The development of the mononuclear phagocyte system requires macrophage colony-stimulating factor (CSF-1) signaling through the CSF-1 receptor (CSF1R, CD115). We examined the effect of an antibody against CSF1R on macrophage homeostasis and function using the MacGreen transgenic mouse (csf1r-enhanced green fluorescent protein) as a reporter. The administration of a novel CSF1R blocking antibody selectively reduced the CD115 ؉ Gr-1 neg monocyte precursor of resident tissue macrophages. CD115 ؉ Gr-1 ؉ inflammatory monocytes were correspondingly increased, supporting the view that monocytes are a developmental series. Within tissue, the antibody almost completely depleted resident macrophage populations in the peritoneum, gastrointestinal tract, liver, kidney, and skin, but not in the lung or female reproductive organs. CSF1R blockade reduced the numbers of tumor-associated macrophages in syngeneic tumor models, suggesting that these cells are resident type macrophages. Conversely, it had no effect on inflammatory monocyte recruitment in models, including lipopolysaccharide-induced lung inflammation, wound healing, peritonitis, and severe acute graft-versus-host disease. Depletion of resident tissue macrophages from bone marrow transplantation recipients actually resulted in accelerated pathology and exaggerated donor T-cell activation. The data indicate that CSF1R signaling is required only for the maturation and replacement of resident-type monocytes and tissue macrophages, and is not required for monocyte production or inflammatory function. (Blood.

The presentation pathways by which allogeneic peptides induce graft-versus-host disease (GVHD) are unclear. We developed a bone marrow transplant (BMT) system in mice whereby presentation of a processed recipient peptide within major histocompatibility complex (MHC) class II molecules could be spatially and temporally quantified. Whereas donor antigen presenting cells (APCs) could induce lethal acute GVHD via MHC class II, recipient APCs were 100-1,000 times more potent in this regard. After myeloablative irradiation, T cell activation and memory differentiation occurred in lymphoid organs independently of alloantigen. Unexpectedly, professional hematopoietic-derived recipient APCs within lymphoid organs had only a limited capacity to induce GVHD, and dendritic cells were not required. In contrast, nonhematopoietic recipient APCs within target organs induced universal GVHD mortality and promoted marked alloreactive donor T cell expansion within the gastrointestinal tract and inflammatory cytokine generation. These data challenge current paradigms, suggesting that experimental lethal acute GVHD can be induced by nonhematopoietic recipient APCs.

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...

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