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

Abstract

<p id="d7423793e444">Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality among allogeneic stem-cell transplantation recipients. An effort to identify selective immune suppression whereby GVHD is reduced and the antitumor activity of the graft is preserved is key to improving the success of blood and marrow transplantation. Here we demonstrate that inhibition of Janus kinase 2 (JAK2) significantly decreases GVHD and maintains tumor killing by the donor T cells. Pharmacologic blockade of JAK1 and JAK2 in myelofibrosis patients is known to impair human T cell subsets broadly. Conversely, we show that JAK2 inhibition impairs alloreactive T cells yet promotes beneficial regulatory T cell and Th2 differentiation. This study emphasizes the relevance of JAK2 in GVHD pathogenesis and prevention. </p><p class="first" id="d7423793e447">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 ( <a data-untrusted="" href="https://clinicaltrials.gov/ct2/show/NCT02891603" id="d7423793e461" target="xrefwindow">https://clinicaltrials.gov/ct2/show/NCT02891603</a>). </p>