IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction — A comparative study of human clinical-applicable DC

Boks, Martine A.; Kager-Groenland, Judith R.; Haasjes, Michiel S.P.; Zwaginga, Jaap Jan; Ham, S. Marieke van; Brinke, Anja ten

doi:10.1016/j.clim.2011.11.011

Cited by 228 publications

(240 citation statements)

References 62 publications

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“…The amount of proinflammatory cytokines released by IL-10-induced regDCs, like IL-6 and TNF-α, is similar to classically matured DCs. In contrast, IL-10 production is dramatically increased suggesting another possible mechanism resulting in tolerance induction [54][55][56]. Several studies showed that in vitro generated tolerogenic IL-10-DCs have an even higher capacity to induce iTreg than tissue resident immature DCs [53].…”

Section: Immunosuppressive and Tolerogenic Activity Of Regulatory Denmentioning

confidence: 99%

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Shurin

2013

Cancer Microenvironment

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Three major functional subsets of dendritic cells (DCs) have been described in the tumor microenvironment in patients with cancer and tumor-bearing animals: (i) conventional DCs with intact antigen-presenting capabilities, (ii) functionally defective DCs with decreased motility and low ability to uptake, process and present antigens or produce cytokines and (iii) regulatory DCs with high capacity to suppress T cell proliferation, induce differentiation of regulatory T cells or support immune tolerance. Phenotypic characteristics of regulatory DCs (regDCs), as well as the mechanisms of T cell inhibition, vary in different experimental conditions and environments, suggesting high level of their plasticity and probably different origin. Although new data demonstrate that regDCs may play an important role at early stages of tumor development, functional differences and clinical significance of emergence of different myeloid regulatory cells (MDSCs, regDCs, M2 macrophages, N2 neutrophils, mast cells) in cancer remain to be determined.

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Section: Immunosuppressive and Tolerogenic Activity Of Regulatory Denmentioning

confidence: 99%

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Shurin

2013

Cancer Microenvironment

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“…89,90 Recently, the clinical applicability of human tol-DCs incubated with IL-10, TGF-b, dexamethasone, vitamin D3 and rapamycin was studied. 91 IL-10-treated tol-DCs were found to be the optimal tol-DCs for functional Treg induction. Additionally, negative regulators of DCs, Zbtb46 and Btbd4 were found to be TLR-responsive, classical DC-specific transcriptional repressors that were partially responsible for preventing classical DC maturation at the steady state.…”

Section: Tol-dcs and Regulatory B Cells (Bregs)mentioning

confidence: 89%

Tolerogenic dendritic cells and their applications in transplantation

Shi

2014

Cell Mol Immunol

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In transplantation immunology, the ultimate goal is always to successfully and specifically induce immune tolerance of allografts. Tolerogenic dendritic cells (tol-DCs) with immunoregulatory functions have attracted much attention as they play important roles in inducing and maintaining immune tolerance. Here, we focused on tol-DCs that have the potential to promote immune tolerance after solid-organ transplantation. We focus on their development and interactions with other regulatory cells, and we also explore various tol-DC engineering protocols. Harnessing tol-DCs represents a promising cellular therapy for promoting long-term graft functional survival in transplant recipients that will most likely be achieved in the future.

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“…Three functional characteristics are required for clinically applicable tDCs (37)(38)(39). First, ex vivo-generated tDCs need to have the capacity for CCR7-dependent migration toward secondary lymphoid organs for induction of suppressive responses in naive T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Third, it is essential to establish whether ex vivo-generated tDCs are stable and maintain their tolerogenic properties when encountering proinflammatory signals in vivo. Two groups have compared migratory capacity, stability, and functional properties among clinical-grade tDCs generated with Vit D 3 , Dexa, Rapa, IL-10, or TGF-b (38,39). Vit D 3 -tDCs, Dexa-tDCs, and IL-10-tDCs had very low CCR7 expression, leading to very poor migration to CCL19 and CCL21, whereas TGF-b-tDCs and Rapa-tDCs had moderate and high CCR7 expression, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…For this purpose, anti-inflammatory cytokines such as and TGF-b (22)(23)(24), vitamin D 3 (Vit D 3 ) (25)(26)(27)(28), neuropeptides, including vasoactive intestinal peptide (17,29,30) and a-melanocyte-stimulating hormone (31), and anti-inflammatory/immunosuppressive drugs such as dexamethasone (Dexa) (28,32,33) and rapamycin (Rapa) (34)(35)(36) are often employed. However, the compound most suitable for clinical application remains undefined from the viewpoint of tolerogenic potential, stability, and capacity for migration toward secondary lymphoid organs, that is, the area where immune responses occur (37)(38)(39). Therefore, to obtain compounds that have stronger tolerogenic potential, we screened libraries of bioactive lipids, nuclear receptor ligands, and kinase inhibitors for molecules that would downregulate the costimulatory molecules CD80 and CD86 on DCs and produce the highest level of IL-10.…”

Section: Endritic Cells (Dcs) Are a Heterogeneous Population Ofmentioning

confidence: 99%

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Protein Kinase C Inhibitor Generates Stable Human Tolerogenic Dendritic Cells

Matsumoto

Hasegawa

Onishi

et al. 2013

The Journal of Immunology

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Tolerogenic dendritic cells (DCs) are a promising tool for a specific form of cellular therapy whereby immunological tolerance can be induced in the context of transplantation and autoimmunity. From libraries of bioactive lipids, nuclear receptor ligands, and kinase inhibitors, we screened conventional protein kinase C inhibitors (PKCIs) bisindolylmaleimide I, Gö6983, and Ro32-0432 with strong tolerogenic potential. PKCI-treated human DCs were generated by subjecting them to a maturation process after differentiation of immature DCs. The PKCI-treated DCs had a semimature phenotype, showing high production of IL-10, and efficiently induced IL-10–producing T cells and functional Foxp3+ regulatory T cells from naive CD4+ T cells, thus eliciting a strong immunosuppressive function. They also showed CCR7 expression and sufficient capacity for migration toward CCR7 ligands. Additionally, PKCI-treated DCs were highly stable when exposed to inflammatory stimuli such as proinflammatory cytokines or LPS. Conventional PKCIs inhibited NF-κB activation of both the canonical and noncanonical pathways of DC maturation, thus suppressing the expression of costimulatory molecules and IL-12 production. High production of IL-10 in PKCI-treated DCs was due to not only an increase of intracellular cAMP, but also a synergistic effect of increased cAMP and NF-κB inhibition. Moreover, PKCI-treated mouse DCs that had properties similar to PKCI-treated human DCs prevented graft-versus-host disease in a murine model of acute graft-versus-host disease. Conventional PKCI-treated DCs may be useful for tolerance-inducing therapy, as they satisfy the required functional characteristics for clinical-grade tolerogenic DCs.

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IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction — A comparative study of human clinical-applicable DC

Cited by 228 publications

References 62 publications

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Immunosuppressive Mechanisms of Regulatory Dendritic Cells in Cancer

Tolerogenic dendritic cells and their applications in transplantation

Protein Kinase C Inhibitor Generates Stable Human Tolerogenic Dendritic Cells

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