Dataset Information

Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies.

ABSTRACT: Myeloid regulatory cell-based therapy has been shown to be a promising cell-based medicinal approach in organ transplantation and for the treatment of autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Crohn's disease and multiple sclerosis. Dendritic cells (DCs) are the most efficient antigen-presenting cells and can naturally acquire tolerogenic properties through a variety of differentiation signals and stimuli. Several subtypes of DCs have been generated using additional agents, including vitamin D3, rapamycin and dexamethasone, or immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). These cells have been extensively studied in animals and humans to develop clinical-grade tolerogenic (tol)DCs. Regulatory macrophages (Mregs) are another type of protective myeloid cell that provide a tolerogenic environment, and have mainly been studied within the context of research on organ transplantation. This review aims to thoroughly describe the ex vivo generation of tolDCs and Mregs, their mechanism of action, as well as their therapeutic application and assessment in human clinical trials.

SUBMITTER: Suuring M

PROVIDER: S-EPMC8348814 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies.

Suuring Maaike M Moreau Aurélie A

International journal of molecular sciences 20210726 15

Myeloid regulatory cell-based therapy has been shown to be a promising cell-based medicinal approach in organ transplantation and for the treatment of autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Crohn's disease and multiple sclerosis. Dendritic cells (DCs) are the most efficient antigen-presenting cells and can naturally acquire tolerogenic properties through a variety of differentiation signals and stimuli. Several subtypes of DCs have been generated using additional age ...[more]

PMID: 34360736

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Project description:Imbalanced immune responses are a prominent hallmark of cancer and autoimmunity. Overactive as well as suppressed immunological activity is evidenced to promote disease. This immunological disbalance is often driven through disrupted immunomodulation by innate myeloid immune cells. Myeloid cells can be overly suppressive, inhibiting protective immune responses or be inactive not controlling autoreactive immune cells. Understanding the mechanisms that induce and drive suppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs) and tolerogenic dendritic cells (TolDCs), can facilitate the development of immune-restoring therapeutic approaches in patients. MDSCs are a major barrier for effective cancer immunotherapy by suppressing anti-tumor immune responses in cancer patients. TolDCs are administered to patients to promote immune tolerance with the intent to control autoimmune disease. Here, we investigated the development and suppressive/tolerogenic activity of human MDSCs and TolDCs derived from monocytes to gain insight into signaling pathways that drive immunosuppression in these different myeloid subsets. Moreover, human monocyte-derived-MDSCs (M-MDSCs) generated in vitro were compared to M-MDSCs isolated from head-and-neck squamous cell carcinoma (HNSCC) patients. PI3K-AKT signaling was identified as being crucial for the induction of human M-MDSCs. PI3K inhibition prevented the downregulation of HLA-DR, the upregulation of reactive oxygen species and MerTK, and subsequent suppressive activity of M-MDSCs towards T cells. In addition, we show for the first time that the suppressive activity of dexamethasone-induced TolDCs is induced by β-catenin-dependent Wnt signaling. The identification of PI3K-AKT and Wnt signal transduction pathways as respective inducers of the immunomodulatory capacity of M-MDSCs and TolDCs provides opportunities to overcome suppressive myeloid cells in cancer patients and optimize therapeutic application of TolDCs in patients with autoimmune diseases. Lastly, the observed similarities between generated- and patient-derived M-MDSCs support the use of in vitro generated M-MDSCs as powerful model to investigate the functionality of human MDSCs.

Dataset Information

Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies.

Publications

Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies.

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