Clinical significance of hemophagocytosis in BM clot sections during the peri-engraftment period following allogeneic hematopoietic SCT

Imahashi, Nobuhiko; Inamoto, Yoshihiro; Ito, Masafumi; Koyama, Daisuke; Goto, Tatsunori; Onodera, Koichi; Seto, Aika; Watanabe, Keisuke; Imahashi, Mayumi; Nishiwaki, Satoshi; Tsukamoto, Shokichi; Yasuda, Takahiko; Ozawa, Yukiyasu; Miyamura, Koichi

doi:10.1038/bmt.2011.95

Cited by 17 publications

(6 citation statements)

References 36 publications

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“…CD163-positive macrophages in the skin and bone marrow have been associated with refractory acute GVHD and poor prognosis. 34, 35 Thus CD163 concentrations might have been strongly influenced by the prior onset of acute GVHD and its treatment, and could have obscured any association with subsequent quiescent-onset cGVHD.…”

Section: Discussionmentioning

confidence: 99%

Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease

Inamoto

Martin

Paczesny

et al. 2017

Biology of Blood and Marrow Transplantation

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Chronic graft-versus-host disease (cGVHD) is the leading cause of long-term morbidity and mortality after allogeneic hematopoietic cell transplantation. In order to identify prognostic plasma proteins associated with de novo or quiescent-onset cGVHD, we performed a discovery and validation proteomic study. The total study cohort included 167 consecutive patients who had no clinical evidence of GVHD under minimum glucocorticoid administration, and had available plasma samples obtained at 80±14 days after transplantation. We first used high-throughput mass spectrometry to screen pooled plasma using 20 cases with subsequent cGVHD and 20 controls without it, and identified 20 candidate proteins. We then measured 12 of the 20 candidates by enzyme-linked immunosorbent assays on the same individual samples and identified 4 proteins for further verification (LGALS3BP, CD5L, CD163 and TXN for de novo onset, and LGALS3BP and CD5L for quiescent onset). The verification cohort included 127 remaining patients. The cumulative incidence of de novo-onset cGVHD was higher in patients with higher plasma soluble CD163 concentrations at day 80 than those with lower concentrations (75% versus 40%, P=0.018). The cumulative incidence of de novo or quiescent-onset cGVHD did not differ statistically according to concentrations of the three other proteins at day 80. CD163 is a macrophage scavenger receptor and is elevated in oxidative conditions. These results suggest that monocyte or macrophage activation or increased oxidative stress may contribute to the pathogenesis of cGVHD.

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Section: Discussionmentioning

confidence: 99%

Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease

Inamoto

Martin

Paczesny

et al. 2017

Biology of Blood and Marrow Transplantation

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“…However, hemophagocytes are not essential to the diagnosis of HLH 3 , and can be seen in juvenile arthritis patients without overt MAS 4 . Additionally, hemophagocytes are found commonly in a host of other inflammatory states including sepsis 5 and following bone marrow transplant 6 . Whether hemophagocytes are inflammatory, anti-inflammatory, or serve different roles in differing diseases is a matter of ongoing study.…”

Section: The Final Common Pathwaymentioning

confidence: 99%

Making Sense of the Cytokine Storm: A Conceptual Framework for Understanding, Diagnosing, and Treating Hemophagocytic Syndromes

Canna

Behrens

2012

Pediatric Clinics of North America

140

137

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SYNOPSIS Cytokine Storm Syndromes (CSS) are a group of disorders representing a variety of inflammatory etiologies with the final common result of overwhelming systemic inflammation, hemodynamic instability, multiple organ dysfunction, and potentially death. The hemophagocytic syndromes hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) represent two clinically similar CSS with an unknown degree of pathoetiologic overlap. The clinical presentations of all CSS can be strikingly similar, creating diagnostic uncertainty. However, clinicians should avoid the temptation to treat all CSS equally, as their inciting inflammatory insults vary widely. Failure to identify and address this underlying trigger will result in delayed, inoptimal, or potentially harmful consequences. This review endeavors to place the hemophagocytic syndromes HLH and MAS within a conceptual model of CSS, and thus provide a logical framework for diagnosis and treatment of CSS of suspected rheumatic origin.

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“…Further studies are needed in this area. In a clinical setting, Imahashi et al evaluated BM clot sections from 70 patients who received a first allogeneic HSCT and diagnosed 23 (33%) of the patients with hemophagocytosis; they suggested that early macrophage activation was a relatively common but unrecognized complication of allogeneic HSCT [28]. We and others also previously showed that hemophagocytosis is required for IL-10 production [15,16] by monocytic dendritic cells and that blocking hemophagocytosis or monocytic dendritic cellederived IL-10 significantly increases cytotoxic lymphocyte activity, tissue damage, and mortality in virus-infected hosts [16].…”

Section: Discussionmentioning

confidence: 99%

Cytosine-Phosphorothionate-Guanine Oligodeoxynucleotides Exacerbates Hemophagocytosis by Inducing Tumor Necrosis Factor–Alpha Production in Mice after Bone Marrow Transplantation

Liu

Guo

Onai

et al. 2016

Biology of Blood and Marrow Transplantation

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Hemophagocytic syndrome (HPS) is frequently associated with hematopoietic stem cell transplantation and is treated with some benefit derived from TNF-α inhibitors. However, the mechanisms of how HPS occurs and how a TNF-α inhibitor exerts some benefit to HPS management have remained unclear. We evaluated the effect of toll-like receptor (TLR) ligands, especially focusing on cytosine-phosphorothionate-guanine oligodeoxynucleotide (CpG), a TLR9 ligand, on HPS in mice that underwent transplantation with syngeneic or allogeneic bone marrow (BM) cells (Syn-BMT, Allo-BMT), or with allogeneic BM cells plus splenocytes to promote graft-versus-host disease (GVHD mice). Hemophagocytosis was a common feature early after all BMT, but it subsided in Syn-BMT and Allo-BMT mice. In GVHD mice, however, hemophagocytosis persisted and was accompanied by upregulated production of IFN-γ but not TNF-α, and it was suppressed by blockade of IFN-γ but not TNF-α. A single injection of the TLR9 ligand CpG promoted HPS in all BMT mice and was lethal in GVHD mice, accompanied by greatly upregulated production of TNF-α, IL-6, and IFN-γ. Blocking of TNF-α, but not IL-6 or IFN-γ, suppressed CpG-induced HPS in all BMT mice and rescued GVHD mice from CpG-induced mortality. Thus, TLR9 signaling mediates TNF-α-driven HPS in BMT mice and is effectively treated through TNF-α inhibition.

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Clinical significance of hemophagocytosis in BM clot sections during the peri-engraftment period following allogeneic hematopoietic SCT

Cited by 17 publications

References 36 publications

Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease

Association of Plasma CD163 Concentration with De Novo–Onset Chronic Graft-versus-Host Disease

Making Sense of the Cytokine Storm: A Conceptual Framework for Understanding, Diagnosing, and Treating Hemophagocytic Syndromes

Cytosine-Phosphorothionate-Guanine Oligodeoxynucleotides Exacerbates Hemophagocytosis by Inducing Tumor Necrosis Factor–Alpha Production in Mice after Bone Marrow Transplantation

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