scholarly journals The Antituberculosis Drug Pyrazinamide Affects the Course of Cutaneous Leishmaniasis In Vivo and Increases Activation of Macrophages and Dendritic Cells

2009 ◽  
Vol 53 (12) ◽  
pp. 5114-5121 ◽  
Author(s):  
Susana Mendez ◽  
Ryan Traslavina ◽  
Meleana Hinchman ◽  
Lu Huang ◽  
Patricia Green ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Interleukin 12 ◽  
Toll Like Receptor ◽  
Proinflammatory Response ◽  
Necrosis Factor Alpha ◽  
Development Of Resistance ◽  
Tuberculosis Chemotherapy

ABSTRACT Antileishmanial therapy is suboptimal due to toxicity, high cost, and development of resistance to available drugs. Pyrazinamide (PZA) is a constituent of short-course tuberculosis chemotherapy. We investigated the effect of PZA on Leishmania major promastigote and amastigote survival. Promastigotes were more sensitive to the drug than amastigotes, with concentrations at which 50% of parasites were inhibited (MIC50) of 16.1 and 8.2 μM, respectively (48 h posttreatment). Moreover, 90% of amastigotes were eliminated at 120 h posttreatment, indicating that longer treatments will result in parasite elimination. Most strikingly, PZA treatment of infected C57BL/6 mice resulted in protection against disease and in a 100-fold reduction in the parasite burden. PZA treatment of J774 cells and bone marrow-derived dendritic cells and macrophages increased interleukin 12, tumor necrosis factor alpha, and activation marker expression, as well as nitric oxide production, suggesting that PZA enhances effective immune responses against the parasite. PZA treatment also activates dendritic cells deficient in Toll-like receptor 2 and 4 expression to initiate a proinflammatory response, confirming that the immunostimulatory effect of PZA is directly caused by the drug and is independent of Toll-like receptor stimulation. These results not only are strongly indicative of the promise of PZA as an alternative antileishmanial chemotherapy but also suggest that PZA causes collateral immunostimulation, a phenomenon that has never been reported for this drug.

scholarly journals Miltefosine Efficiently Eliminates Leishmania major Amastigotes from Infected Murine Dendritic Cells without Altering Their Immune Functions

2009 ◽  
Vol 54 (2) ◽  
pp. 652-659 ◽  
Author(s):  
Klaus Griewank ◽  
Caroline Gazeau ◽  
Andreas Eichhorn ◽  
Esther von Stebut
Keyword(s):  
Dendritic Cells ◽  
Leishmania Major ◽  
Interleukin 12 ◽  
Immune Functions ◽  
Necrosis Factor Alpha ◽  
Mhc Ii ◽  
Intracellular Parasites ◽  
Factor Alpha

ABSTRACT As a treatment for leishmaniasis, miltefosine exerts direct toxic effects on the parasites. Miltefosine also modulates immune cells such as macrophages, leading to parasite elimination via oxidative radicals. Dendritic cells (DC) are critical for initiation of protective immunity against Leishmania through induction of Th1 immunity via interleukin 12 (IL-12). Here, we investigated the effects of miltefosine on DC in Leishmania major infections. When cocultured with miltefosine for 4 days, the majority of in vitro-infected DC were free of parasites. Miltefosine treatment did not influence DC maturation (upregulation of major histocompatibility complex II [MHC II] or costimulatory molecules, e.g., CD40, CD54, and CD86) or significantly alter cytokine release (IL-12, tumor necrosis factor alpha [TNF-α], or IL-10). Further, miltefosine DC treatment did not alter antigen presentation, since unrestricted antigen-specific proliferation of CD4+ and CD8+ T cells was observed upon stimulation with miltefosine-treated, infected DC. In addition, miltefosine application in vivo did not lead to maturation/emigration of skin DC. DC NO− production, a mechanism used by phagocytes to rid themselves of intracellular parasites, was also unaltered upon miltefosine treatment. Our data confirm prior studies indicating that in contrast to, e.g., pentavalent antimonials, miltefosine functions independently of the immune system, mostly through direct toxicity against the Leishmania parasite.

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 Rotavirus Infection Activates Dendritic Cells from Peyer's Patches in Adult Mice

2009 ◽  
Vol 84 (4) ◽  
pp. 1856-1866 ◽  
Author(s):  
Delia V. Lopez-Guerrero ◽  
Selene Meza-Perez ◽  
Oscar Ramirez-Pliego ◽  
Maria A. Santana-Calderon ◽  
Pavel Espino-Solis ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Cell Number ◽  
Peyer's Patches ◽  
Interleukin 12 ◽  
Peyer’S Patches ◽  
Necrosis Factor Alpha ◽  
Activation Markers ◽  
Rotavirus Infection

ABSTRACT This study used an in vivo mouse model to analyze the response of dendritic cells (DCs) in Peyer's patches (PPs) within the first 48 h of infection with the wild-type murine rotavirus EDIM (EDIMwt). After the infection, the absolute number of DCs was increased by 2-fold in the PPs without a modification of their relative percentage of the total cell number. Also, the DCs from PPs of infected mice showed a time-dependent migration to the subepithelial dome (SED) and an increase of the surface activation markers CD40, CD80, and CD86. This response was more evident at 48 h postinfection (p.i.) and depended on viral replication, since DCs from PPs of mice inoculated with UV-treated virus did not show this phenotype. As a result of the activation, the DCs showed an increase in the expression of mRNA for the proinflammatory cytokines interleukin-12/23p40 (IL-12/23p40), tumor necrosis factor alpha (TNF-α), and beta interferon (IFN-β), as well as for the regulatory cytokine IL-10. These results suggest that, a short time after rotavirus infection, the DCs from PPs play a critical role in controlling the infection and, at the same time, avoiding an excessive inflammatory immune response.

scholarly journals Cholera Toxin and Heat-Labile Enterotoxin Activate Human Monocyte-Derived Dendritic Cells and Dominantly Inhibit Cytokine Production through a Cyclic AMP-Dependent Pathway

2002 ◽  
Vol 70 (10) ◽  
pp. 5533-5539 ◽  
Author(s):  
Kenneth C. Bagley ◽  
Sayed F. Abdelwahab ◽  
Robert G. Tuskan ◽  
Timothy R. Fouts ◽  
George K. Lewis
Keyword(s):  
Dendritic Cells ◽  
Cyclic Amp ◽  
Cholera Toxin ◽  
Human Monocyte ◽  
Cell Types ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Heat Labile

ABSTRACT Cholera toxin (CT) and heat-labile enterotoxin (LT) are powerful mucosal adjuvants whose cellular targets and mechanism of action are unknown. There is emerging evidence that dendritic cells (DC) are one of the principal cell types that mediate the adjuvant effects of these toxins in vivo. Here we investigate the effects of CT and LT on the maturation of human monocyte-derived DC (MDDC) in vitro. We found that an enzymatically active A domain is necessary for both CT and LT to induce the maturation of MDDC and that this activation is strictly cyclic AMP (cAMP) dependent. ADP-ribosylation-defective derivatives of these toxins failed to induce maturation of MDDC, whereas dibutyryl-cyclic-3′,5′-AMP and Forskolin mimic the maturation of MDDC induced by CT and LT. In addition, an inhibitor of cAMP-dependent kinases, Rp-8-Br-cAMPs, blocked the ability of CT, LT, and Forskolin to activate MDDC. CT, LT, dibutyryl-cyclic-3′,5′-AMP, and Forskolin also dominantly inhibit interleukin 12 and tumor necrosis factor alpha production by MDDC in the presence of saturating concentrations of lipopolysaccharide. Taken together, these results show that the effects of CT and LT on MDDC are mediated by cAMP.

scholarly journals Unconventional Maturation of Dendritic Cells Induced by Particles from the Laminated Layer of Larval Echinococcus granulosus

2014 ◽  
Vol 82 (8) ◽  
pp. 3164-3176 ◽  
Author(s):  
Cecilia Casaravilla ◽  
Álvaro Pittini ◽  
Dominik Rückerl ◽  
Paula I. Seoane ◽  
Stephen J. Jenkins ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Echinococcus Granulosus ◽  
Thick Layer ◽  
Host Cells ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
The Impact ◽  
Laminated Layer

ABSTRACTThe larval stage of the cestode parasiteEchinococcus granulosuscauses hydatid disease in humans and livestock. This infection is characterized by the growth in internal organ parenchymae of fluid-filled structures (hydatids) that elicit surprisingly little inflammation in spite of their massive size and persistence. Hydatids are protected by a millimeter-thick layer of mucin-based extracellular matrix, termed the laminated layer (LL), which is thought to be a major factor determining the host response to the infection. Host cells can interact both with the LL surface and with materials that are shed from it to allow parasite growth. In this work, we analyzed the response of dendritic cells (DCs) to microscopic pieces of the native mucin-based gel of the LL (pLL).In vitro, this material induced an unusual activation state characterized by upregulation of CD86 without concomitant upregulation of CD40 or secretion of cytokines (interleukin 12 [IL-12], IL-10, tumor necrosis factor alpha [TNF-α], and IL-6). When added to Toll-like receptor (TLR) agonists, pLL-potentiated CD86 upregulation and IL-10 secretion while inhibiting CD40 upregulation and IL-12 secretion.In vivo, pLL also caused upregulation of CD86 and inhibited CD40 upregulation in DCs. Contrary to expectations, oxidation of the mucin glycans in pLL with periodate did not abrogate the effects on cells. Reduction of disulfide bonds, which are known to be important for LL structure, strongly diminished the impact of pLL on DCs without altering the particulate nature of the material. In summary, DCs respond to the LL mucin meshwork with a “semimature” activation phenotype, bothin vitroandin vivo.

scholarly journals Interleukin 12 is effective treatment for an established systemic intracellular infection: experimental visceral leishmaniasis.

1995 ◽  
Vol 181 (1) ◽  
pp. 387-391 ◽  
Author(s):  
H W Murray ◽  
J Hariprashad
Keyword(s):  
Cell Response ◽  
Leishmania Major ◽  
Acquired Resistance ◽  
Interleukin 12 ◽  
Th1 Cell ◽  
Necrosis Factor Alpha ◽  
Ifn Gamma ◽  
Intracellular Infection ◽  
Clear Cut

When administered at or near the initiation of experimental intracellular infection caused by Leishmania major, Toxoplasma gondii, or Cryptococcus neoformans, treatment with the immuno-regulatory cytokine interleukin 12 (IL-12), induces protective antimicrobial activity. In contrast, once infections are established, IL-12 exerts considerably less or no effect in the face of a suppressive Th2 cell-associated response (L. major) or rapidly progressive fatal infection (T. gondii). To test the efficacy of IL-12 in an established intracellular protozoal infection but under quite different immunologic conditions (Th1 cell response, acquired resistance), L. donovani-infected BALB/c mice were treated starting 2 wk after challenge coincident with the onset of the Th1 cell response. In this environment, 7 d of IL-12 treatment reduced liver parasite burdens by 47%, an effect comparable to that induced by exogenous interferon (IFN) gamma. The in vivo mechanism responsive to IL-12 was complex, and required both CD4+ and CD8+ T cells as well as natural killer cells and the action of multiple endogenous antileishmanial cytokines (IFN-gamma, IL-2, tumor necrosis factor alpha). Early treatment with IL-12 before the expression of the Th1 cell response was also effective and induced an accelerated, near-cure response via an IFN-gamma-dependent mechanism. These results extend the antimicrobial-inducing capacity of IL-12 beyond prophylaxis by indicating that IL-12 can exert clear-cut therapeutic activity in an established intracellular infection.

scholarly journals Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 635-643 ◽  
Author(s):  
Masashi Ohtani ◽  
Shigenori Nagai ◽  
Shuhei Kondo ◽  
Shinta Mizuno ◽  
Kozue Nakamura ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Leishmania Major ◽  
Glycogen Synthase ◽  
Active Form ◽  
Mammalian Target Of Rapamycin ◽  
Glycogen Synthase Kinase ◽  
Target Of Rapamycin ◽  
Glycogen Synthase Kinase 3 ◽  
Interleukin 12

AbstractPhosphoinositide 3-kinase (PI3K) negatively regulates Toll-like receptor (TLR)–mediated interleukin-12 (IL-12) expression in dendritic cells (DCs). We show here that 2 signaling pathways downstream of PI3K, mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 (GSK3), differentially regulate the expression of IL-12 in lipopolysaccharide (LPS)–stimulated DCs. Rapamycin, an inhibitor of mTOR, enhanced IL-12 production in LPS-stimulated DCs, whereas the activation of mTOR by lentivirus-mediated transduction of a constitutively active form of Rheb suppressed the production of IL-12. The inhibition of protein secretion or deletion of IL-10 cancelled the effect of rapamycin, indicating that mTOR regulates IL-12 expression through an autocrine action of IL-10. In contrast, GSK3 positively regulates IL-12 production through an IL-10–independent pathway. Rapamycin-treated DCs enhanced Th1 induction in vitro compared with untreated DCs. LiCl, an inhibitor of GSK3, suppressed a Th1 response on Leishmania major infection in vivo. These results suggest that mTOR and GSK3 pathways regulate the Th1/Th2 balance though the regulation of IL-12 expression in DCs. The signaling pathway downstream of PI3K would be a good target to modulate the Th1/Th2 balance in immune responses in vivo.

scholarly journals WDFY4 is required for cross-presentation in response to viral and tumor antigens

Science ◽  
2018 ◽  
Vol 362 (6415) ◽  
pp. 694-699 ◽  
Author(s):  
Derek J. Theisen ◽  
Jesse T. Davidson ◽  
Carlos G. Briseño ◽  
Marco Gargaro ◽  
Elvin J. Lauron ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Antigens ◽  
Critical Role ◽  
Tumor Rejection ◽  
Interleukin 12 ◽  
Cross Presentation ◽  
Histocompatibility Complex ◽  
Crispr Screen

During the process of cross-presentation, viral or tumor-derived antigens are presented to CD8+ T cells by Batf3-dependent CD8α+/XCR1+ classical dendritic cells (cDC1s). We designed a functional CRISPR screen for previously unknown regulators of cross-presentation, and identified the BEACH domain–containing protein WDFY4 as essential for cross-presentation of cell-associated antigens by cDC1s in mice. However, WDFY4 was not required for major histocompatibility complex class II presentation, nor for cross-presentation by monocyte-derived dendritic cells. In contrast to Batf3–/– mice, Wdfy4–/– mice displayed normal lymphoid and nonlymphoid cDC1 populations that produce interleukin-12 and protect against Toxoplasma gondii infection. However, similar to Batf3–/– mice, Wdfy4–/– mice failed to prime virus-specific CD8+ T cells in vivo or induce tumor rejection, revealing a critical role for cross-presentation in antiviral and antitumor immunity.

scholarly journals Cross-reactive, natural IgG recognizing L. major promote parasite internalization by dendritic cells and promote protective immunity

2021 ◽  
Author(s):  
Filiz Dermicik ◽  
Susanna Lopez Kostka ◽  
Stefan Tenzer ◽  
Ari Waisman ◽  
Esther Von Stebut
Keyword(s):  
Dendritic Cells ◽  
B Cell ◽  
Protective Immunity ◽  
Normal Mouse ◽  
Leishmania Major ◽  
Mouse Serum ◽  
List Type ◽  
Susceptibility To Infection ◽  
Large Numbers

Abstract In cutaneous leishmaniasis, infection of dendritic cells (DC) is essential for generation of T cell-dependent protective immunity. DC acquires Leishmania major through Fc receptor (FcR)-mediated uptake of complexes comprising antibodies bound to parasites. We now assessed the development of the initial B cell and DC response to the parasite itself and if natural IgG play a role. L. major parasites display large numbers of phospholipids on their surface. Parasites were opsonized with normal mouse serum (NMS), or serum containing anti-phospholipid IgG (PL). We found that L. major bound to PL which significantly enhanced parasite phagocytosis by DC as compared to NMS. Similar results were obtained with cross-reactive human PL antibodies using myeloid primary human DC. In addition, mice infected with PL-opsonized parasites showed significantly improved disease outcome compared to mice infected with NMS-opsonized parasites. Finally, IgMi mice, which produce membrane-bound IgM only and no secreted antibodies, displayed increased susceptibility to infection as compared to wild types. Interestingly, once NMS was administered to IgMi mice, their phenotype was normalized to that of wild types. Upon incubation with IgG-opsonized parasite (IgG derived from infected mice or using PL antibodies), also the IgMi mice were able to show superior immunity. Our findings suggest that “natural” cross-reactive antibodies (e.g., anti-PL Ab) in NMS bind to pathogens to facilitate phagocytosis, which leads to induction of protective immunity via preferential DC infection. Prior L. major-specific B cell-priming does not seem to be absolutely required to facilitate clearance of this important human pathogen in vivo. Key messages We found that anti-phospholipid (anti-PL) antibodies enhance phagocytosis of L. major by DCs. We also found that normal mouse sera have natural antibodies that can imitate PL specific antibodies. Using different genetically modified mice, we found that these antibodies can be IgG, not only IgM.

scholarly journals Expression of Inducible Nitric Oxide Synthase in Skin Lesions of Patients with American Cutaneous Leishmaniasis

2002 ◽  
Vol 70 (8) ◽  
pp. 4638-4642 ◽  
Author(s):  
Muna Qadoumi ◽  
Inge Becker ◽  
Norbert Donhauser ◽  
Martin Röllinghoff ◽  
Christian Bogdan
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Cutaneous Leishmaniasis ◽  
Leishmania Donovani ◽  
Leishmania Major ◽  
Parasite Burden ◽  
Skin Lesions ◽  
And Function ◽  
Oxide Synthase

ABSTRACT Cytokine-inducible (or type 2) nitric oxide synthase (iNOS) is indispensable for the resolution of Leishmania major or Leishmania donovani infections in mice. In contrast, little is known about the expression and function of iNOS in human leishmaniasis. Here, we show by immunohistological analysis of skin biopsies from Mexican patients with local (LCL) or diffuse (DCL) cutaneous leishmaniasis that the expression of iNOS was most prominent in LCL lesions with small numbers of parasites whereas lesions with a high parasite burden (LCL or DCL) contained considerably fewer iNOS-positive cells. This is the first study to suggest an antileishmanial function of iNOS in human Leishmania infections in vivo.

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