Post-BMT lung injury occurs independently of the expression of CCL2 or its receptor, CCR2, on host cells

Panoskaltsis‐Mortari, Angela; Hermanson, John R.; Taras, Elizabeth; Wangensteen, O. Douglas; Charo, Israel F.; Rollins, Barrett J.; Blazar, Bruce R.

doi:10.1152/ajplung.00154.2003

Cited by 12 publications

(10 citation statements)

References 36 publications

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“…Using the same haploidentical BMT model, a critical role of donor leukocyte expression of CCR2 has been shown for the development of pulmonary GVHD, 25 and in a fully mismatched BMT model, CCR2 expression of the host did not contribute to pulmonary dysfunction after allo-BMT. 81 Terwey et al 29 reported the requirement of CCR2 expression on donor cells for intestinal and hepatic aGVHD, but not for cutaneous CD8 þ T-cell-mediated aGVHD. In CD4 þ T-cell-mediated hepatic aGVHD, CCR2 deficiency of donor T cells rather led to increased T-cell infiltrates.…”

Section: Discussionmentioning

confidence: 99%

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

et al. 2009

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Acute graft-versus-host disease (aGVHD) is a major complication after allogeneic bone marrow transplantation (allo-BMT), and infiltration of donor leukocytes into aGVHD target organs is partially orchestrated by chemokines. Using a murine BMT model, the expression of 30 chemokines or chemokine receptors in the lung, liver, gut and tongue was analyzed using real-time PCR at 1, 2, 3 and 6 weeks after BMT during the development of clinical aGVHD and target organ histopathology. CXCL9-11 expression was linked to elevated expression of CXCR3 in the gut, lung and tongue. In contrast, hepatic CXCR3 expression was not changed, whereas a clear association was seen for CXCL16 and CXCR6 expression. An elevated intestinal CCL3 expression 1 week after allo-BMT was associated with an increased expression of CCR5 but not CCR1 or CCR3, and in the lung and liver CCL3-CCL5 expression was associated with increases in CCR1 and CCR5. Overexpression of CCL2, CCL8, CCL12 and their receptor CCR2 was found in the liver and lung, but not in the gut and tongue. On the basis of the differences in kinetics and organ distribution, more studies are required to better characterize specific targets within this network, as this will allow the development of novel preventive and therapeutic approaches by using single or multiple targeting reagents.

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Section: Discussionmentioning

confidence: 99%

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

et al. 2009

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“…These and our data suggest that CCL2 may not be the primary macrophagerecruiting factor in obese adipose tissue. Although CCL2 is an important macrophage-recruiting factor in several inflammatory conditions (18 -21), there are circumstances in which CCL2 is elevated but does not contribute to macrophage recruitment (31,32). For example, macrophage infiltration into skin incision wounds is not reduced in CCL2 Ϫ/Ϫ mice, even though CCL2 levels at wound sites are high in normal animals (31).…”

Section: Ccr2mentioning

confidence: 99%

“…The reason for the worsened metabolic regulation in our animals is not known. It should be noted, however, that deficiency of CCL2 has complex effects on immune function, causing both upregulation and downregulation of inflammatory factors (32,38,39). In endotoxin-treated mice, neutralization of CCL2 increases serum TNF-␣ and IL-12 levels (39), and in CCL2 Ϫ/Ϫ or CCL2-neutralized mice, others have found higher levels of TNF-␣ and IL-10 (32,38).…”

Section: Ccr2mentioning

confidence: 99%

Absence of CC Chemokine Ligand 2 Does Not Limit Obesity-Associated Infiltration of Macrophages Into Adipose Tissue

et al. 2007

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Macrophage recruitment to adipose tissue in obesity contributes to enhanced adipose tissue inflammatory activity and thus may underlie obesity-associated metabolic dysfunction. Obese adipose tissue exhibits increases in CC chemokine ligand 2 (CCL2, or monocyte chemoattractant protein-1), an important macrophage-recruiting factor. We therefore hypothesized that elevated CCL2 may contribute to obesity-associated adipose tissue macrophage recruitment. Male 6-week-old CCL2؊/؊ and wild-type mice (n ‫؍‬ 11-14 per group) were fed standard and high-fat diets until 34 weeks of age. At 12-16 and 25-29 weeks of age, blood was collected for plasma glucose and hormone measurements, and glucose tolerance and insulin tolerance tests were performed. Adipose tissue was collected at 34 weeks for analysis of macrophage infiltration. Surprisingly, CCL2؊/؊ mice on high-fat diet showed no reductions in adipose tissue macrophages. CCL2 ؊/؊ mice on standard and high-fat diet were also glucose intolerant and had mildly increased plasma glucose and decreased serum adiponectin levels compared with wild-type mice. On high-fat diet, CCL2؊/؊ mice also gained slightly more weight and were hyperinsulinemic compared with wild-type mice. Because macrophage levels were unchanged in CCL2 ؊/؊ mice, the phenotype appears to be caused by lack of CCL2 itself. The fact that metabolic function was altered in CCL2 ؊/؊ mice, despite no changes in adipose tissue macrophage levels, suggests that CCL2 has effects on metabolism that are independent of its macrophage-recruiting capabilities. Importantly, we conclude that CCL2 is not critical for adipose tissue macrophage recruitment. The dominant factor for recruiting macrophages in adipose tissue during obesity therefore remains to be identified.

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“…11 In GVHD, the expression of CCL2 in the gut, liver, skin, and lung coincides with the increase of the inflammatory cytokines IL-1, TNF-␣, IFN-␥ early after transplantation [12][13][14] and the time course of CCL2 levels correlates with the severity of cellular infiltrates in the lung during GVHD-related idiopathic pneumonia syndrome (IPS). 15 Blockade of CCL2 with a monoclonal antibody results in reduced severity of IPS after allogeneic HSCT. 16 CCR2 belongs to the class of hepta-helical G-protein-coupled transmembrane CC chemokine receptors and is the predominant receptor for CCL2.…”

Section: Introductionmentioning

confidence: 99%

CCR2 is required for CD8-induced graft-versus-host disease

Terwey

Kim

Kochman

et al. 2005

Blood

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Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT).Migration of donor-derived T cells into GVHD target organs plays a critical role in the development of GVHD and chemokines and their receptors are important molecules involved in this process. Here, we demonstrate in murine bone marrow transplantation models that the expression of the inflammatory CC chemokine receptor 2 (CCR2) on donor-derived CD8 ؉ T cells is relevant for the control of CD8 ؉ T-cell migration and development of GVHD. Recipients of CCR2-deficient (CCR2 ؊/؊ ) CD8 ؉ T cells developed less damage of gut and liver than recipients of wild-type CD8 ؉ T cells, which correlated with a reduction in overall GVHD morbidity and mortality. Assessment of donor CD8 ؉ T-cell target organ infiltration revealed that CCR2 ؊/؊ CD8 ؉ T cells have an intrinsic migratory defect to the gut and liver. Other causes for the reduction in GVHD could be excluded, as alloreactive proliferation, activation, IFN-␥ production and cytotoxicity of CCR2 ؊/؊ CD8 ؉ T cells were intact. Interestingly, the graft-versustumor effect mediated by CCR2 ؊/؊ CD8 ؉ T cells was preserved, which suggests that interference with T-cell migration by blockade of CCR2 signaling can separate GVHD from GVT activity. ( IntroductionAllogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapy for a variety of malignant and nonmalignant disorders of the hematopoietic system and for certain solid tumors. 1 A major complication limiting the success and wider application of allogeneic HSCT is the occurrence of acute graft-versus-host disease (GVHD), which is a rapidly progressive illness with immunosuppression, cachexia and specific target organ damage of liver, intestines, skin, and lung. 2 Donor-derived alloreactive T cells play a major role in the pathogenesis of GVHD and depletion of T cells from the donor cell inoculum remains the most effective approach to prevent the development of disease. 3 However, alloreactive donor T cells also display graft-versus-tumor (GVT) activity, which is increasingly being recognized as an important component of the overall antitumor effect of an allogeneic HSCT. 4 Recent murine bone marrow transplantation studies suggest that specifically interfering with T-cell migration represents an attractive therapeutic approach toward the goal of amelioration of GVHD without reducing GVT activity. 5,6 It is known that 3 families of migration molecules (selectins, chemokines, integrins, and their respective ligands and receptors) control T-cell migration in homeostasis and inflammation 7 and members of all 3 families have been identified as important players during GVHD. 5 CC chemokine receptor 2 (CCR2) and its main ligand chemokine ligand 2 (CCL2) are among the chemokine receptor-ligand pairs that control leukocyte migration during inflammatory processes. 8,9 CCL2 (originally termed monocyte chemoattractant protein-1 [MCP-1]) belongs to the family of inflammatory CC chemokines and was one...

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Post-BMT lung injury occurs independently of the expression of CCL2 or its receptor, CCR2, on host cells

Cited by 12 publications

References 36 publications

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

Absence of CC Chemokine Ligand 2 Does Not Limit Obesity-Associated Infiltration of Macrophages Into Adipose Tissue

CCR2 is required for CD8-induced graft-versus-host disease

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