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

doi:10.1073/pnas.1712452115

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

28 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 language	English (US)
Pages (from-to)	1582-1587
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1712452115
State	Published - Feb 13 2018

Keywords

GVHD
GVL
Graft rejection
JAK2

ASJC Scopus subject areas

General

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10.1073/pnas.1712452115

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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

Betts, BC, Bastian, D, Iamsawat, S, Nguyen, H, Heinrichs, JL, Wu, Y, Daenthanasanmak, A, Veerapathran, A, O’Mahony, A, Walton, K, Reff, J, Horna, P, Sagatys, EM, Lee, MC, Singer, J, Chang, YJ, Liu, C, Pidala, J, Anasetti, C & Yu, XZ 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, vol. 115, no. 7, pp. 1582-1587. https://doi.org/10.1073/pnas.1712452115

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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).",

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AU - Betts, Brian C.

AU - Bastian, David

AU - Iamsawat, Supinya

AU - Nguyen, Hung

AU - Heinrichs, Jessica L.

AU - Wu, Yongxia

AU - Daenthanasanmak, Anusara

AU - Veerapathran, Anandharaman

AU - O’Mahony, Alison

AU - Walton, Kelly

AU - Reff, Jordan

AU - Horna, Pedro

AU - Sagatys, Elizabeth M.

AU - Lee, Marie C.

AU - Singer, Jack

AU - Chang, Ying Jun

AU - Liu, Chen

AU - Pidala, Joseph

AU - Anasetti, Claudio

AU - Yu, Xue Zhong

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N2 - 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).

AB - 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).

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

Abstract

Keywords

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