Dichotomous role of interferon-gamma in allogeneic bone marrow transplant

Abstract

Interferon (IFN)-gamma is a pleiotropic cytokine with a central role in innate and adaptive immunity. As a potent pro-inflammatory and antitumor cytokine, IFN-gamma is conventionally thought to be responsible for driving cellular immune response. On the other hand, accumulating evidence suggests that IFN-gamma also has immunosuppressive activity. An important role for IFN-gamma in inhibiting graft-versus-host disease (GVHD) has been demonstrated in murine models, despite IFN-gamma being one of the key factors amplifying T cell activation during the process of acute GVHD (aGVHD), the major complication and cause of post-transplant mortality in allogeneic bone marrow transplantation (BMT). At the same time, IFN-gamma facilitates graft-versus-leukemia (GVL) activity. Dissociation of GVL effects from GVHD has been the ultimate goal of allogeneic BMT in the treatment of hematologic malignancies. This paradoxic role of IFN-gamma makes modulating its activity a promising strategy to maximize GVL while minimizing GVHD and improve clinical outcomes in BMT. In this review, the effects of IFN-gamma on GVHD and GVL are discussed with consideration of the mechanism of IFN-gamma action.

Figure 1. IFN-γ-producing cells show different effects on GVHD and GVL

⊕ increase; ⊝ inhibit; unknown

Figure 2. Role of IFN-γ during the development of GVHD and GVL

The conditioning regimen leads to damage of host tissues and allows the translocation of LPS and other pro-inflammatory cytokines into the circulation, leading to the activation of donor T-cell by host APC[17]. Interaction between donor IL-12-producing APC with donor T cells can increase the IFN-γ production by activated T-cells. High local levels of IFN-γ subsequently induce IDO expression on donor APC [Lu et al. 2009, in preparation]. IDO⁺ APCs help maintain the tolerant phenotype of T-reg which inhibits the Th1 and Th17 polarization of donor T-cells, resulting in down-modulation of T-cell allo-reactivity and GVHD effect[83].

Figure 3. IFN-γ-induced IDO expression on host epithelial cells inhibits GVHD

Donor T-cells induce GVHD effects that cause target epithelial cell apoptosis [17, 22]. IDO expression on host epithelial cells induced by IFN-γ from donor T-cells inhibits GVHD [85]. In addition, IFN-γ enhances GVL effect through both direct and indirect mechanisms, resulting in apoptosis of tumor cells[18].