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In vitro prediction of in vivo pseudo-allergenic response via MRGPRX2.
John, Linu M; Dalsgaard, Charlotte M; Jeppesen, Claus B; Conde-Frieboes, Kilian W; Baumann, Katrine; Knudsen, Niels P H; Skov, Per S; Wulff, Birgitte S.
Afiliación
  • John LM; Global Research, Novo Nordisk A/S, Maaloev, Denmark.
  • Dalsgaard CM; Global Research, Novo Nordisk A/S, Maaloev, Denmark.
  • Jeppesen CB; Global Research, Novo Nordisk A/S, Maaloev, Denmark.
  • Conde-Frieboes KW; Global Research, Novo Nordisk A/S, Maaloev, Denmark.
  • Baumann K; RefLab ApS, Copenhagen N, Denmark.
  • Knudsen NPH; RefLab ApS, Copenhagen N, Denmark.
  • Skov PS; RefLab ApS, Copenhagen N, Denmark.
  • Wulff BS; Odense Research Center of Anaphylaxis, Odense University Hospital, Odense, Denmark.
J Immunotoxicol ; 18(1): 30-36, 2021 12.
Article en En | MEDLINE | ID: mdl-33570451
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degranulación de la Célula / Receptores de Neuropéptido Tipo de estudio: Prognostic_studies / Risk_factors_studies Aspecto: Ethics Límite: Animals / Humans Idioma: En Revista: J Immunotoxicol Asunto de la revista: ALERGIA E IMUNOLOGIA / TOXICOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Degranulación de la Célula / Receptores de Neuropéptido Tipo de estudio: Prognostic_studies / Risk_factors_studies Aspecto: Ethics Límite: Animals / Humans Idioma: En Revista: J Immunotoxicol Asunto de la revista: ALERGIA E IMUNOLOGIA / TOXICOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Dinamarca Pais de publicación: Reino Unido