Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation

Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):1582-1587. doi: 10.1073/pnas.1712452115. Epub 2018 Jan 30.


Janus kinase 2 (JAK2) signal transduction is a critical mediator of the immune response. JAK2 is implicated in the onset of graft-versus-host disease (GVHD), which is a significant cause of transplant-related mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Transfer of JAK2-/- donor T cells to allogeneic recipients leads to attenuated GVHD yet maintains graft-versus-leukemia. Th1 differentiation among JAK2-/- T cells is significantly decreased compared with wild-type controls. Conversely, iTreg and Th2 polarization is significantly increased among JAK2-/- T cells. Pacritinib is a multikinase inhibitor with potent activity against JAK2. Pacritinib significantly reduces GVHD and xenogeneic skin graft rejection in distinct rodent models and maintains donor antitumor immunity. Moreover, pacritinib spares iTregs and polarizes Th2 responses as observed among JAK2-/- T cells. Collectively, these data clearly identify JAK2 as a therapeutic target to control donor alloreactivity and promote iTreg responses after allo-HCT or solid organ transplantation. As such, a phase I/II acute GVHD prevention trial combining pacritinib with standard immune suppression after allo-HCT is actively being investigated (

Keywords: GVHD; GVL; JAK2; graft rejection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation*
  • Female
  • Graft vs Host Disease / genetics
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / prevention & control
  • Graft vs Leukemia Effect / genetics
  • Graft vs Leukemia Effect / immunology*
  • Janus Kinase 2 / physiology*
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Primary Myelofibrosis / genetics
  • Primary Myelofibrosis / immunology*
  • Primary Myelofibrosis / prevention & control
  • Skin Transplantation
  • T-Lymphocytes / immunology*
  • Th2 Cells / immunology*
  • Xenograft Model Antitumor Assays


  • Jak2 protein, mouse
  • Janus Kinase 2

Associated data