang Mell and Peter E Deak
The journal of pharmacology and experimental therapeutics, Forthcoming
24 Apr 2026
DOI: https://doi.org/10.1016/j.jpet.2026.104899
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https://doi.org/10.1016/j.jpet.2026.104899View
Published, Version of Record (VoR) Open Access via Drexel Libraries Read and Publish Program 2026 Open CC BY-NC-ND V4.0

Abstract

Restoring antigen-specific immune tolerance remains a central challenge in the treatment of autoimmune diseases, as conventional immunosuppressive therapies lack specificity and can compromise protective immunity. Tolerogenic dendritic cell (tolDC) therapies offer a promising strategy for inducing durable, antigen-specific regulatory T cell (Treg) responses, but current methods for generating tolDCs are limited by poor longevity and Treg generative capacity. This study evaluates the clinical potential of Push/Pull Immunomodulation (PPI), a novel combinatorial approach identified through high-throughput molecular screening, in human monocyte derived dendritic cells (moDCs). The phenotype, cytokine profile, and longevity of PPI-treated moDCs were benchmarked against conventional tolDC induction agents. Functional assays assessed the capacity of PPI-tolDCs to induce antigen-specific Tregs. PPI-treated moDCs exhibited increased expression of tolerogenic markers (IL-10, PD-L1, BTLA), enhanced in vitro longevity, and a unique transcriptomic signature characterized by upregulation of IDO1, IDO2, and T cell-sustaining cytokines. Notably, PPI9 induced robust, antigen-specific Treg responses, suggesting the potential for long-term tolerance induction. While transient TNFα release and moderate upregulation of CD40 and CD86 were observed, these did not impair Treg generation, indicating that PPI-tolDCs overcome key barriers associated with conventional tolDC therapies. Push/Pull Immunomodulation enables the generation of stable, long-lived human tolDCs with superior capacity to induce antigen-specific Tregs. Ongoing studies will further explore the translational potential of PPI-tolDCs for clinical applications in autoimmunity and transplantation.

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