IFNγ differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract

Abstract

Although proinflammatory cytokines are key mediators of tissue damage during graft-versus-host disease (GVHD), IFN␥ has previously been attributed with both protective and pathogenic effects. We have resolved this paradox by using wildtype (wt), IFN␥ ؊/؊ , and IFN␥R ؊/؊ mice as donors or recipients in well-described models of allogeneic stem cell transplantation (SCT). We show that donor-derived IFN␥ augments acute GVHD via direct effects on (1) the donor T cell to promote T helper 1 (Th1) differentiation and (2) the gastrointestinal (GI) tract to augment inflammatory cytokine generation. However, these detrimental effects are overwhelmed by a protective role of IFN␥ in preventing the development of idiopathic pneumonia syndrome (IPS). This is the result of direct effects on pulmonary parenchyma to prevent donor cell migration and expansion within the lung. Thus, IFN␥ is the key cytokine differentially controlling the development of IPS and gastrointestinal GVHD after allogeneic SCT. IntroductionAllogeneic bone marrow transplantation (BMT) is a definitive curative therapy for most hematologic malignancies and severe immunodeficiencies. The major complication of allogeneic BMT remains graft-versus-host disease (GVHD) in which the skin, gastrointestinal (GI) tract, liver, and lung are preferentially damaged by the transplanted donor immune system. 1 GVHD occurs in most (50%-70%) recipients and is largely responsible for the high mortality associated with allogeneic BMT. Idiopathic pneumonia syndrome (IPS) is an acute noninfectious lung injury that typically occurs 3 to 4 weeks after BMT, responds poorly to therapy, and is associated with a high mortality. 2 There is thus a pressing need for new treatment approaches to both prevent and treat the full spectrum of GVHD, based on a logical understanding of the underlying disease pathophysiology.Current paradigms suggest that GVHD occurs via a complex cellular network initiated by the interaction of antigen-presenting cells (APCs) and naive donor T cells. [3][4][5] Subsequent T helper 1 (Th1) differentiation leads to the generation of donor cytotoxic T lymphocytes (CTLs) and large amounts of inflammatory cytokines that damage host tissue by both major histocompatibility complex (MHC)-dependent and -independent pathways. 6 Of the Th1 cytokines, IFN␥ is perhaps the most immunologically dominant, influencing a plethora of cell subsets during allograft rejection. 7 However the effects of this cytokine on GVHD are unclear, with a number of contradictory studies [8][9][10][11] suggesting that a clearer understanding of the mechanisms involved are needed. We have re-examined this issue using both IFN␥ Ϫ/Ϫ and IFN␥R Ϫ/Ϫ stem cell transplantation (SCT) donors or recipients following myeloablative conditioning. We demonstrate that donor-derived IFN␥ indeed has both positive and negative effects on GVHD due to differential effects on donor and host tissue, and individual target organs. First, IFN␥ augments acute GVHD via direct affects on the donor T cell to promote Th1 differen...

Risk model incorporating donor IL6 and IFNG genotype and gastrointestinal GVHD can discriminate patients at high risk of steroid refractory acute GVHD

“…Surprisingly, only donor SNPs for IL6 and IFNG but not from recipient were significantly associated with increased risk of SR aGVHD, which means that donor level of IL6 and Interferon-γ plays a role in the pathogenesis of SR-GVHD, as suggested by other studies. 49 This suggests that this model can potentially be used to choose a donor when more than one donor is available in order to decrease the risk of SR aGVHD and improve outcome of HCT. There was no difference in risk of relapse among the different genotypes suggesting that there may not be any difference in graft vs disease effect in these donors.…”

“…48 IFN-γ can cause direct effects on gastrointestinal tract GVHD. 49 Corticosteroid treatment results in decreased production of Interferon-γ in PBMC. 50 IFN-γ has also been implicated in steroid resistance in asthma by activation of MyD88-dependent pathways in macrophages.…”

New perspectives on the biology of acute GVHD

“…Recent studies also suggest that IFN-g might have a differential role in the severity of distinct GVHD target organs. 105 Thus, whether Th1 cytokines exerts their effect as the regulators or inducers of GVHD severity might be contextual. Several different cytokines that polarize donor T cells to Th2 such as IL-4, G-CSF, IL-18, IL-11, rapamycin and the secretion of IL-4 by NK1.1 þ T cells can reduce acute GVHD.…”

Donor-Derived Regulatory T Cells Attenuate the Severity of Acute Graft-Versus-Host Disease after Cord Blood Transplantation

“…Without finding significant difference in alloactivation and proliferation between CB and APB CD4 + ATs, we further investigated whether their cytokine-producing subsets were different in composition. Th1 and Th2 cells are typical members of Teffs, and Th1 was found to arouse GI tract injury (Burman et al 2007), while Th2 predominantly mediated idiopathic pneumonia syndrome /GVHD in the lung (Yi et al 2009). Varied findings were reported about the Th1 and Th2 differences in CB and APB depending on different ways of stimulation or detection methods used in individual studies (Chalmers et al 1998;Garcia Vela et al 2000;Krampera et al 2000;Slavcev et al 2002).…”