AUTHOR=Nikolic Tatjana , Suwandi Jessica S. , Wesselius Joris , Laban Sandra , Joosten Antoinette M. , Sonneveld Petra , Mul Dick , Aanstoot Henk-Jan , Kaddis John S. , Zwaginga Jaap Jan , Roep Bart O. TITLE=Tolerogenic dendritic cells pulsed with islet antigen induce long-term reduction in T-cell autoreactivity in type 1 diabetes patients JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1054968 DOI=10.3389/fimmu.2022.1054968 ISSN=1664-3224 ABSTRACT=Introduction

Restoration of immune tolerance may halt progression of autoimmune diseases. Tolerogenic dendritic cells (tolDC) inhibit antigen-specific proinflammatory T-cells, generate antigen-specific regulatory T-cells and promote IL-10 production in-vitro, providing an appealing immunotherapy to intervene in autoimmune disease progression.

Methods

A placebo-controlled, dose escalation phase 1 clinical trial in nine adult patients with long-standing type 1 diabetes (T1D) demonstrated the safety and feasibility of two (prime-boost) vaccinations with tolDC pulsed with a proinsulin peptide. Immunoregulatory effects were monitored by antigen-specific T-cell assays and flow and mass cytometry.

Results

The tolDC vaccine induced a profound and durable decline in pre-existing autoimmune responses to the vaccine peptide up to 3 years after therapy and temporary decline in CD4 and CD8+ T-cell responses to other islet autoantigens. While major leukocyte subsets remained stable, ICOS+CCR4+TIGIT+ Tregs and CD103+ tissue-resident and CCR6+ effector memory CD4+ T-cells increased in response to the first tolDC injection, the latter declining thereafter below baseline levels.

Discussion

Our data identify immune correlates of mechanistic efficacy of intradermally injected tolDC reducing proinsulin autoimmunity in T1D.