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

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

Author information

1
Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL 12902; brian.betts@moffitt.org yux@musc.edu.
2
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425.
3
Department of Medicine, Medical University of South Carolina, Charleston, SC 29425.
4
Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL 12902.
5
BioSeek, DiscoverX, South San Francisco, CA 94080.
6
CTI BioPharma, Seattle, WA 98121.
7
Institute of Hematology, Peking University People's Hospital, Beijing, China.
8
Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901.
9
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; brian.betts@moffitt.org yux@musc.edu.

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).

KEYWORDS:

GVHD; GVL; JAK2; graft rejection

PMID:
29382747
PMCID:
PMC5816153
DOI:
10.1073/pnas.1712452115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of interest statement: B.C.B. has participated in advisory boards related to pacritinib (CTI BioPharma) and ruxolitinib (Incyte) in GVHD. J.S. is employed by CTI BioPharma with related equity ownership. A.O. is an employee at BioSeek. All other authors have no competing financial interests to declare.

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