Tolerogenic Immunotherapy: Targeting DC Surface Receptors to Induce Antigen-Specific Tolerance

Abstract

Dendritic cells (DCs) are well-established as major players in the regulation of immune responses. They either induce inflammatory or tolerogenic responses, depending on the DC-subtype and stimuli they receive from the local environment. This dual capacity of DCs has raised therapeutic interest for their use to modify immune-activation via the generation of tolerogenic DCs (tolDCs). Several compounds such as vitamin D3, retinoic acid, dexamethasone, or IL-10 and TGF-β have shown potency in the induction of tolDCs. However, an increasing interest exists in defining tolerance inducing receptors on DCs for new targeting strategies aimed to develop tolerance inducing immunotherapies, on which we focus particular in this review. Ligation of specific cell surface molecules on DCs can result in antigen presentation to T cells in the presence of inhibitory costimulatory molecules and tolerogenic cytokines, giving rise to regulatory T cells. The combination of factors such as antigen structure and conformation, delivery method, and receptor specificity is of paramount importance. During the last decades, research provided many tools that can specifically target various receptors on DCs to induce a tolerogenic phenotype. Based on advances in the knowledge of pathogen recognition receptor expression profiles in human DC subsets, the most promising cell surface receptors that are currently being explored as possible targets for the induction of tolerance in DCs will be discussed. We also review the different strategies that are being tested to target DC receptors such as antigen-carbohydrate conjugates, antibody-antigen fusion proteins and antigen-adjuvant conjugates.

Targeting DCs for Tolerance Induction: Don’t Lose Sight of the Neutrophils

“…( 33 ) Due to the laborious and expensive nature of ex vivo tolDC generation, new approaches are in development for the in vivo induction of tolerogenic programs in DCs. These new in vivo approaches are focusing on selective targeting of disease-relevant autoantigens toward (inhibitory) DC receptors, resulting in an antigen-specific anti-inflammatory response ( 100 ). Alternatively, nanoparticles or liposomes can be targeted to DCs ( 76 , 101 ).…”

Therapeutic Liposomal Vaccines for Dendritic Cell Activation or Tolerance

“…Several CLRs and Siglecs are under scrutiny for targeting, as an attempt to specify tolerogenic in vivo DC therapies. For an extensive review on this subject we refer the reader to a very recent piece published by our colleagues ( 21 ). The CLR DEC-205 is highly expressed on the cross-presenting cDC1 DC subset (as well as on cDC2s and moDCs) and is therefore a widely studied receptor for nanoparticle DC targeting, for example via antibodies ( 143 ).…”

“…One type of treatment focusses on the targeting of DCs via antibody-antigen or glycan-antigen conjugates for routing to various surface receptors predominantly expressed on these antigen presenting cells (APCs), as recently reviewed in the context of cancer or immune tolerance elsewhere ( 20 , 21 ).…”

Role of IL‐37‐ and IL‐37‐Treated Dendritic Cells in Acute Coronary Syndrome

“…Dendritic cells (DCs), one of the antigen-presenting cells, orchestrate both immunity and tolerance; therefore, they are pivotal targets for immunotherapy [21][22][23][24][25]. One previous publication showed that semimature DCs are tolerogenic and mature DCs are immunogenic [26].…”

“…One previous publication showed that semimature DCs are tolerogenic and mature DCs are immunogenic [26]. Unlike mature DCs, tDCs are associated with an increased secretion of immunosuppressive cytokines, decreased IL-12, and reduced costimulatory molecules and MHC-II and eventually induce Treg cells and deliver inadequate signals for effector T cell activation [24,25,27]. Several clinical studies have used autologous tolerogenic dendritic cells (tDCs) for therapy in auto-immune diseases [28][29][30].…”