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

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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).

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
Externally published	Yes

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. The Flow Cytometry, University of South Florida (USF) Comparative Medicine and Vivarium, Analytic Microscopy, and Tissue Cores at Moffitt/USF were utilized in completing this work. The core facilities are supported partially by the Moffitt Cancer Center Support Grant P30-CA076292. This work was supported by Grants R01 CA143812 and CA169116 (to X.-Z.Y.) and Grants K08 HL11654701A1 and R01 HL133823 (to B.C.B.) from the National Institutes of Health.

Publisher Copyright:
© 2018 National Academy of Sciences.All Rights Reserved.

Keywords

GVHD
GVL
Graft rejection
JAK2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816153

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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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N1 - Funding Information: ACKNOWLEDGMENTS. The Flow Cytometry, University of South Florida (USF) Comparative Medicine and Vivarium, Analytic Microscopy, and Tissue Cores at Moffitt/USF were utilized in completing this work. The core facilities are supported partially by the Moffitt Cancer Center Support Grant P30-CA076292. This work was supported by Grants R01 CA143812 and CA169116 (to X.-Z.Y.) and Grants K08 HL11654701A1 and R01 HL133823 (to B.C.B.) from the National Institutes of Health. Publisher Copyright: © 2018 National Academy of Sciences.All Rights Reserved.

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

Abstract

Bibliographical note

Keywords

UN SDGs

Access

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