Pharmacologic inhibition of JAK1/JAK2 signaling reduces Experimental murine acute GVHD while preserving GVT effects

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

Research output: Contribution to journalArticlepeer-review

Abstract

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. 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. 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/JAK2inhibitiondidnotimpair the in vivo acquisition of donor T-cell alloreactivity; this observation may account, at least in part, to the preserved GVT effect. Rather, JAK1/JAK2inhibition of GVHD was associated with the modulation of chemokine receptor expression, whichmay have been one factor in the reduced infiltration of donor T cells in GVHD target organs. Conclusions: These data provide further evidence that JAK inhibition represents a new and potentially clinically relevant approach to GVHD prevention.

Original languageEnglish
Pages (from-to)3740-3749
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number16
DOIs
Publication statusPublished - Aug 15 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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