scholarly journals Immunomodulatory drugs suppress Th1-inducing ability of dendritic cells but enhance Th2-mediated allergic responses

2020 ◽  
Vol 4 (15) ◽  
pp. 3572-3585
Author(s):  
Vien Phan ◽  
Tomoki Ito ◽  
Muneo Inaba ◽  
Yoshiko Azuma ◽  
Kayoko Kibata ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Interleukin 12 ◽  
Immunomodulatory Drugs ◽  
Myeloid Dendritic Cells ◽  
Th2 Response ◽  
Cell Responses ◽  
Th2 Cell ◽  
Ox40 Ligand ◽  
Ligand Expression ◽  
Good Partial Response

Abstract Immunomodulatory drugs (IMiDs), lenalidomide and pomalidomide, are widely used treatments for multiple myeloma; however, they occasionally lead to episodes of itchy skin and rashes. Here, we analyzed the effects of IMiDs on human myeloid dendritic cells (mDCs) as major regulators of Th1 or Th2 responses and the role they play in allergy. We found that lenalidomide and pomalidomide used at clinical concentrations did not affect the survival or CD86 and OX40-ligand expression of blood mDCs in response to lipopolysaccharide (LPS) and thymic stromal lymphopoietin (TSLP) stimulation. Both lenalidomide and pomalidomide dose-dependently inhibited interleukin-12 (IL-12) and TNF production and STAT4 expression, and enhanced IL-10 production in response to LPS. When stimulated with TSLP, both IMiDs significantly enhanced CCL17 production and STAT6 and IRF4 expression and promoted memory Th2-cell responses. In 46 myeloma patients, serum CCL17 levels at the onset of lenalidomide-associated rash were significantly higher than those without rashes during lenalidomide treatment and those before treatment. Furthermore, serum CCL17 levels in patients who achieved a very good partial response (VGPR) were significantly higher compared with a less than VGPR during lenalidomide treatment. The median time to next treatment was significantly longer in lenalidomide-treated patients with rashes than those without. Collectively, IMiDs suppressed the Th1-inducing capacity of DCs, instead promoting a Th2 response. Thus, the lenalidomide-associated rashes might be a result of an allergic response driven by Th2-axis activation. Our findings suggest clinical efficacy and rashes as a side effect of IMiDs are inextricably linked through immunostimulation.

Morin Promotes the Production of Th2 Cytokine by Modulating Bone Marrow-Derived Dendritic Cells

2006 ◽  
Vol 34 (04) ◽  
pp. 667-684 ◽  
Author(s):  
Chia-Yang Li ◽  
Jau-Ling Suen ◽  
Bor-Luen Chiang ◽  
Pei-Dawn Lee Chao ◽  
Shih-Hua Fang
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Dendritic Cells ◽  
Interleukin 12 ◽  
Th2 Response ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Th Differentiation ◽  
Th1 And Th2 Responses

Our previous studies had reported that morin decreased the interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-α) production in lipopolysaccharide (LPS)-activated macrophages, suggesting that morin may promote helper T type 2 (Th2) response in vivo. Dendritic cells (DCs) are the most potent antigen presenting cells and known to play a major role in the differentiation of helper T type 1 (Th1) and Th2 responses. This study aimed to reveal whether morin is able to control the Th differentiation through modulating the maturation and functions of DCs. Bone marrow-derived dendritic cells (BM-DCs) were incubated with various concentrations of morin and their characteristics were studied. The results indicated that morin significantly affects the phenotype and cytokine expression of BM-DCs. Morin reduced the production of IL-12 and TNF-α in BM-DCs, in response to LPS stimulation. In addition, the proliferative response of stimulated alloreactive T cells was significantly decreased by morin in BM-DCs. Furthermore, allogeneic T cells secreted higher IL-4 and lower IFN-γ in response to morin in BM-DCs. In conclusion, these results suggested that morin favors Th2 cell differentiation through modulating the maturation and function of BM-DCs.

scholarly journals Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Kun He ◽  
Angela Hettinga ◽  
Sagar Laxman Kale ◽  
Sanmei Hu ◽  
Markus M. Xie ◽  
...  
Keyword(s):  
Allergic Airway Inflammation ◽  
Cell Development ◽  
Th2 Cells ◽  
Th2 Response ◽  
Cell Responses ◽  
Th2 Cell ◽  
Th2 Immune Response ◽  
Upstream Promoter ◽  
Gata3 Expression ◽  
Anti Inflammatory Cytokine

A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung to inhaled but not systemically delivered allergens but is dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, leading to increased GATA3 expression in lung Th2 cells. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to up-regulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10–STAT3–Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.

scholarly journals Intra-articular CD1c-expressing myeloid dendritic cells from rheumatoid arthritis patients express a unique set of T cell-attracting chemokines and spontaneously induce Th1, Th17 and Th2 cell activity

2013 ◽  
Vol 15 (5) ◽  
pp. R155 ◽  
Author(s):  
Frederique M Moret ◽  
Cornelis E Hack ◽  
Kim MG van der Wurff-Jacobs ◽  
Wilco de Jager ◽  
Timothy RDJ Radstake ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Activity ◽  
Myeloid Dendritic Cells ◽  
Th2 Cell

scholarly journals Blimp-1 is essential for Th2 cell development and allergic asthma

2019 ◽  
Author(s):  
Kun He ◽  
Angela Hettinga ◽  
Sagar Laxman Kale ◽  
Sanmei Hu ◽  
Markus M. Xie ◽  
...  
Keyword(s):  
Transcriptional Repressor ◽  
Allergic Airway Inflammation ◽  
Cell Development ◽  
Th2 Cells ◽  
Th2 Response ◽  
Cell Responses ◽  
Th2 Cell ◽  
Th2 Immune Response ◽  
Upstream Promoter ◽  
Gata3 Expression

AbstractA Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung, but dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, which is necessary to drive GATA3 expression. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to upregulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.SummaryThe transcriptional repressor Blimp-1 acts via a pro-inflammatory IL-10-STAT3 axis as a critical positive regulator of Th2 cells in the lung in response to allergens driving pathophysiology associated with asthma disease.

scholarly journals Migratory CD103+ dendritic cells suppress helminth-driven type 2 immunity through constitutive expression of IL-12

2015 ◽  
Vol 213 (1) ◽  
pp. 35-51 ◽  
Author(s):  
Bart Everts ◽  
Roxane Tussiwand ◽  
Leentje Dreesen ◽  
Keke C. Fairfax ◽  
Stanley Ching-Cheng Huang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Constitutive Expression ◽  
Helminth Parasites ◽  
Th2 Response ◽  
Heligmosomoides Polygyrus ◽  
Th2 Cell ◽  
Type 2 Immunity ◽  
Necessary And Sufficient

CD8α+ and CD103+ dendritic cells (DCs) play a central role in the development of type 1 immune responses. However, their role in type 2 immunity remains unclear. We examined this issue using Batf3−/− mice, in which both of these DC subsets are missing. We found that Th2 cell responses, and related events such as eosinophilia, alternative macrophage activation, and immunoglobulin class switching to IgG1, were enhanced in Batf3−/− mice responding to helminth parasites. This had beneficial or detrimental consequences depending on the context. For example, Batf3 deficiency converted a normally chronic intestinal infection with Heligmosomoides polygyrus into an infection that was rapidly controlled. However, liver fibrosis, an IL-13–mediated pathological consequence of wound healing in chronic schistosomiasis, was exacerbated in Batf3−/− mice infected with Schistosoma mansoni. Mechanistically, steady-state production of IL-12 by migratory CD103+ DCs, independent of signals from commensals or TLR-initiated events, was necessary and sufficient to exert the suppressive effects on Th2 response development. These findings identify a previously unrecognized role for migratory CD103+ DCs in antagonizing type 2 immune responses.

Differentiation of myeloid dendritic cells into CD8α-positive dendritic cells in vivo

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1865-1872 ◽  
Author(s):  
Miriam Merad ◽  
Lawrence Fong ◽  
Jakob Bogenberger ◽  
Edgar G. Engleman
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Wild Type Mouse ◽  
Interleukin 12 ◽  
Myeloid Dendritic Cells ◽  
Myeloid Antigens

Bone marrow-derived dendritic cells (DC) represent a family of antigen-presenting cells (APC) with varying phenotypes. For example, in mice, CD8α+ and CD8α− DC are thought to represent cells of lymphoid and myeloid origin, respectively. Langerhans cells (LC) of the epidermis are typical myeloid DC; they do not express CD8α, but they do express high levels of myeloid antigens such as CD11b and FcγR. By contrast, thymic DC, which derive from a lymphoid-related progenitor, express CD8α but only low levels of myeloid antigens. CD8α+ DC are also found in the spleen and lymph nodes (LN), but the origin of these cells has not been determined. By activating and labeling CD8α− epidermal LC in vivo, it was found that these cells expressed CD8α on migration to the draining LN. Similarly, CD8α− LC generated in vitro from a CD8 wild-type mouse and injected into the skin of a CD8αKO mouse expressed CD8α when they reached the draining LN. The results also show that CD8α+ LC are potent APC. After migration from skin, they localized in the T-cell areas of LN, secreted high levels of interleukin-12, interferon-γ, and chemokine-attracting T cells, and they induced antigen-specific T-cell activation. These results demonstrate that myeloid DC in the periphery can express CD8α when they migrate to the draining LN. CD8α expression on these DC appears to reflect a state of activation, mobilization, or both, rather than lineage.

Enhancing the immunostimulatory function of dendritic cells by transfection with mRNA encoding OX40 ligand

Blood ◽  
2005 ◽  
Vol 105 (8) ◽  
pp. 3206-3213 ◽  
Author(s):  
Jens Dannull ◽  
Smita Nair ◽  
Zhen Su ◽  
David Boczkowski ◽  
Christian DeBeck ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Human Monocyte ◽  
Interleukin 12 ◽  
T Helper ◽  
Cell Responses ◽  
Mrna Transfection

Abstract The objective of this study was to investigate whether the immunostimulatory properties of human monocyte-derived dendritic cells (DCs) could be enhanced by triggering OX40/OX40L signaling. Since monocyte-derived DCs possess only low-cell surface levels of OX40L in the absence of CD40 signaling, OX40L was expressed by transfection of DCs with the corresponding mRNA. We show that OX40L mRNA transfection effectively enhanced the immunostimulatory function of DCs at multiple levels: OX40L mRNA transfection augmented allogeneic and HLA class II epitope-specific CD4+ T-cell responses, improved the stimulation of antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without interfering with the prostaglandin E2 (PGE2)–mediated migratory function of the DCs, and facilitated interleukin 12 p70 (IL-12p70)–independent T helper type 1 (Th1) polarization of naive CD4+ T-helper cells. Furthermore, vaccination of tumor-bearing mice using OX40L mRNA–cotransfected DCs resulted in significant enhancement of therapeutic antitumor immunity due to in vivo priming of Th1-type T-cell responses. Our data suggest that transfection of DCs with OX40L mRNA may represent a promising strategy that could be applied in clinical immunotherapy protocols, while circumventing the current unavailability of reagents facilitating OX40 ligation.

scholarly journals Paramyxovirus Infection Regulates T Cell Responses by BDCA-1+ and BDCA-3+ Myeloid Dendritic Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e99227 ◽  
Author(s):  
Meera R. Gupta ◽  
Deepthi Kolli ◽  
Claudio Molteni ◽  
Antonella Casola ◽  
Roberto P. Garofalo
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Myeloid Dendritic Cells ◽  
Cell Responses

scholarly journals Interferon-α and interleukin-12 are induced, respectively, by double-stranded DNA and single-stranded RNA in human myeloid dendritic cells

Immunology ◽  
2010 ◽  
Vol 132 (2) ◽  
pp. 165-173 ◽  
Author(s):  
Yuichi Katashiba ◽  
Rie Miyamoto ◽  
Akira Hyo ◽  
Keiko Shimamoto ◽  
Naoko Murakami ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Interleukin 12 ◽  
Interferon Α ◽  
Myeloid Dendritic Cells ◽  
Double Stranded Dna

scholarly journals Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells

2013 ◽  
Vol 81 (4) ◽  
pp. 1064-1077 ◽  
Author(s):  
Adriana Pina ◽  
Eliseu Frank de Araujo ◽  
Maíra Felonato ◽  
Flávio V. Loures ◽  
Claudia Feriotti ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Responses ◽  
Effector T Cells ◽  
Interleukin 12 ◽  
Content Type ◽  
Cell Responses ◽  
Plasmacytoid Dcs

ABSTRACTThe protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response toParacoccidioides brasiliensisinfection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified thatP. brasiliensisinfection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-β, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane-bound transforming growth factor β was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis.

Sign in / Sign up

Export Citation Format

Share Document