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

Brian C. Betts, David Bastian, Supinya Iamsawat, Hung Nguyen, Jessica L. Heinrichs, Yongxia Wu, Anusara Daenthanasanmak, Anandharaman Veerapathran, Alison O’Mahony, Kelly Walton, Jordan Reff, Pedro Horna, Elizabeth M. Sagatys, Marie C. Lee, Jack Singer, Ying Jun Chang, Chen Liu, Joseph Pidala, Claudio Anasetti, Xue Zhong Yu

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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 (https://clinicaltrials.gov/ct2/show/NCT02891603).

Original languageEnglish (US)
Pages (from-to)1582-1587
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number7
DOIs
StatePublished - Feb 13 2018
Externally publishedYes

Keywords

  • GVHD
  • GVL
  • Graft rejection
  • JAK2

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    Betts, B. C., Bastian, D., Iamsawat, S., Nguyen, H., Heinrichs, J. L., Wu, Y., Daenthanasanmak, A., Veerapathran, A., O’Mahony, A., Walton, K., Reff, J., Horna, P., Sagatys, E. M., Lee, M. C., Singer, J., Chang, Y. J., Liu, C., Pidala, J., Anasetti, C., & Yu, X. Z. (2018). Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation. Proceedings of the National Academy of Sciences of the United States of America, 115(7), 1582-1587. https://doi.org/10.1073/pnas.1712452115