Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response

Fujita, Shigeharu; Seino, Ken‐ichiro; Sato, Kaori; Sato, Yumiko; Eizumi, Kawori; Yamashita, Naohide; Taniguchi, Masaru; Sato, Katsuaki

doi:10.1182/blood-2005-10-4190

Cited by 123 publications

(109 citation statements)

References 24 publications

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“…Our data show that AADC expressed similar levels of surface intercellular adhesion molecules to GMDC, but reduced CCR7 expression-the latter consistent with their more immature phenotype and reduced responsiveness to CCL19 (57). However, AADC appeared to traffic normally in vivo to draining lymph nodes and spleens of quiescent, prospective organ allograft recipients.…”

Section: Discussionmentioning

confidence: 49%

“…The preferential autocrine production of IL-10 by AADC that we observed, and that appears to involve cAMP-mediated activation of protein kinase A (36), may be involved in the defective production of these proinflammatory cytokines. This view is strengthened by the observation that AADC propagated from IL-10 knockout mice show reduced impairment of proinflammatory cytokine production (36).…”

Section: Discussionmentioning

confidence: 68%

“…TGF-␤ blocks NF B activation and interferes with TLR ligand-induced responses (50). Moreover, Fujita et al (36) have observed that in AADC, activation of LPS-induced signaling events involving MAPK and NF B is impaired. They have suggested that potent expression of I B proteins in AADC may suppress NF B-mediated production of proinflammatory cytokines, such as IL-12 (as shown in the present study), IL-1␤, TNF-␣, and IL-6.…”

Section: Discussionmentioning

confidence: 99%

“…The present study was prompted by recent observations that such AADC, propagated from mouse BM in IL-10 and TGF-␤ then stimulated with LPS, exhibit potent immunoregulatory properties. Thus, it has been reported that a single systemic injection of AADC can control the ability of transplanted T cells to induce lethal GVHD (34), or protect mice against lethal endotoxemia and peritonitis (36). Such potent regulatory DC appear to be more effective in controlling adverse inflammatory/ immune responses in vivo than DC conditioned in IL-10 or TGF-␤ alone, or modified to express transgenes encoding these cytokines and that exert a comparatively modest effect on allograft rejection without immunosuppression therapy (32,33,48).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, evidence has emerged that regulatory or "alternatively activated" (AA) DC, generated in IL-10 and TGF-␤1, then exposed to LPS, protect mice from lethal GVHD (34,35) or lethal endotoxemia (36). These recipient-matched DC display low levels of costimulatory molecules and impair allogeneic effector T cell functions.…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

See 4 more Smart Citations

“Alternatively Activated” Dendritic Cells Preferentially Secrete IL-10, Expand Foxp3+CD4+ T Cells, and Induce Long-Term Organ Allograft Survival in Combination with CTLA4-Ig

Lan

Wang²,

Raimondi³

et al. 2006

The Journal of Immunology

147

139

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In this study, we propagated myeloid dendritic cells (DC) from BALB/c (H2d) mouse bone marrow progenitors in IL-10 and TGF-β, then stimulated the cells with LPS. These “alternatively activated” (AA) DC expressed lower TLR4 transcripts than LPS-stimulated control DC and were resistant to maturation. They expressed comparatively low levels of surface MHC class II, CD40, CD80, CD86, and programmed death-ligand 2 (B7-DC; CD273), whereas programmed death-ligand 1 (B7-H1; CD274) and inducible costimulatory ligand expression were unaffected. AADC secreted much higher levels of IL-10, but lower levels of IL-12p70 compared with activated control DC. Their poor allogeneic (C57BL/10; B10) T cell stimulatory activity and ability to induce alloantigen-specific, hyporesponsive T cell proliferation was not associated with enhanced T cell apoptosis. Increased IL-10 production was induced in the alloreactive T cell population, wherein CD4+Foxp3+ cells were expanded. The AADC-expanded allogeneic CD4+CD25+ T cells showed enhanced suppressive activity for T cell proliferative responses compared with freshly isolated T regulatory cells. In vivo migration of AADC to secondary lymphoid tissue was not impaired. A single infusion of BALB/c AADC to quiescent B10 recipients induced alloantigen-specific hyporesponsive T cell proliferation and prolonged subsequent heart graft survival. This effect was potentiated markedly by CTLA4-Ig, administered 1 day after the AADC. Transfer of CD4+ T cells from recipients of long-surviving grafts (>100 days) that were infiltrated with CD4+Foxp3+ cells, prolonged the survival of donor-strain hearts in naive recipients. These data enhance insight into the regulatory properties of AADC and demonstrate their therapeutic potential in vascularized organ transplantation.

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Section: Discussionmentioning

confidence: 49%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Endritic Cells (Dc)mentioning

confidence: 99%

See 3 more Smart Citations

“Alternatively Activated” Dendritic Cells Preferentially Secrete IL-10, Expand Foxp3+CD4+ T Cells, and Induce Long-Term Organ Allograft Survival in Combination with CTLA4-Ig

Lan

Wang²,

Raimondi³

et al. 2006

The Journal of Immunology

147

139

View full text Add to dashboard Cite

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Suppression of Experimental Autoimmune Uveoretinitis by Regulatory Dendritic Cells in Mice

Usui

Takeuchi²,

Hattori³

et al. 2009

Arch Ophthalmol

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To examine the effects of bone marrowderived regulatory dendritic cells (DCs) with potent immunoregulatory properties on the development of experimental autoimmune uveoretinitis (EAU). Methods: Bone marrow cells obtained from C57BL/6 mice were treated with granulocyte-macrophage colonystimulating factor, transforming growth factor ␤, and interleukin (IL) 10 and stimulated with lipopolysaccharide to produce mature and regulatory DCs. Expression of major histocompatibility complex and costimulatory molecules was analyzed by flow cytometry. Then EAU was induced by immunization with human interphotoreceptor retinoid-binding protein (hIRBP) peptide 1-20, followed by intravenous injection of hIRBP peptidepulsed regulatory DCs. Control mice received transforming growth factor ␤ and IL-10 nontreated mature DC or phosphate-buffered saline. We evaluated EAU clinically and histopathologically. Immunologic responses to hIRBP peptide were assessed by delayed-type hypersensitivity and T-cell proliferation and cytokine production. Results: Regulatory DCs expressed comparable levels of major histocompatibility complex class II molecules but reduced levels of CD80, CD86, and CD40 compared with mature DCs. Delayed-type hypersensitivity to hIRBP peptide and the development of EAU were markedly suppressed in mice receiving regulatory DCs compared with control mice. Lymph node cells from regulatory DC-treated mice showed significantly reduced hIRBP-specific T-cell proliferation and interferon ␥ production but increased IL-10 production. Conclusion: Administration of regulatory DCs potentially inhibited the development of EAU. Clinical Relevance: Application of regulatory DCs may be a novel candidate for immunotherapy for human endogenous uveitis.

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Galectin‐9 expands immunosuppressive macrophages to ameliorate T‐cell‐mediated lung inflammation

et al. 2010

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Galectin-9 (Gal-9) plays pivotal roles in the modulation of innate and adaptive immunity to suppress T-cell-mediated autoimmune models. However, it remains unclear if Gal-9 plays a suppressive role for T-cell function in non-autoimmune disease models. We assessed the effects of Gal-9 on experimental hypersensitivity pneumonitis induced by Trichosporon asahii. When Gal-9 was given subcutaneously to C57BL/6 mice at the time of challenge with T. asahii, it significantly suppressed T. asahii-induced lung inflammation, as the levels of IL-1, IL-6, IFN-gamma, and IL-17 were significantly reduced in the BALF of Gal-9-treated mice. Moreover, co-culture of anti-CD3-stimulated CD4 T cells with BALF cells harvested from Gal-9-treated mice on day 1 resulted in diminished CD4 T-cell proliferation and decreased levels of IFN-gamma and IL-17. CD11b(+)Ly-6C(high)F4/80(+) BALF Mphi expanded by Gal-9 were responsible for the suppression. We further found in vitro that Gal-9, only in the presence of T. asahii, expands CD11b(+)Ly-6C(high)F4/80(+) cells from BM cells, and the cells suppress T-cell proliferation and IFN-gamma and IL-17 production. The present results indicate that Gal-9 expands immunosuppressive CD11b(+)Ly-6C(high) Mphi to ameliorate Th1/Th17 cell-mediated hypersensitivity pneumonitis.

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Regulatory dendritic cells act as regulators of acute lethal systemic inflammatory response

Cited by 123 publications

References 24 publications

“Alternatively Activated” Dendritic Cells Preferentially Secrete IL-10, Expand Foxp3+CD4+ T Cells, and Induce Long-Term Organ Allograft Survival in Combination with CTLA4-Ig

“Alternatively Activated” Dendritic Cells Preferentially Secrete IL-10, Expand Foxp3+CD4+ T Cells, and Induce Long-Term Organ Allograft Survival in Combination with CTLA4-Ig

Suppression of Experimental Autoimmune Uveoretinitis by Regulatory Dendritic Cells in Mice

Galectin‐9 expands immunosuppressive macrophages to ameliorate T‐cell‐mediated lung inflammation

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