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Current treatment for patients with autoimmune disorders including rheumatoid arthritis, multiple sclerosis and type 1 diabetes, often consists of long-term drug regimens that broadly dampen immune responses. These non-specific treatments are frequently associated with severe side effects creating an urgent need for safer and more effective therapy to promote peripheral tolerance in autoimmune diseases. Cell-based immunotherapy may offer an encouraging alternative, where tolerogenic CD14 + myeloid cells are infused to inhibit autoreactive effector cells. In this review, we compared in depth three promising tolerogenic CD14 + candidates for the treatment of autoimmune disease: 1) tolerogenic dendritic cells, 2) monocytic myeloid-derived suppressor cells and 3) CD14 + type 2 conventional dendritic cells. TolDC-based therapy has entered clinical testing whereas evidence from the latter two cell types m-MDSCs and CD14 + cDC2s is predominantly coming from cancer immunology research. These three cell types have distinct cellular properties and immunosuppressive mechanisms offering unique opportunities to be explored. However, these cells differ in stage of development towards immunotherapy each facing additional hurdles. Therefore, we speculate on the potential benefits and risks of these cell types as novel cell-based immunotherapies to control autoimmune disease in patients., (Copyright © 2021. Published by Elsevier Ltd.)

There are adaptive T-cell and antibody autoimmune responses to myelin-derived peptides in multiple sclerosis (MS) and to aquaporin-4 (AQP4) in neuromyelitis optica spectrum disorders (NMOSDs). Strategies aimed at antigen-specific tolerance to these autoantigens are thus indicated for these diseases. One approach involves induction of tolerance with engineered dendritic cells (tolDCs) loaded with specific antigens. We conducted an in-human phase 1b clinical trial testing increasing concentrations of autologous tolDCs loaded with peptides from various myelin proteins and from AQP4. We tested this approach in 12 patients, 8 with MS and 4 with NMOSD. The primary end point was the safety and tolerability, while secondary end points were clinical outcomes (relapses and disability), imaging (MRI and optical coherence tomography), and immunological responses. Therapy with tolDCs was well tolerated, without serious adverse events and with no therapy-related reactions. Patients remained stable clinically in terms of relapse, disability, and in various measurements using imaging. We observed a significant increase in the production of IL-10 levels in PBMCs stimulated with the peptides as well as an increase in the frequency of a regulatory T cell, known as Tr1, by week 12 of follow-up. In this phase 1b trial, we concluded that the i.v. administration of peptide-loaded dendritic cells is safe and feasible. Elicitation of specific IL-10 production by peptide-specific T cells in MS and NMOSD patients indicates that a key element in antigen specific tolerance is activated with this approach. The results warrant further clinical testing in larger trials., Competing Interests: Conflict of interest statement: E.F. and L.S. published an obituary on two leaders in MS [Kildebeck EJ, et al. (2017) The emergence of neuroepidemiology, neurovirology and neuroimmunology: The legacies of John F. Kurtzke and Richard “Dick” T. Johnson. J Neurol 264:817–828]. I.Z. has received travel reimbursement from Genzyme, Biogen, and Merck for national and international meetings over the last 3 y. E.H.M.-L. has received speaker honoraria from Biogen, Roche, Novartis, and Sanofi and a travel reimbursement from Biogen, Roche, Novartis, and Sanofi. E.H.M.-L. has participated in advisory boards for Roche and Sanofi. A.S. has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd., Roche, and Novartis. S.L. has received speaker honoraria and travel reimbursement from Biogen, Merck, Novartis, and Teva. I.P.-V. has received travel reimbursement from Roche Spain and Genzyme-Sanofi, European Academy of Neurology, and the European Committee for Treatment and Research in Multiple Sclerosis for international and national meetings over the last 3 y; I.P.-V. holds a patent for an affordable eye-tracking system to measure eye movement in neurologic diseases and holds stock in Aura Innovative Robotics. N.S.-V. received compensation for consulting services and speaker honoraria from Genzyme-Sanofi, Biogen idec, Merck-Serono, and Bayer-Schering. P.V. holds stocks and has received compensation from Bionure Farma SL; Health Engineering SL; Spiral Therapeutics, Inc.; and QMenta SL. L.S. received compensation from Novartis, Celgene, Bionure, Tolerion, Katexco, Atreca, and TG Therapeutics. All other authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Dendritic cells (DCs) are APCs essential in regulating the immune response. PGE 2 , produced during inflammation, has a pivotal role in the maturation of DCs and, therefore, is vital for the immune response. The large variety of biologic functions governed by PGE 2 is mediated by its signaling through 4 distinct E-type prostanoid (EP) receptors. Immunogenic DCs express EP 2 and EP 4 , which mediate the PGE 2 signaling. However, the expression and function of EP receptors in human tolerogenic DCs (tol-DCs), which present an inhibitory phenotype, have not yet, to our knowledge, been assessed. To clarify the role of EP receptors in tol-DCs, we examined the expression of different EP receptors and their effect using selective agonists in human cells. We find that EP 2 and EP 3 expression are up-regulated in in vitro-generated tol-DCs compared with mature DCs (mDCs). Activation of EP 2 -EP 4 has a direct effect on the surface expression of costimulatory molecules and maturation receptors, such as CD80, CD83, and CD86 or MHCII and CCR7 in tol-DCs, the latter being exclusively modulated by PGE 2 -EP 4 signaling. Importantly, we find that EP 2 and EP 3 receptors are involved in tolerance induction through IL-10 production by tol-DCs. These results are in sharp contrast with the inflammatory role of EP 4 Moreover, we show that DCs generated in the presence of agonists for EP receptors, induce naive T cell differentiation toward polarized Th1/Th17 cells. Given the differential effects of EP receptors, our results suggest that EP receptor agonist/antagonists might become relevant novel drug templates to modulate immune response., (© Society for Leukocyte Biology.)

The design of innovative strategies to selectively target cells, such antigen-presenting cells and dendritic cells, in vivo to induce immune tolerance is gaining interest and relevance for the treatment of immune-mediated diseases. A novel loaded-nanosystem strategy to generate tolerogenic dendritic cells (tol-DCs) was evaluated. Hence budesonide (BDS) was encapsulated in multiwalled polyurethane-polyurea nanoparticles (PUUa NPs-BDS) based on self-stratified polymers by hydrophobic interactions at the oil-water interface. DCs treated with encapsulated BDS presented a prominent downregulation of costimulatory molecules (CD80, CD83 and MHCII) and upregulation of inhibitory receptors. Moreover, DCs treated with these PUUa NPs-BDS also secreted large amounts of IL-10, a crucial anti-inflammatory cytokine to induce tolerance, and inhibited T lymphocyte activation in a specific manner compared to those cells generated with free BDS. These results demonstrate that PUUa NPs-BDS are a highly specific and efficient system through which to induce DCs with a tolerogenic profile. Given the capacity of PUUa NPs-BDS, this delivery system has a clear advantage for translation to in vivo studies., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The aim of this study was to test the hypothesis whether MERTK, which is up-regulated in human DCs treated with immunosuppressive agents, is directly involved in modulating T cell activation. MERTK is a member of the TAM family and contributes to regulating innate immune response to ACs by inhibiting DC activation in animal models. However, whether MERTK interacts directly with T cells has not been addressed. Here, we show that MERTK is highly expressed on dex-induced human tol-DCs and participates in their tolerogenic effect. Neutralization of MERTK in allogenic MLR, as well as autologous DC-T cell cultures, leads to increased T cell proliferation and IFN-γ production. Additionally, we identify a previously unrecognized noncell-autonomous regulatory function of MERTK expressed on DCs. Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK ligand PROS1. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine proproliferative mechanism. Collectively, these results suggest that MERTK on DCs controls T cell activation and expansion through the competition for PROS1 interaction with MERTK in the T cells. In conclusion, this report identified MERTK as a potent suppressor of T cell response., (© Society for Leukocyte Biology.)