Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration

Willekens, Barbara; Presas-Rodríguez, Silvia; Mansilla, María José; Derdelinckx, Judith; Lee, Wai-Ping; Nijs, Griet; Laere, Maxime De; Wens, Inez; Cras, Patrick; Parizel, Paul M.; Hecke, Wim Van; Ribbens, Annemie; Billiet, Thibo; Adams, Geert; Couttenye, Marie-Madeleine; Navarro‐Barriuso, Juan; Teniente-Serra, Aina; Quirant‐Sánchez, Bibiana; Cerio, Ascensión López‐Díaz de; Inogés, Susana; Prósper, Felipe; Kip, Anke E; Verheij, Herman; Groß, Catharina C.; Wiendl, Heinz; Ham, Marieke Sm van; Brinke, Anja ten; Barriocanal, Ana María; Massuet-Vilamajó, A.; Hens, Niel; Berneman, Zwi N.; Martínez-Cáceres, Eva; Cools, Nathalie; Ramo-Tello, Cristina

doi:10.1136/bmjopen-2019-030309

Cited by 77 publications

(70 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the role of DCs in vitamin D-mediated immunomodulation is not fully understood. In addition, DCs with tolerogenic function (TolDCs) have become a promising immunotherapeutic tool for reinstating immune tolerance in autoimmune diseases and in allogeneic bone marrow transplantation (Vanherwegen et al, 2019b(Vanherwegen et al, , 2019aWillekens et al, 2019). The stability of the tolerogenic phenotype suggests that regulatory mechanisms that allow the maintenance of stable changes of gene expression are involved.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

Català-Moll

Ciudad

et al. 2020

Preprint

View full text Add to dashboard Cite

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces stable tolerogenesis in dendritic cells (DCs). This process involves the vitamin D receptor (VDR), which translocates to the nucleus, binds its cognate genomic sites, and promotes epigenetic and transcriptional remodeling. In this study, we investigated the interplay between the VDR and other transcription factors to induce DNA methylation changes that might provide phenotypic stability to the tolerogenic phenotype of DCs.Our study reveals the occurrence of vitamin D-specific DNA demethylation and transcriptional activation at VDR binding sites associated with the acquisition of tolerogenesis. Tolerogenic properties in DCs are acquired together with activation of the IL6-JAK-STAT3 pathway. In fact, VDR directly binds the IL6 gene, and JAK2-mediated STAT3 phosphorylation is specific to vitamin D stimulation. VDR and the phosphorylated form of STAT3 interact with each other and with methylcytosine dioxygenase TET2 following vitamin D treatment. Most importantly, pharmacological inhibition of STAT3 phosphorylation reverts the vitamin-induced tolerogenic properties of DCs. Our results reveal an interplay between VDR and STAT3 leading to the DNA demethylation-dependent induction of tolerogenesis by vitamin D.

show abstract

Section: Introductionmentioning

confidence: 99%

Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

Català-Moll

Ciudad

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous studies have investigated the transfer of other kinds of tolDCs induced by immunomodulators to colitis mice signi cantly reduced the severity of colon in ammation (38)(39)(40). In humans, ex vivo tolDC injection has been applied to clinical type 1 diabetes(41) and multiple sclerosis (42). The clinical trial in patients with CD is on the way.…”

Section: Discussionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Activation Ameliorates Experimental Colitis by Modulating the Tolerogenic Dendritic and Regulatory T Cell Formation

Cui

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Intestinal immune dysfunction is involved in the onset of Crohn's disease (CD). The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor widely expressed in various immune cells, including DCs. Although AhR plays an important role in immune tolerance, its role in the DCs is unclear. The purpose of this study was to investigate whether the activation of AhR can induce tolerogenic DCs (tolDCs) and the differentiation of regulatory T (Treg) cells, as well as ameliorate experimental colitis. Methods Bone marrow derived DCs were incubated with or without FICZ(100 nM) which was a kind of AhR for 12 hours, subsequently the cells were stimulated to mature. Scanning electron microscope (SEM) was used to observe dendritic formation on DC surface. Proliferation of T lymphocytes was evaluated by proliferation experiment. The expression of surface markers in DCs were detected by flow cytometry and the gene expression levels of cytokines were measured using RT-qPCR. The levels of cytokines in cell supernatants were determined by ELISA. The expression of cytochrome P450 1A1(CYP1A1) and forkhead box P3 (Foxp3) were measured by Western blotting. TolDCs were transferred to murine colitis model and the intestinal inflammation were evaluated. T-helper (Th) 17 cells and Treg in spleens and mesenteric lymph nodes (MLNs) were analyzed by flow cytometry. Results AhR activation in the DCs resulted in a lower expression of surface markers such as CD80, CD83, CD86, and pro-inflammatory cytokine production, and higher anti-inflammatory production (IL-1β, IL-23, and IL-12) compared to the control DCs. The surface dendrites in DCs were significantly reduced following AhR activation by FICZ. Such DCs with FICZ-mediated activation of AhR, namely tolDCs, inhibited CD4+ T cell proliferation and promoted Treg cell differentiation. Adoptive transfer of tolDCs to a TNBS-induced colitis mouse model significantly alleviated the severity of inflammation by decreasing the frequency of Th17 cells and increasing the frequency of Treg cells. Conclusions Activation of AhR in the DCs could induce tolDCs, and the transplantation of tolDCs may help in relieving intestinal inflammation and maintaining the Th17/Treg differentiation balance. Thus, our data suggest that AhR may be a potential therapeutic target for CD.

show abstract

“…The group of Thomas treated DC with a nuclear factor-kB (NF-kB) inhibitor and pulsed them with citrullinated peptide Ags before injection into RA patients ( 45 ). More recently DC differentiated with vitamin D3 and dexamethasone alone or in combination have been or are currently used to treat RA, Crohn's disease, and MS patients [NCT01352858-AutoDECRA ( 46 ); NCT02618902-MS-tolDC; NCT02283671-TolDecEM/NMO ( 47 – 49 ); NCT02903537-Tolervit-MS ( 48 , 49 ); NCT03337165-TolDCfoRA; ( 120 )].…”

Section: Cell-based Approachesmentioning

confidence: 99%

Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

Passerini

Gregori

2020

Front. Immunol.

View full text Add to dashboard Cite

The development of novel approaches to control unwanted immune responses represents an ambitious goal in the management of a number of clinical conditions, including autoimmunity, autoinflammatory diseases, allergies and replacement therapies, in which the T cell response to self or non-harmful antigens threatens the physiological function of tissues and organs. Current treatments for these conditions rely on the use of non-specific immunosuppressive agents and supportive therapies, which may efficiently dampen inflammation and compensate for organ dysfunction, but they require lifelong treatments not devoid of side effects. These limitations induced researchers to undertake the development of definitive and specific solutions to these disorders: the underlying principle of the novel approaches relies on the idea that empowering the tolerogenic arm of the immune system would restore the immune homeostasis and control the disease. Researchers effort resulted in the development of cell-free strategies, including gene vaccination, protein-based approaches and nanoparticles, and an increasing number of clinical trials tested the ability of adoptive transfer of regulatory cells, including T and myeloid cells. Here we will provide an overview of the most promising approaches currently under development, and we will discuss their potential advantages and limitations. The field is teaching us that the success of these strategies depends primarily on our ability to dampen antigen-specific responses without impairing protective immunity, and to manipulate directly or indirectly the immunomodulatory properties of antigen presenting cells, the ultimate in vivo mediators of tolerance.

show abstract

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration

Cited by 77 publications

References 44 publications

Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

Aryl Hydrocarbon Receptor Activation Ameliorates Experimental Colitis by Modulating the Tolerogenic Dendritic and Regulatory T Cell Formation

Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

Contact Info

Product

Resources

About