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Carniti, Cristiana; Gimondi, Silvia; Vendramin, Antonio; Recordati, Camilla; Confalonieri, Davide; Bermema, Anisa; Corradini, Paolo; Mariotti, Jacopo

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

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  • Medientyp: E-Artikel
  • Titel: Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects
  • Beteiligte: Carniti, Cristiana; Gimondi, Silvia; Vendramin, Antonio; Recordati, Camilla; Confalonieri, Davide; Bermema, Anisa; Corradini, Paolo; Mariotti, Jacopo
  • Erschienen: American Association for Cancer Research (AACR), 2015
  • Erschienen in: Clinical Cancer Research, 21 (2015) 16, Seite 3740-3749
  • Sprache: Englisch
  • DOI: 10.1158/1078-0432.ccr-14-2758
  • ISSN: 1078-0432; 1557-3265
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Purpose: Immune-mediated graft-versus-tumor (GVT) effects can occur after allogeneic hematopoietic stem cell transplantation (HSCT), but GVT is tightly linked to its main complication, graft-versus-host disease (GVHD). Strategies aimed at modulating GVHD, while maintaining the GVT effect, are needed to improve the cure rate of transplant. Given the emerging role of Janus-activated kinase (JAK) signaling in lymphoproliferative and myeloproliferative diseases and its established function at dictating T-cell differentiation, we postulated that JAKs might be potential therapeutic targets through a pharmacologic approach.</jats:p> <jats:p>Experimental Design: We examined the effect of JAK1/JAK2 modulation by ruxolitinib in a mouse model of fully MHC mismatched bone marrow transplant comprising in vivo tumor inoculation.</jats:p> <jats:p>Results: JAK1/JAK2 inhibition by ruxolitinib improved both overall survival (P = 0.03) and acute GVHD pathologic score at target organs (P ≤ 0.001) of treated mice. In addition, treatment with ruxolitinib was associated with a preserved GVT effect, as evidenced by reduction of tumor burden (P = 0.001) and increase of survival time (P = 0.01). JAK1/JAK2 inhibition did not impair the in vivo acquisition of donor T-cell alloreactivity; this observation may account, at least in part, to the preserved GVT effect. Rather, JAK1/JAK2 inhibition of GVHD was associated with the modulation of chemokine receptor expression, which may have been one factor in the reduced infiltration of donor T cells in GVHD target organs.</jats:p> <jats:p>Conclusions: These data provide further evidence that JAK inhibition represents a new and potentially clinically relevant approach to GVHD prevention. Clin Cancer Res; 21(16); 3740–9. ©2015 AACR.</jats:p>
  • Zugangsstatus: Freier Zugang