TY - JOUR
T1 - Pharmacologic inhibition of JAK1/JAK2 signaling reduces Experimental murine acute GVHD while preserving GVT effects
AU - Carniti, Cristiana
AU - Gimondi, Silvia
AU - Vendramin, Antonio
AU - Recordati, Camilla
AU - Confalonieri, Davide
AU - Bermema, Anisa
AU - Corradini, Paolo
AU - Mariotti, Jacopo
PY - 2015/8/15
Y1 - 2015/8/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-14-2758
DO - 10.1158/1078-0432.CCR-14-2758
M3 - Article
C2 - 25977345
AN - SCOPUS:84942850964
VL - 21
SP - 3740
EP - 3749
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 16
ER -