Targeting IFN activity to both B cells and plasmacytoid dendritic cells induces a robust tolerogenic response and protection against EAE

Cauwels, Anje; Lint, Sandra Van; Rogge, Elke; Verhee, Annick; Eeckhout, Bram Van Den; Pang, Shengru; Prinz, Marco; Kley, Niko; Uzé, Gilles; Tavernier, Jan

doi:10.1038/s41598-021-00891-6

Cited by 7 publications

(4 citation statements)

References 40 publications

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“…Further, in this study, yhe phosphorylation of STAT1/3 was increased by IFNβ-1a. IFNβ exerts its immunomodulatory, beneficial effects by the induction of T-reg cells and IL-10 secretion by binding to interferon receptors [ 38 , 39 ]. IFN-receptors, in turn, activate the Janus kinase (JAK) to phosphorylate STAT1 and STAT2 [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Interferon Beta-1a versus Combined Interferon Beta-1a and Oligodendrocyte-Specific FGFR1 Deletion in Experimental Autoimmune Encephalomyelitis

Rajendran

Rajendran²,

Gupta³

et al. 2022

IJMS

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Recombinant beta interferons-1 (IFNβ-1) are used as first line therapies in patients with relapsing multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the CNS. IFNβ-1a/b has moderate effects on the prevention of relapses and slowing of disease progression. Fibroblast growth factors (FGFs) and FGF receptors (FGFRs) are known to play a key role in the pathology of MS and its model EAE. To investigate the effects of short-term treatment with s.c. IFNβ-1a versus the combined application of s.c. IFNβ-1a and oligodendrocyte-specific deletion of FGFR1 (Fgfr1ind−/− mice) in MOG35-55-induced EAE. IFNβ-1a (30 mg/kg) was applied s.c. from days 0–7 p.i. of EAE in controls and Fgfr1ind−/− mice. FGFR signaling proteins associated with inflammation/degeneration in MS/EAE were analyzed by western blot in the spinal cord. Further, FGFR1 in Oli-neu oligodendrocytes were inhibited by PD166866 and treated with IFNβ-1a (400 ng/mL). Application of IFNβ-1a over 8 days resulted in less symptoms only at the peak of disease (days 9–11) compared to controls. Application of IFNβ-1a in Fgfr1ind−/− mice resulted in less symptoms primarily in the chronic phase of EAE. Fgfr1ind−/− mice treated with IFNβ-1a showed increased expression of pERK and BDNF. In Oli-neu oligodendrocytes, treatment with PD166866 and IFNβ-1a also showed an increased expression of pERK and BDNF/TrkB. These data suggest that the beneficial effects in the chronic phase of EAE and on signaling molecules associated with ERK and BDNF expression are caused by the modulation of FGFR1 and not by interferon beta-1a. FGFR may be a potential target for therapy in MS.

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Section: Discussionmentioning

confidence: 99%

Interferon Beta-1a versus Combined Interferon Beta-1a and Oligodendrocyte-Specific FGFR1 Deletion in Experimental Autoimmune Encephalomyelitis

Rajendran

Rajendran²,

Gupta³

et al. 2022

IJMS

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“…As such, AcTakines only exert potent activity on targeted cells, while avoiding pleiotropic systemic cytokine activity and associated toxicities [ 9 ]. We already provided evidence for the broad applicability of AcTakines in cancer immunotherapy [ 10 – 13 ], auto-immunity [ 14 , 15 ] and as an adjuvant in prophylactic vaccination strategies such as influenza [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

A bispecific Clec9A-PD-L1 targeted type I interferon profoundly reshapes the tumor microenvironment towards an antitumor state

Van Lint,

Van Parys,

Van Den Eeckhout

et al. 2023

Mol Cancer

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Despite major improvements in immunotherapeutic strategies, the immunosuppressive tumor microenvironment remains a major obstacle for the induction of efficient antitumor responses. In this study, we show that local delivery of a bispecific Clec9A-PD-L1 targeted type I interferon (AcTaferon, AFN) overcomes this hurdle by reshaping the tumor immune landscape.Treatment with the bispecific AFN resulted in the presence of pro-immunogenic tumor-associated macrophages and neutrophils, increased motility and maturation profile of cDC1 and presence of inflammatory cDC2. Moreover, we report empowered diversity in the CD8+ T cell repertoire and induction of a shift from naive, dysfunctional CD8+ T cells towards effector, plastic cytotoxic T lymphocytes together with increased presence of NK and NKT cells as well as decreased regulatory T cell levels. These dynamic changes were associated with potent antitumor activity. Tumor clearance and immunological memory, therapeutic immunity on large established tumors and blunted tumor growth at distant sites were obtained upon co-administration of a non-curative dose of chemotherapy.Overall, this study illuminates further application of type I interferon as a safe and efficient way to reshape the suppressive tumor microenvironment and induce potent antitumor immunity; features which are of major importance in overcoming the development of metastases and tumor cell resistance to immune attack. The strategy described here has potential for application across to a broad range of cancer types.

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“…iDCs are also known as tolDCs because they do not provide sufficient signal for T cell activation, thereby inducing immune tolerance [9]. Currently, a variety of protocols have been developed for the generation of tolDCs and have shown significant potential in the treatment of autoimmune diseases [10][11][12][13]. In a clinical trial, tolDCs loaded with proinsulin peptide were infused into nine patients with type 1 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Tolerogenic dendritic cells alleviate collagen‐induced arthritis by forming microchimerism and affecting the expression of immune checkpoint molecules

Wan

Bao

et al. 2022

Eur J Immunol

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Tolerogenic dendritic cells (tolDCs) have the potential to treat rheumatoid arthritis (RA) by inducing immune tolerance. However, the mechanism of intervention needs further study. Here, we investigated whether tolDCs formed microchimerism and their effect on the expression of immune checkpoint molecules after infusion of tolDCs into rats with collagen-induced arthritis (CIA). TolDCs derived from male SD rats were labeled with fluorescence and infused into female CIA rats. The fluorescence signals as well as the sex-determining region of Y-chromosome (SRY) gene revealed that tolDCs formed microchimerism in the mesenteric lymph nodes and ankle joints. We further explored the effect of tolDCs on the expression of immune checkpoint molecules in mesenteric lymph nodes and ankle joints. For stimulatory immune checkpoint molecules, the expressions of CD86 and CD40 decreased in mesenteric lymph nodes, and the expressions of CD40, CD40L, CD28, CD80, and CD86 also decreased in rat ankle joints. In contrast, the inhibitory immune checkpoint molecule PDL1 increased in mesenteric lymph nodes, and PD1, PDL1, and CTLA4 increased in ankle joints. In conclusion, our results suggested that intervention of tolDCs in CIA is associated with the formation of microchimerism and the effect on immune checkpoints.

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Targeting IFN activity to both B cells and plasmacytoid dendritic cells induces a robust tolerogenic response and protection against EAE

Cited by 7 publications

References 40 publications

Interferon Beta-1a versus Combined Interferon Beta-1a and Oligodendrocyte-Specific FGFR1 Deletion in Experimental Autoimmune Encephalomyelitis

Interferon Beta-1a versus Combined Interferon Beta-1a and Oligodendrocyte-Specific FGFR1 Deletion in Experimental Autoimmune Encephalomyelitis

A bispecific Clec9A-PD-L1 targeted type I interferon profoundly reshapes the tumor microenvironment towards an antitumor state

Tolerogenic dendritic cells alleviate collagen‐induced arthritis by forming microchimerism and affecting the expression of immune checkpoint molecules

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