Pimecrolimus and tacrolimus differ in their inhibition of lymphocyte activation during the sensitization phase of contact hypersensitivity

Bavandi, A.; Fahrngruber, Hermann; Aschauer, Heinrich; Hartmann, Boris; Meingassner, Josef G.; Kalthoff, Frank

doi:10.1016/j.jdermsci.2006.04.001

Cited by 10 publications

(7 citation statements)

References 24 publications

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“…This is in agreement with in vivo animal studies indicating that systemic tacrolimus treatment of mice interferes with lymphocyte activation and affects draining lymph node hyperplasia during sensitization with the contact allergen oxazolone [48] . Hence, the DC-based in vitro assay presented in the current study can be regarded as a suitable tool for further immunopharmacological investigations of antigen-presenting cells as emerging targets of immunosuppressive drugs, particularly calcineurin inhibitors.…”

Section: Discussionsupporting

confidence: 91%

Tacrolimus Modulates Dendritic Cell Activation in the Sensitization Phase of Allergic Contact Dermatitis

Ott

Baron

Heise

et al. 2010

Skin Pharmacol Physiol

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Background: Knowledge of the effect of topically applied calcineurin antagonists such as tacrolimus on the sensitization phase of allergic contact dermatitis is currently limited. Objective: To investigate tacrolimus-dependent immunomodulation on gene expression alterations in human antigen-presenting cells which are stimulated with small-molecular-weight contact allergens. Methods: Monocyte-derived dendritic cells (moDC) and THP-1 cells were stimulated with the contact sensitizer cinnamic aldehyde (CAld) and compared with the very strong experimental sensitizer 2,4,6-trinitrobenzene sulfonic acid (TNBS) in vitro. Quantitative PCR analysis was used to detect gene expression changes, particularly of interleukin (IL) 8, as an indicator of differential dendritic cell (DC) gene expression after sensitizer stimulation in the absence or presence of tacrolimus and betamethasone at two different concentrations. Results: DC activation was clearly demonstrated by a significant IL-8 upregulation after 24 h, whereas tacrolimus or betamethasone alone did not affect IL-8 baseline expression. Betamethasone and, to a lesser extent, tacrolimus led to a marked reduction of chemical-induced IL-8 expression by TNBS and CAld. Conclusion: The results of the present study support the hypothesis that the calcineurin inhibitor tacrolimus has modulatory effects on human antigen-presenting cells during the sensitization phase of allergic contact dermatitis. In addition, moDC as well as THP-1 cells may serve as a system to study immune-modulating effects of drugs such as glucocorticoids or calcineurin antagonists.

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Section: Discussionsupporting

confidence: 91%

Tacrolimus Modulates Dendritic Cell Activation in the Sensitization Phase of Allergic Contact Dermatitis

Ott

Baron

Heise

et al. 2010

Skin Pharmacol Physiol

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“…Despite a high degree of structural similarity ( Fig. 1), pimecrolimus and tacrolimus display characteristic differences in terms of pharmacological profile (Stuetz et al, 2001;Meingassner et al, 2003;Grassberger et al, 2004;Bavandi et al, 2006;Kalthoff et al, 2007), and physicochemical and pharmacokinetic properties. Regarding physicochemical properties, the higher lipophilicity of pimecrolimus is noteworthy: pimecrolimus features an 8-fold higher octanol-water distribution coefficient than tacrolimus (Billich et al, 2004).…”

mentioning

confidence: 99%

Binding of Pimecrolimus and Tacrolimus to Skin and Plasma Proteins: Implications for Systemic Exposure after Topical Application

Weiss

Fresneau²,

Moenius³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Pimecrolimus and tacrolimus are calcineurin inhibitors used for the topical treatment of atopic dermatitis. Although structurally similar, they display specific differences including higher lipophilicity and lower skin permeation of pimecrolimus. The aim of the present study was to understand the reason for the differences in skin permeation; in addition, plasma protein binding of the two drugs was analyzed side by side as a basis for comparison of systemic exposure to free drug. Permeation of pimecrolimus and tacrolimus through a silicon membrane was found to be similar; therefore, we assumed that differences in skin permeation could be caused by differences in affinity to skin components. To test this hypothesis, we investigated binding of pimecrolimus and tacrolimus to a preparation of soluble human skin proteins. One binding protein of approximately 15 kDa, probably corresponding to macrophilin12, displayed a similar binding capacity for pimecrolimus and tacrolimus. However, less specific, nonsaturating binding to other proteins was approximately 3-fold higher for pimecrolimus. Because of the high local drug concentration after topical administration, the unspecific, high-capacity binding is probably dominating the permeation through skin. In plasma both drugs bound predominantly to lipoproteins, which may affect disposition differently from albumin binding. The unbound fraction of pimecrolimus in human plasma was approximately 9-fold lower compared with that of tacrolimus (0.4 ؎ 0.1 versus 3.7 ؎ 0.8%). In conclusion, these results provide an explanation for the observed lower systemic exposure to pimecrolimus than to tacrolimus after topical application and suggest that differences in systemic exposure to free drug might be even more pronounced.

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“…While oral administration of tacrolimus inhibited the sensitization phase in mice, pimecrolimus was ineffective. In contrast, both drugs were able to prevent elicitation due to inhibition of lymphocyte activation [77] . Other treatment strategies try to interfere with the crucial innate immune response by dampening inflammation.…”

Section: Treatment Options In Acdmentioning

confidence: 85%

Chemical-Induced Contact Hypersensitivity in the Mouse Model

Martin¹

2007

Drug Hypersensitivity

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Hypersensitivity reactions to drugs most commonly manifest in skin. Like chemical-or metal ion-induced allergic contact dermatitis and contact hypersensitivity, most acute adverse drug reactions are mediated by cytotoxic T cells and controlled by immunosuppressive regulatory T cells. In both cases, progress has been made in the identification of the recognition structures for T cells and of the effector and regulatory mechanisms of disease, especially with respect to the adaptive immune response. However, a crucial, yet poorly understood event in these hypersensitivities is the activation of the innate immune system and the subsequent induction and polarization of the adaptive immune response. Recent findings in this field using the mouse contact hypersensitivity model will be discussed here. Future challenges are similar for the management of drug-and chemical-induced hypersensitivities. Thus, great efforts are being made to develop reliable in vitro assay systems for predictive risk assessment. The success of this research in assay development is tightly linked to progress in basic research that will not only lead to a more detailed understanding of the pathomechanisms, but also to the development of new treatments for these clinically and economically increasingly important hypersensitivity reactions.

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Pimecrolimus and tacrolimus differ in their inhibition of lymphocyte activation during the sensitization phase of contact hypersensitivity

Cited by 10 publications

References 24 publications

Tacrolimus Modulates Dendritic Cell Activation in the Sensitization Phase of Allergic Contact Dermatitis

Tacrolimus Modulates Dendritic Cell Activation in the Sensitization Phase of Allergic Contact Dermatitis

Binding of Pimecrolimus and Tacrolimus to Skin and Plasma Proteins: Implications for Systemic Exposure after Topical Application

Chemical-Induced Contact Hypersensitivity in the Mouse Model

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