Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Abstract

Purpose: Immune-mediated graft-versus-tumor (GVT) effects can occur after allogeneic hematopoietic stem cell transplantation (HSCT), but GVT is tightly linked to its main complication, graft-versus-host disease (GVHD). Strategies aimed at modulating GVHD, while maintaining the GVT effect, are needed to improve the cure rate of transplant. Given the emerging role of Janus-activated kinase (JAK) signaling in lymphoproliferative and myeloproliferative diseases and its established function at dictating T-cell differentiation, we postulated that JAKs might be potential therapeutic targets through a pharmacologic approach.Experimental Design: We examined the effect of JAK1/JAK2 modulation by ruxolitinib in a mouse model of fully MHC mismatched bone marrow transplant comprising in vivo tumor inoculation.Results: JAK1/JAK2 inhibition by ruxolitinib improved both overall survival (P ¼ 0.03) and acute GVHD pathologic score at target organs (P 0.001) of treated mice. In addition, treatment with ruxolitinib was associated with a preserved GVT effect, as evidenced by reduction of tumor burden (P ¼ 0.001) and increase of survival time (P ¼ 0.01). JAK1/JAK2 inhibition did not impair the in vivo acquisition of donor T-cell alloreactivity; this observation may account, at least in part, to the preserved GVT effect. Rather, JAK1/JAK2 inhibition of GVHDwas associated withthe modulation of chemokine receptor expression, which may have been one factor in the reduced infiltration of donor T cells in GVHD target organs.Conclusions: These data provide further evidence that JAK inhibition represents a new and potentially clinically relevant approach to GVHD prevention.

CML cells actively evade host immune surveillance through cytokine-mediated downregulation of MHC-II expression

“…44,45 However, despite its anti-inflammatory properties, RUX was able to preserve the graft-versus-leukemia effect in graft-versus-host disease mouse models comprising in vivo tumor inoculation. 46,47 Some of these selective effects were explained by differential responses of distinct T-cell subsets to RUX, particularly when used at different concentrations. 45 It is therefore possible to speculate that the modulation of the immune system by RUX is cell context dependent and potentially affected by the intensity of the inflammatory responses.…”

Mechanistic approaches for the prevention and treatment of chronic GVHD

“…Proinflammatory cytokines are characteristically elevated in both acute and chronic GVHD, and inhibition of JAK1/JAK2 signaling with ruxolitinib has been shown to reduce GVHD in murine models. [46][47][48] This novel approach has been tested in patients with steroid-refractory acute and chronic GVHD with encouraging results in both settings. 46 [50][51][52][53][54][55] Treg impairment is associated with loss of tolerance, autoimmunity, and chronic GVHD.…”

Myelofibrosis: to transplant or not to transplant?

“…36,38,[41][42][43][44][45][46] The key questions have been how to best integrate JAK inhibitor therapy into HCT protocols prior to transplant and whether there is any role in the posttransplant setting.…”

“…Decrease in GVHD Increased risk of infections JAK 1/2 inhibitor therapy has recently been shown to be effective in reducing the risk of GVHD in a mouse model by inhibiting donor T-cell expansion and inflammatory cytokine production 43,44 Beneficial effect also demonstrated on 6 patients with steroid refractory GVHD 43 Murine models show silencing of T-helper cytokine secretion and profound reduction in T-regulatory cells 45 Proven increased risk of urinary tract infections and zoster infection in comparison with other available treatments 46 Anecdotal case reports of opportunistic infections (reactivation of hepatitis, mycobacterial infections, and invasive fungal infections)…”