In vitro treatment of dendritic cells with tacrolimus: impaired T-cell activation and IP-10 expression

Tiefenthaler, Martin; Hofer, Susanne; Ebner, Susanne; Ivarsson, Lennart; Neyer, Susanne; Herold, Manfred; Mayer, Gert; Fritsch, Peter; Heufler, Christine

doi:10.1093/ndt/gfg594

Cited by 29 publications

(22 citation statements)

References 27 publications

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“…Both MHC class II restricted and non-restricted antigen presentation was strongly inhibited by tacrolimus. It has been suggested earlier that tacrolimus inhibits the T cell stimulatory capacity of DCs [16–18]. Here we show that this concept can be extended to non-classical ways of lipid antigen presentation.…”

Section: Discussionsupporting

confidence: 67%

Local Immune Regulation of Mucosal Inflammation by Tacrolimus

et al. 2009

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PurposeTacrolimus is a potent immunomodulator that is effective in the treatment of inflammatory bowel disease (IBD). However, potential toxicity and systemic effects with oral intake limit its use. Local tacrolimus treatment is effective in a subgroup of proctitis patients. This study aimed to evaluate whether colonic mucosal immune cells are susceptible to locally applied tacrolimus in vitro. Our in vivo studies aimed at evaluating whether local tacrolimus treatment in mice would bring about local immune suppression and to compare colonic and systemic tacrolimus levels after locally and systemically applied tacrolimus.ResultsIn vitro tacrolimus inhibited the activation of multiple cell types present in colonic tissue; lamina propria T cells, NKT cells, and both classical- and non- classical antigen presenting cells. However, the cytokine production of epithelial cells was not inhibited by tacrolimus at these concentrations. After rectal administration in mice, tacrolimus blood levels were comparable to those obtained by oral intake. However, rectally treated mice exhibited a 14-fold higher concentration of tacrolimus within their colonic tissue than orally treated mice. Moreover, rectally applied tacrolimus resulted in a local but not a systemic immune suppression in mice.ConclusionsTacrolimus inhibits activation of several pivotal immune cells of the intestinal mucosa. Murine studies indicate that colonic application of tacrolimus induces local rather than systemic immune suppression.

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Section: Discussionsupporting

confidence: 67%

Local Immune Regulation of Mucosal Inflammation by Tacrolimus

et al. 2009

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“…It was reported that FK506 at very low concentrations (2·4 nmol L −1 ) was capable of modulating immune cells including T cells 8 . As the pathogenesis of vitiligo involves autoimmune mechanisms, suppression of T cells may also participate in the repigmentation of vitiligo.…”

Section: Discussionmentioning

confidence: 99%

FK506 increases pigmentation and migration of human melanocytes

Kang

Choi

2006

British Journal of Dermatology

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SummaryBackground Topical tacrolimus (FK506) is a potential therapeutic option for vitiligo management. Despite its clinical efficacy, the underlying mechanism of how topical tacrolimus induces repigmentation in vitiligo has scarcely been investigated. Objectives To investigate the direct effects of FK506 on pigmentation and migration of human melanocytes. Methods Cell proliferation was measured using a Coulter counter. The effects on pigmentation were investigated by measuring melanin contents, tyrosinase activity and tyrosinase expression. To determine the effects of FK506 on cell migration, we performed scratch assays and Boyden chamber assays. Results FK506 treatment increased melanin contents, although there was an inhibitory effect on growth of melanocytes. The increase of pigmentation was due to the result of the stimulatory action of FK506 on tyrosinase activity and its expression, which eventually led to melanin biosynthesis. Furthermore, cell migration was enhanced by FK506 treatment. Conclusions These findings provide in vitro evidence demonstrating direct effects of FK506 on pigmentation and melanocyte migration and may provide a possible mechanism for the effect of tacrolimus in vitiligo.

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“…However, such DCs displayed a reduced allostimulatory capacity and IL-12 production, and skewed CD4+ T cells towards a Th2-like response [49]. In a recent study, FK506-treated DCs produced less IP-10 (CXCL10), which is known to be involved in allograft rejection [50].…”

Section: Calcineurin Inhibitors and Dcsmentioning

confidence: 99%

Regulation of Dendritic Cell Function with Immunomodulatory Drugs

Mohty¹,

Gaugler²,

Mami³

et al. 2005

CMCAIAA

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Dendritic cells (DC) represent a sentinel-like system with the capacity to capture and process antigens, to migrate into secondary lymphoid organs, and to activate naive T lymphocytes. DCs are considered as important elements in the induction of specific immune responses. The potency of DCs for induction of immune responses can be affected by a number of aspects related to their maturation stage and state of activation. For a long time, the critical role of DCs in many clinical situations was underscored. DCs in vivo might represent a favored target for immune tolerance (cancer) or immune activation (auto-immune diseases and allergic hypersensitivity). For immunotherapeutic applications, it is crucial to identify factors and agents that might affect the differentiation, maturation and function of DCs. This review will focus on the impact of the most widely used immunomodulatory drugs in the clinical setting on the properties and functions of DCs. The modulation and manipulation of DC functions through exposure of DCs to immunomodulatory agents both in vitro and in vivo is an approach that could result in therapeutic benefit in many clinical situations.

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In vitro treatment of dendritic cells with tacrolimus: impaired T-cell activation and IP-10 expression

Abstract: Tacrolimus treatment reduces the ability of DC to stimulate T cells and the impaired production of DC-derived IP-10 (CXCL10) and IL-12 might play a role in the immunosuppressive action of tacrolimus.

Cited by 29 publications

References 27 publications

Local Immune Regulation of Mucosal Inflammation by Tacrolimus

Local Immune Regulation of Mucosal Inflammation by Tacrolimus

FK506 increases pigmentation and migration of human melanocytes

Regulation of Dendritic Cell Function with Immunomodulatory Drugs

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