Eosinophils are multifunctional leukocytes implicated in numerous inflammatory diseases. The present study was conducted to clarify the precise role of eosinophils in the development of colitis by using eosinophil-depleted mice and a novel chemokine-binding protein that neutralizes CCL11 action. Colitis was induced by administration of dextran sodium sulfate (DSS) to wild-type and eosinophil-deficient ⌬dblGATA-1 mice. Accumulation of eosinophils in the gut of mice given DSS paralleled worsening of clinical score and weight loss. In response to DSS, ⌬dblGATA-1 mice showed virtual absence of eosinophil recruitment, amelioration of clinical score, weight loss, and tissue destruction, and no lethality. There was a decrease in CXCL1 and CCL3 production and decreased neutrophil influx in the intestine of ⌬dblGATA-1 mice. Transfer of bone marrow cells from wild-type mice reconstituted disease manifestation in DSS-treated ⌬dblGATA-1 mice, and levels of CCL11 were increased after DSS treatment and localized to inflammatory cells. Treatment with the chemokine-binding protein evasin-4 at a dose that prevented the function of CCL11 greatly ameliorated clinical score, weight loss, overall tissue destruction, and death rates. In conclusion, the influx of eosinophils is critical for the induction of colitis by DSS. Treatment with a novel chemokine-binding protein decreased eosinophil influx and greatly ameliorated colitis, suggesting that strategies that interfere with the recruitment of eosinophils may be useful as therapy for colitis.

CCL3 is a protein of the CC chemokine family known to be important for T cell recruitment in inflammatory diseases. The aim of the current study was to evaluate the effects and putative mechanism of action of evasin-1, a novel CCL3-binding protein, in the pathogenesis of acute graft-versus-host disease (GVHD). GVHD was induced by the transplantation of splenocytes from C57BL/6J to B6D2F1 mice. Treatment of recipient mice with evasin-1 prevented mortality associated with GVHD. This was correlated with reduced weight loss and clinical disease severity. Analysis of the small intestine showed that evasin-1 treatment reduced the histopathological score and decreased levels of IFN-γ and CCL5. Mechanistically, evasin-1 treatment reduced the number of CD4+ and CD8+ T cells infiltrating the small intestine, as assessed by immunohistochemistry, and the adhesion of leukocytes to intestinal venules of recipient mice, as assessed by intravital microscopy. Evasin-1 was also able to decrease liver damage, as seen by reduction of inflammatory infiltrate and IFN-γ levels. Treatment with evasin-1 did not interfere with graft-versus-leukemia. Altogether, our studies demonstrate that CCL3 plays a major role in mediating GVHD, but not graft-versus-leukemia in mice and suggest that blockade of CCL3 with evasin-1 has potential therapeutic application in patients undergoing bone marrow transplantation.

Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome.

PI(3)Kγ is thought to mediate leukocyte migration to injured tissues and may be important in the pathogenesis of various T-lymphocyte-dependent pathologies, including autoimmune and inflammatory diseases. The present study evaluated the relevance of PI(3)Kγ in donor cells for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PI(3)Kγ(-/-) C57BL/6J mice to B6D2F1 mice, and mice that received PI(3)Kγ(-/-) cells showed reduced clinical signs of disease, bacterial translocation, tissue injury, and lethality rates. This was associated with reduced production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and reduced infiltration of CD8(+), CD4(+), and CD11c(+) cells in the small intestine. Mechanistically, in addition to decreasing production of proinflammatory mediators, absence or pharmacological blockade of PI(3)Kγ was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PI(3)Kγ(-/-) leukocytes were transferred into WT mice. In conclusion, PI(3)Kγ plays a critical role in GVHD by mediating leukocyte influx and activation in tissues. PI(3)Kγ inhibitors may be useful in the treatment of GVHD in patients undergoing BMT.

The atypical chemokine receptor D6 is a decoy and scavenger receptor for most inflammatory CC chemokines and prevents the development of exacerbated inflammatory reactions. Here we report that mice lacking D6 expression in the nonhematopoietic compartment have a selective increase in the number of IntroductionThe chemokine system represents the main orchestrator of leukocyte recruitment. [1][2][3][4] Among several regulatory mechanisms, a prominent role has been recently recognized to a set of chemokine receptors indicated as atypical in that structurally unable to directly mediate cell migration. 5 Atypical chemokine receptors are structurally and functionally heterogeneous, but they share the biologic role of regulating signaling receptors' activity, by clearance, transport, or presentation of their cognate ligands. [5][6][7] D6 is one of these atypical chemokine receptors, and its main function is to bind and drive to degradation the majority of inflammatory CC chemokines. [8][9][10] By this chemokine scavenger function, D6 acts as a negative regulator of inflammation, as demonstrated by D6-deficient mice that are characterized by increased levels of inflammatory CC chemokines and development of exaggerated inflammatory reactions in different organs expressing D6 on lymphatic vessels, 11 including skin, 12,13 liver, 14 colon, 15,16 lungs, 17,18 and placenta, where its expression is restricted to trophoblast cells. 19 On the contrary, in certain conditions, the uncontrolled local inflammation observed in D6 Ϫ/Ϫ mice has been shown to impair the development of specific immune responses, protecting mice from development of autoimmune diseases. 20 Although D6 Ϫ/Ϫ mice have been investigated extensively, several aspects of D6 biology, including the precise mechanisms by which it regulates inflammatory responses, are not yet fully understood.In recent years, it became evident that inflammatory CC chemokines control not only monocyte recruitment at inflammatory sites but also regulate monocyte homeostasis and mobilization from the BM in infectious and hypercholesterolemia models. [21][22][23] Based on the expression of the myeloid differentiation antigen Ly6C and the chemokine receptors CCR2 and CX3CR1, 2 phenotypic and functional monocyte subsets have been described in mice. 24 Classic monocytes are Ly6C high /CCR2 ϩ /CX3CR1 low and are also called inflammatory monocytes because they produce high levels of TNF-␣ and IL-1␤ in inflamed tissues and lymph nodes (LNs) during infection or tissue damage. 25 The second subset is represented by nonclassic Ly6C Ϫ /CCR2 Ϫ /CX3CR1 high monocytes, also called patrolling monocytes because they crawl on the endothelium in homeostatic conditions, although they are the first extravasating cell type during an inflammatory response. 26 Interestingly, cells with classic monocyte phenotype are a component of the heterogeneous population of myeloid cells with immunoregulatory function called myeloid-derived suppressor cells (MDSCs). 27 This population consists of cells of myeloid ori...

Bone marrow transplantation (BMT) is the current therapy of choice for several malignancies and severe autoimmune diseases. Graft versus host disease (GVHD) is the major complication associated with BMT. T lymphocytes and other leukocytes migrate into target organs during GVHD, become activated and mediate tissue damage. Chemokines are well known inducers of leukocyte trafficking and activation and contribute to the pathogenesis of GVHD. Here, we review the major animal models used to study GVHD and the role of chemokines in mediating tissue damage in these models. The role of these molecules in promoting potential beneficial effects of the graft, especially graft versus leukemia, is also discussed. Finally, the various pharmacological strategies to block the chemokine system or downstream signaling events in the context of GVHD are discussed.

Rezende et al. report that the transplant of 5-lipoxygenase (5-LO)−deficient leukocytes protects mice from GVHD. Treatment with the 5-LO inhibitor zileuton or a LTB4 antagonist at the initial phase of the transplant achieves similar protective effects. 5-LO is a crucial contributor to tissue damage in GVHD.

PAF is a potent lipid mediator involved in several manifestations of acute inflammation, including leukocyte influx, leukocyte interaction with endothelium, and production of inflammatory cytokines. The present study evaluated the relevance of PAFR for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PAFR(-/-) C57BL/6J to B6D2F1 mice. Mice, which received PAFR(-/-) splenocytes or treatment with the PAFR antagonist, showed reduced clinical signs of disease and no mortality. In GVHD mice receiving PAFR(-/-) splenocytes, there was deceased bacterial translocation and tissue injury. Furthermore, production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and accumulation of CD8(+) cells in intestine and liver were reduced in mice transplanted with the PAFR(-/-) splenocyte. Mechanistically, an absence or pharmacological blockade of PAFR was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PAFR(-/-) leukocytes were transferred into WT mice. In conclusion, PAFR on donor leukocytes plays a critical role in GVHD by mediating leukocyte influx and cytokine production in target tissues. PAFR antagonist may potentially be useful in the treatment of GVHD in bone marrow-transplanted patients.