Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pimecrolimus is a new non-steroidal inhibitor of T cell and mast cell activation. In the present study, we compared the potency of pimecrolimus and cyclosporin A (CyA) to inhibit cytokine synthesis of alloantigen-primed T cells and the expression of CD134 (OX40), an inducible co-receptor molecule thought to be critical for the survival and expansion of inflammation-mediating T cells. To mimic the physiological situation of recurrent antigenic stimulation, we have used dendritic cells (DC) as stimulators of purified CD4+ T cells in the primary and secondary allogeneic mixed lymphocyte culture (allo-MLC). Pimecrolimus inhibited surface expression of OX40 and prevented the up-regulation of CD25 and CD54 with a 10-fold higher potency compared to CyA. Similarly, 50% inhibition of allo-DC-mediated T cell proliferation by pimecrolimus was obtained at 0.55 nm, compared to about 12 nm for CyA. Furthermore, pimecrolimus blocked the increase of OX40 on primed T cells restimulated on day 10 in secondary allo-MLC. Allo-DC-primed T cells showed a restricted cytokine profile characterized by the production of TNF-alpha, IFN-gamma and IL-2 but low to undetectable levels of IL-4 and IL-10. The synthesis of TNF-alpha and IFN-gamma and the up-regulation of OX40 on T cells after secondary allogeneic stimulation were almost entirely blocked by 10 nm pimecrolimus. Taken together, pimecrolimus inhibits T cell proliferation and Th1 cytokine synthesis and also prevents the up-regulation of the OX40 co-receptor on primed T cells indicating its potential in the therapy of chronic inflammation and autoimmunity.
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PMID:Pimecrolimus inhibits up-regulation of OX40 and synthesis of inflammatory cytokines upon secondary T cell activation by allogeneic dendritic cells. 1229 57

Pimecrolimus is a calcineurin inhibitor developed for the topical therapy of inflammatory skin diseases, particularly atopic dermatitis (AD). Pimecrolimus selectively targets T cells and mast cells. Pimecrolimus inhibits T-cell proliferation, as well as production and release of interleukin-2 (IL-2), IL-4, interferon-gamma and tumour necrosis factor-alpha. Moreover, pimecrolimus inhibits mast cell degranulation. In contrast to tacrolimus, pimecrolimus has no effects on the differentiation, maturation and functions of dendritic cells. In contrast to corticosteroids, pimecrolimus does not affect endothelial cells and fibroblasts and does not induce skin atrophy. Given the low capacity of pimecrolimus to permeate through the skin, it has a very low risk of systemic exposure and subsequent systemic side-effects. In different randomised controlled trials, topical pimecrolimus as cream 1% (Elidel) has been shown to be effective, well tolerated and safe in both adults and children with mild to moderate AD. In addition, pimecrolimus has been successfully used in inflammatory skin diseases other than AD, including seborrheic dermatitis, intertriginous psoriasis, lichen planus and cutaneous lupus erythematosus.
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PMID:Pimecrolimus in dermatology: atopic dermatitis and beyond. 1603 22

Pimecrolimus, an ascomycin macrolactam derivative, is an inhibitor of T-cell and mast cell activation under development by Novartis for the potential treatment of psoriasis and allergic dermatitis. Novartis is developing both topical and oral formulations of the compound. By December 1998, the topical form of the compound was in phase III trials and the oral form was in phase II trials. Phase III trials were initiated in July 1999 for the treatment of atopic dermatitis. In December 1998, Warburg Dillon Read predicted sales of SFr 30 million in 2000 rising to SFr 184 million in 2002. In March 1999, Credit Suisse First Boston predicted sales of 10 million USD in 2001 rising to 90 million USD in 2003.
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PMID:Pimecrolimus (Novartis). 1611 91

Mast cells, the multi-functional secretory cells, are the pivotal effector cells in immune response, and contribute to the pathogenesis of many diverse diseases, like asthma and mastocytosis, by releasing numerous proinflammatory mediators. Pimecrolimus (SDZ ASM 981) is a derivative of the macrolactam ascomycin and is a member of the calcineurin inhibitor class of immunosuppressors. It inhibits the calcineurin-dependent activation of nuclear factor of activated T cells and the expression of a number of proinflammatory cytokines in turn. Pimecrolimus has high and selective anti-inflammatory activity within the skin, and with much lower potential to affect local and systemic immune responses. Therefore it has been widely used for treatment of various inflammatory skin diseases. It has a cellselective mode of action, and mast cells are its specific target cells. Pimecrolimus inhibits the release of both preformed and de novo synthesized mediators from activated mast cells and inhibits accumulation of mast cells by inducing apoptosis. Several experimental and clinical reports have demonstrated the successful application of pimecrolimus and other calcineurin inhibitors, such as tacrolimus and cyclosporine A, to treat mastocytosis, a spectrum of disorders characterized by mast cell hyperplasia, especially cutaneous mastocytosis. These new findings suggest that pimecrolimus and other calcineurin inhibitors may be a novel and effective therapeutic approach for mast cell-associated diseases such as asthma and mastocytosis.
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PMID:Mast cells as targets of pimecrolimus. 2211 44