WF10 Stimulates NK Cell Cytotoxicity by Increasing LFA‐1‐Mediated Adhesion to Tumor Cells

Kühne, Louisa; Konstandin, Mathias; Samstag, Yvonne; Meuer, Stefan; Giese, Thomas; Watzl, Carsten

doi:10.1155/2011/436587

Cited by 7 publications

(9 citation statements)

References 19 publications

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“…A significant reduction of CTL-mediated killing could be observed from 200 μ M WF-10 and above, which are considered therapeutic concentrations. 20 , 22 To scrutinize whether a similar result could be achieved with another pro-oxidative reagent, namely H 2 O 2 , we incubated CTLs with 50 μ M of H 2 O 2 prior to the redirected killing assay ( Supplementary Figure S2A ). For comparison, we treated the cells with the reducing agent N -acetylcysteine (NAC).…”

Section: Resultsmentioning

confidence: 99%

“… 16 It is known to inhibit proliferation and IL-2 production of CD3-stimulated PBMC, 18 while innate immunity by macrophages and NK cells was rather enhanced. 19 , 20 On the contrary to other reactive oxygen species (ROS), for example, H 2 O 2 , WF-10 can be intravenously injected. It was initially developed to control wound healing and opportunistic infections during acquired immunodeficiency syndrome.…”

Section: Introductionmentioning

confidence: 99%

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The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

Wabnitz

Balta

Schindler

et al. 2016

Cell Death Discovery

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Cytotoxic T-cells (CTLs) play an important role in many immune-mediated inflammatory diseases. Targeting cytotoxicity of CTLs would allow to interfere with immune-mediated tissue destruction. Here we demonstrate that WF-10, a pro-oxidative compound, inhibits CTL-mediated cytotoxicity. WF-10 did not influence early steps of target-cell killing, but impaired the ability of CTLs to detach from the initial target cell and to move to a second target cell. This reduced serial killing was accompanied by stronger enrichment of the adhesion molecule LFA-1 in the cytolytic immune synapse. LFA-1 clustering requires activation of the actin-bundling protein L-plastin and was accordingly diminished in L-plastin knockdown cells. Interestingly, WF-10 likely acts through regulating L-plastin: (I) It induced L-plastin activation through phosphorylation leading to enhanced LFA-1-mediated cell adhesion, and, importantly, (II) WF-10 lost its influence on target-cell killing in L-plastin knockdown cells. Finally, we demonstrate that WF-10 can improve immunosuppression by conventional drugs. Thus, while cyclosporine A alone had no significant effect on cytotoxicity of CTLs, a combination of cyclosporine A and WF-10 blocked target-cell killing synergistically. Together, our findings suggest that WF-10 – either alone or in combination with conventional immunosuppressive drugs – may be efficient to control progression of diseases, in which CTLs are crucially involved.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

Wabnitz

Balta

Schindler

et al. 2016

Cell Death Discovery

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“…Although the oxidative processes and molecular mechanisms underlying these findings have not yet been defined in detail, pharmaceutical NaClO 2 clearly promotes cell proliferation, hematopoiesis, and microcirculatory blood and oxygen supply, modulates the functions of immune cells, and limits inflammatory responses [40]–[44].…”

Section: Introductionmentioning

confidence: 99%

Rapid Healing of Cutaneous Leishmaniasis by High-Frequency Electrocauterization and Hydrogel Wound Care with or without DAC N-055: A Randomized Controlled Phase IIa Trial in Kabul

et al. 2014

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BackgroundAnthroponotic cutaneous leishmaniasis (CL) due to Leishmania (L.) tropica infection is a chronic, frequently disfiguring skin disease with limited therapeutic options. In endemic countries healing of ulcerative lesions is often delayed by bacterial and/or fungal infections. Here, we studied a novel therapeutic concept to prevent superinfections, accelerate wound closure, and improve the cosmetic outcome of ACL.Methodology/Principal FindingsFrom 2004 to 2008 we performed a two-armed, randomized, double-blinded, phase IIa trial in Kabul, Afghanistan, with patients suffering from L. tropica CL. The skin lesions were treated with bipolar high-frequency electrocauterization (EC) followed by daily moist-wound-treatment (MWT) with polyacrylate hydrogel with (group I) or without (group II) pharmaceutical sodium chlorite (DAC N-055). Patients below age 5, with facial lesions, pregnancy, or serious comorbidities were excluded. The primary, photodocumented outcome was the time needed for complete lesion epithelialization. Biopsies for parasitological and (immuno)histopathological analyses were taken prior to EC (1st), after wound closure (2nd) and after 6 months (3rd). The mean duration for complete wound closure was short and indifferent in group I (59 patients, 43.1 d) and II (54 patients, 42 d; p = 0.83). In patients with Leishmania-positive 2nd biopsies DAC N-055 caused a more rapid wound epithelialization (37.2 d vs. 58.3 d; p = 0.08). Superinfections occurred in both groups at the same rate (8.8%). Except for one patient, reulcerations (10.2% in group I, 18.5% in group II; p = 0.158) were confined to cases with persistent high parasite loads after healing. In vitro, DAC N-055 showed a leishmanicidal effect on pro- and amastigotes.Conclusions/SignificanceCompared to previous results with intralesional antimony injections, the EC plus MWT protocol led to more rapid wound closure. The tentatively lower rate of relapses and the acceleration of wound closure in a subgroup of patients with parasite persistence warrant future studies on the activity of DAC N-055.Trial RegistrationClinicalTrails.gov NCT00947362

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“…In macrophages, WF10 is known to decrease the expression of TNFα [11], to diminish the antigen presentation that diminishes Tcell proliferation [21,22], and to enhance the interaction with fibroblasts [11]. WF10 inactivates AIDS viruses [10,23], enhances the cytotoxicity of natural killer cells [24], and prolongs cardiac graft survival in a rodent xenotransplantation model [25]. Further, the application of WF10 attenuates the disease state in radiation-associated tissue damage [12,26,27], in diabetic foot ulcera [13], and in wound healing [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, WF10 is a promising tool to inhibit proinflammatory states of immune cells. By general inhibition of macrophage activation in the presence of inflammatory mediators, WF10 affects not only the activation state of these key immune cells but also the interaction of macrophages with T-cells, fibroblasts, and other cells at inflammatory sites [11,21,22,24]. Many diseases are accompanied by long-lasting chronic inflammations with disturbed processes of immune regulation.…”

Section: Discussionmentioning

confidence: 99%

Effects of WF10 on Glycosaminoglycan Sulphation in Proinflammatory Monocytes and Macrophages

Schönberg¹,

Schlorke²,

Arnhold³

2016

Flow Cytometry - Select Topics

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The chlorite-based drug solution WF has been successfully applied to dampen strong inflammatory disease states and to improve wound healing processes. However, the molecular mechanisms of this drug are not well understood. This study is directed to investigate how WF and its components affect the expression of surface markers and sulphated proteoglycans and glycosaminoglycans in proinflammatorystimulated monocytes and macrophages.Human blood-derived macrophages were cultivated from monocytes in the presence of U/ml granulocyte-macrophage colony-stimulating factor and activated by a mixture of ng/ml lipopolysaccharide LPS and ng/ml interferon γ IFNγ . These cells were identified and characterised by their specific cell-surface receptors CD , CD , CD , CD , CD , and CD using flow cytometry approaches. The sulphation level of proteoglycans and glycosaminoglycans was assessed by the Blyscan™ dye-binding assay. The expression of the surface marker CD , a proteoglycan with sulphated glycosaminoglycan side chains, was followed by antibodies against CD . The binding of fluorescence-labelled hyaluronan to CD was also investigated by flow cytometry. All analyses were performed after incubation of monocytes and macrophages with WF or with its main components chlorite and chlorate.The drug substance WF inhibited the activation of LPS/IFNγ-stimulated human monocyte-derived macrophages. Among them are the diminished expression of proinflammatory surface markers, the inhibition of the expression of the hyaluronan receptor CD , and the binding of hyaluronan to CD . Further, the overall amount of sulphated proteoglycans and glycosaminoglycans was down-regulated by WF . These in vitro experiments indicate that WF is able to inhibit the proinflammatory activation of macrophages. The results suggested that chlorite is the active principle in WF as chlorite caused principally the same changes in targets as WF . The WF component chlorate inhibited only the overall sulphation level of proteoglycans and glycosaminoglycans and the binding of hyaluronan to CD .

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WF10 Stimulates NK Cell Cytotoxicity by Increasing LFA‐1‐Mediated Adhesion to Tumor Cells

Cited by 7 publications

References 19 publications

The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

The pro-oxidative drug WF-10 inhibits serial killing by primary human cytotoxic T-cells

Rapid Healing of Cutaneous Leishmaniasis by High-Frequency Electrocauterization and Hydrogel Wound Care with or without DAC N-055: A Randomized Controlled Phase IIa Trial in Kabul

Effects of WF10 on Glycosaminoglycan Sulphation in Proinflammatory Monocytes and Macrophages

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