title: Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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/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.
  
  
  CONCLUSIONS
  These data provide further evidence that JAK inhibition represents a new and potentially clinically relevant approach to GVHD prevention.
authors.affiliation: Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Carniti
authors.affiliation: Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gimondi
authors.affiliation: Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vendramin
authors.affiliation: Mouse and Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Recordati
authors.affiliation: Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Confalonieri
authors.affiliation: Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Anisa
authors.initials: A
authors.lastname: Bermema
authors.affiliation: Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Chair of Hematology, Università degli Studi di Milano, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Corradini
authors.affiliation: Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. jacopo.mariotti@istitutotumori.mi.it.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Mariotti
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D009570:Nitriles; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2