In vitro prediction of in vivo pseudo-allergenic response via MRGPRX2

Autor:	Charlotte M. Dalsgaard, Katrine Baumann, Niels Peter Hell Knudsen, Kilian Conde-Frieboes, Linu M. John, Claus Bekker Jeppesen, Per Stahl Skov, Birgitte Schjellerup Wulff
Jazyk:	angličtina
Rok vydání:	2021
Předmět:	Immunology Peptide Immunotoxicology 010501 environmental sciences Pharmacology Biology Toxicology 01 natural sciences 03 medical and health sciences In vivo RA1190-1270 030304 developmental biology 0105 earth and related environmental sciences chemistry.chemical_classification 0303 health sciences pseudo-allergenic response injection site reactions RC581-607 drug development 3r In vitro immunotoxicology Drug development chemistry mrgprx2 Toxicology. Poisons Immunologic diseases. Allergy
Zdroj:	Journal of Immunotoxicology, Vol 18, Iss 1, Pp 30-36 (2021) John, L M, Dalsgaard, C M, Jeppesen, C B, Conde-Frieboes, K W, Baumann, K, Knudsen, N P H, Skov, P S & Wulff, B S 2021, ' In vitro prediction of in vivo pseudo-allergenic response via MRGPRX2 ', Journal of Immunotoxicology, vol. 18, no. 1, pp. 30-36 . https://doi.org/10.1080/1547691X.2021.1877375
ISSN:	1547-6901
DOI:	10.1080/1547691X.2021.1877375
Popis:	In development of peptide therapeutics, rodents are commonly-used preclinical models when screening compounds for efficacy endpoints in the early stages of discovery projects. During the screening process, some peptides administered subcutaneously to rodents caused injection site reactions manifesting as localized swelling. Screening by postmortem evaluations of injection site swelling as a marker for local subcutaneous histamine release, were conducted in rats to select drug candidates without this adverse effect. Histological analysis of skin samples revealed that the injection site reactions were concurrent with mast cell degranulation, resulting in histamine release. Mast cell activation can be mediated by MRGPRX2, a GPCR that induces a pseudo-allergenic immune response. The present study demonstrates that a commercially-available cell-based MRGPRX2 assay reliably identifies compounds that induce histamine release or localized edema in ex vivo human and rodent skin samples. In vitro screening was subsequently implemented using the MRGPRX2 assay as a substitute for postmortem injection site evaluation, thus achieving a significant reduction in animal use. Thus, in cases where injection site reactions are encountered during in vivo screening, to enable faster screening during the early drug discovery process, an MRGPRX2 in vitro assay can be used as an efficient, more ethical tool with human translational value for the development of safer pharmacotherapies for patients.
Databáze:	OpenAIRE
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