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...

According to the current model for tissue-specific homing, specificity is conferred by the selective recruitment of lymphocyte populations from peripheral blood, based on their expression of chemokine and adhesion receptors (endothelial selection). In this study, we provide evidence for an alternative stromal induction mechanism that operates in chronic inflammation. We show that the human rheumatoid synovial microenvironment directly induces functional inflammatory (CCR5 and CXCR3) and constitutive (CCR7 and CXCR4) chemokine receptors on infiltrating CD4+ T cells. Expression of the corresponding inflammatory chemokine ligands (CCL5 and CXCL11) was confined to stromal areas in the synovium. However, expression of the constitutive ligands (CCL19 and CXCL12) was inappropriately high on both vascular and lymphatic endothelium, suggesting that the vascular to lymphatic chemokine gradient involved in lymphatic recirculation becomes subverted in the rheumatoid synovium. These results challenge the view that leukocyte trafficking is regulated solely by selective recruitment of pre-existing chemokine receptor-positive cells from peripheral blood, by providing an alternative explanation based on aberrant lymphocyte retention and compromised lymphatic return.

Host antigen-presenting cells (APCs) are known to be critical for the induction of graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT), but the relative contribution of specific APC subsets remains unclear. We have studied the role of host B cells in GVHD by using B-cell-deficient MT mice as BMT recipients in a model of CD4-dependent GVHD to major histocompatibility complex antigens. We demonstrate that acute GVHD is initially augmented in MT recipients relative to wild-type recipients (mortality: 85% vs 44%, P < .01), and this is the result of an increase in donor T-cell proliferation, expansion, and inflammatory cytokine production early after BMT. Recipient B cells were depleted 28-fold at the time of BMT by total body irradiation (TBI) administered 24 hours earlier, and we demonstrate that TBI rapidly induces sustained interleukin-10 (