The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils

Zuberbier, Torsten; Chong, Sie-Uen; Grunow, Karl; Guhl, Sven; Welker, Pia; Grassberger, Maximilian A.; Henz, Beate M.

doi:10.1067/mai.2001.116865

Cited by 105 publications

(71 citation statements)

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“…Pimecrolimus represents a clinically established treatment option for atopic dermatitis, and was previously found by us to interfere with Fc"RI-mediated activation of skMCs. 12) As shown in Fig. 3, pimecrolimus suppressed histamine release in SCFþIL-4 cultured skMCs in a clearly dose-dependent fashion.…”

Section: 2)mentioning

confidence: 91%

“…6,11) The expression level and function of Fc"RI in skMCs from different human subjects are highly variable, and on average only about 15-25% of histamine is released upon Fc"RI cross-linking in freshly purified skMCs. 10,12,13) To be suitable for pharmacological testing of anti-allergic drugs, MCs should display vigorous Fc"RI mediated responses. It would likewise be advantageous to have MCs available that are tissuederived, non-transformed, and of human origin, but which can be expanded in culture to overcome the limitations in cell numbers pertinent to human MC research.…”

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confidence: 99%

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Long-Term Cultured Human Skin Mast Cells Are Suitable for Pharmacological Studies of Anti-Allergic Drugs Due to High Responsiveness to FcεRI Cross-Linking

Guhl

Artuc

Neou

et al. 2011

Bioscience, Biotechnology, and Biochemistry

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Human skin mast cells proliferated in the presence of interleukin (IL)-4þSCF (expanding 18-fold in 8 weeks) and acquired profound responsiveness towards high affinity IgE receptor (Fc"RI) cross-linking, liberating about 75% of their histamine. In a proof-of-concept, we found that these cells are useful for pharmacological testing. Even a subtle inhibition of degranulation can be visualized. This model might prove valuable in tests of novel anti-allergic drugs.Key words: mast cells; allergy; IgE receptor; drug testing Allergic diseases are on the increase worldwide and now affect about 30% of the Western population. 1,2) Mast cells (MCs) are major effector cells of allergic reactions by virtue of their high affinity IgE receptor (Fc"RI).3) During an allergic episode, MC-bound IgE becomes cross-linked by a multivalent allergen, leading to immediate release and de novo synthesis of various mediators. 4) MCs are divergent and differ not only across species, but also depending on the tissue context. Interleukin-4 (IL-4), the signature cytokine of Th2 cells, is intimately associated with the allergic phenotype. 5) In the MC lineage, however, IL-4 can exert opposing effects depending on the MC subset under study, e.g., proliferation of intestinal human MCs, but growth arrest and apoptosis in transformed MC lines, in differentiating cord-blood derived MCs and (IL-6 depleted) lung MCs. [6][7][8][9] Although of hematopoietic origin, MCs complete their maturation in tissues from which they need to be extracted for research purposes, a costly procedure which is moreover associated with limitations in obtainable cell numbers. Having established a technique to purify MCs to homogeneity from human skin, we have observed that IL-4 prolongs the survival of skin-derived MCs (skMCs). 8,10) It is unknown, however, whether IL-4 can promote skMC proliferation, and whether IL-4 treated skMCs increase in responsiveness towards Fc"RI aggregation, as found for several types of MCs. 6,11) The expression level and function of Fc"RI in skMCs from different human subjects are highly variable, and on average only about 15-25% of histamine is released upon Fc"RI cross-linking in freshly purified skMCs. 10,12,13) To be suitable for pharmacological testing of anti-allergic drugs, MCs should display vigorous Fc"RI mediated responses. It would likewise be advantageous to have MCs available that are tissuederived, non-transformed, and of human origin, but which can be expanded in culture to overcome the limitations in cell numbers pertinent to human MC research.Hence we addressed the question whether skMCs can be induced to proliferate in a long-term culture system by the addition of stem cell factor (SCF) and IL-4. To this end, skMCs were isolated from human breast skin tissue, essentially as described elsewhere.10) The skin was obtained from cosmetic breast reduction surgeries, with the informed consent of the patients and approval by the ethics committee of the Charité Universitätsme-dizin Berlin. The skin was cut into strips and treated with di...

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Section: 2)mentioning

confidence: 91%

mentioning

confidence: 99%

Long-Term Cultured Human Skin Mast Cells Are Suitable for Pharmacological Studies of Anti-Allergic Drugs Due to High Responsiveness to FcεRI Cross-Linking

Guhl

Artuc

Neou

et al. 2011

Bioscience, Biotechnology, and Biochemistry

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“…Cells, 2 ϫ 10 6 , were incubated in medium containing 1% BSA, 25 ng/ml PMA (Sigma), and 250 nM of the calcium ionophore A23187 (Sigma). Isolated skin mast cells were stimulated in Tyrode's buffer (10 mM HEPES, 130 mM NaCl, 5 mM KCl, 1.4 mM CaCl 2 , 1 mM MgCl 2 , 5.6 mM glucose, and 0.1% BSA) containing anti-IgE at a dilution of 1:20,000 (CalbiochemNovabiochem, Bad Soden, Germany) or substance P (10 M; Sigma), with cells at a density of 5 ϫ 10 5 /ml in 24-well plates (Greiner, Germany) (14,21). Plates were incubated for 30 min at 37°C in 5% CO 2 /95% air.…”

Section: Cell Stimulationmentioning

confidence: 99%

LAMP‐1 and LAMP‐2, but not LAMP‐3, are reliable markers for activation‐induced secretion of human mast cells

et al. 2004

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BackgroundMast cells are resident tissue cells that induce anaphylactic reactions by rapidly releasing mediators after antigen‐mediated cross‐linking of immunoglobulin E receptors. In the similarly active peripheral blood basophilic leukocyte, lysosome‐associated membrane protein 3 (LAMP‐3; CD63) has been described as an activation marker, but LAMPs have not been investigated in normal tissue mast cells.MethodsIntra‐ and extracellular expressions of LAMP‐1 (CD107a), LAMP‐2 (CD107b), and LAMP‐3 (CD63) were analysed by flow cytometry, immunocytochemistry, and functional assays in unstimulated and stimulated leukemic human mast cell line 1 (HMC‐1) and skin mast cells.ResultsOn flow cytometry, all mast cells expressed LAMP‐3 at their cell membranes, whereas LAMP‐1 and LAMP‐2 were barely detectable (HMC‐1 cells) or expressed at low levels (<10% of skin mast cells). After fixation and permeabilisation, high intracellular levels of all three LAMPs were noted in both cell types. After stimulation, a rapid translocation of intracellular LAMPs to the cell membrane, with an associated release of histamine, leukotriene C4 and prostaglandin D2, was ascertained in skin mast cells only.ConclusionThese results show that LAMP‐1 and LAMP‐2 are activation markers for normal mast cells. The lack of LAMP translocation after activation of leukemic mast cells may be related to maturation or malignancy‐associated defects of these cells. © 2004 Wiley‐Liss, Inc.

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“…Both tacrolimus and pimecrolimus selectively inhibit the activation of T cells. 74,75 T cells play a key role in the characteristic inflammation of the skin in eczema. Pimecrolimus has also been trialled as an oral treatment for eczema, which is discussed later in this review (see Chapter 11).…”

Section: Introductionmentioning

confidence: 99%

Scoping systematic review of treatments for eczema

Nankervis

Kim

Delamere

et al. 2016

Programme Grants Appl Res

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BackgroundEczema is a very common chronic inflammatory skin condition.ObjectivesTo update the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) systematic review of treatments for atopic eczema, published in 2000, and to inform health-care professionals, commissioners and patients about key treatment developments and research gaps.Data sourcesElectronic databases including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Skin Group Specialised Register, Latin American and Caribbean Health Sciences Literature (LILACS), Allied and Complementary Medicine Database (AMED) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from the end of 2000 to 31 August 2013. Retrieved articles were used to identify further randomised controlled trials (RCTs).Review methodsStudies were filtered according to inclusion criteria and agreed by consensus in cases of uncertainty. Abstracts were excluded and non-English-language papers were screened by international colleagues and data were extracted. Only RCTs of treatments for eczema were included, as other forms of evidence are associated with higher risks of bias. Inclusion criteria for studies included availability of data relevant to the therapeutic management of eczema; mention of randomisation; comparison of two or more treatments; and prospective data collection. Participants of all ages were included. Eczema diagnosis was determined by a clinician or according to published diagnostic criteria. The risk of bias was assessed using the Cochrane Collaboration risk-of-bias tool. We used a standardised approach to summarising the data and the assessment of risk of bias and we made a clear distinction between what the studies found and our own interpretation of study findings.ResultsOf 7198 references screened, 287 new trials were identified spanning 92 treatments. Trial reporting was generally poor (randomisation method: 2% high, 36% low, 62% unclear risk of bias; allocation concealment: 3% high, 15% low, 82% unclear risk of bias; blinding of the intervention: 15% high, 28% low, 57% unclear risk of bias). Only 22 (8%) trials were considered to be at low risk of bias for all three criteria. There was reasonable evidence of benefit for the topical medications tacrolimus, pimecrolimus and various corticosteroids (with tacrolimus superior to pimecrolimus and corticosteroids) for both treatment and flare prevention; oral ciclosporin; oral azathioprine; narrow band ultraviolet B (UVB) light; Atopiclair™ and education. There was reasonable evidence to suggest no clinically useful benefit for twice-daily compared with once-daily topical corticosteroids; corticosteroids containing antibiotics for non-infected eczema; probiotics; evening primrose and borage oil; ion-exchange water softeners; protease inhibitor SRD441 (Serentis Ltd); furfuryl palmitate in emollient; cipamfylline cream; andMycobacterium vaccaevaccine. Additional research evidence is needed for emollients, bath additives, antibacterials, specialist clothing and complementary and alternative therapies. There was no RCT evidence for topical corticosteroid dilution, impregnated bandages, soap avoidance, bathing frequency or allergy testing.LimitationsThe large scope of the review coupled with the heterogeneity of outcomes precluded formal meta-analyses. Our conclusions are still limited by a profusion of small, poorly reported studies.ConclusionsAlthough the evidence base of RCTs has increased considerably since the last NIHR HTA systematic review, the field is still severely hampered by poor design and reporting problems including failure to register trials and declare primary outcomes, small sample size, short follow-up duration and poor reporting of risk of bias. Key areas for further research identified by the review include the optimum use of emollients, bathing frequency, wash products, allergy testing and antiseptic treatments. Perhaps the greatest benefit identified is the use of twice weekly anti-inflammatory treatment to maintain disease remission. More studies need to be conducted in a primary care setting where most people with eczema are seen in the UK. Future studies need to use the same core set of outcomes that capture patient symptoms, clinical signs, quality of life and the chronic nature of the disease.FundingThe National Institute for Health Research Programme Grants for Applied Research programme.

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The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils

Cited by 105 publications

References 28 publications

Long-Term Cultured Human Skin Mast Cells Are Suitable for Pharmacological Studies of Anti-Allergic Drugs Due to High Responsiveness to FcεRI Cross-Linking

Long-Term Cultured Human Skin Mast Cells Are Suitable for Pharmacological Studies of Anti-Allergic Drugs Due to High Responsiveness to FcεRI Cross-Linking

LAMP‐1 and LAMP‐2, but not LAMP‐3, are reliable markers for activation‐induced secretion of human mast cells

Scoping systematic review of treatments for eczema

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