Organ siderosis and hemophagocytosis during acute graft-versus-host disease

Nogai, Axel; Shi, Yu; Pérez-Hernández, Daniel; Cordes, Steffen; Mengwasser, Jörg; Mertlitz, Sarah; Riesner, Katarina; Kalupa, Martina; Erdmann, Jan-Hendrik; Ziebig, Reinhard; Dittmar, Gunnar; Penack, Olaf

doi:10.3324/haematol.2016.144519

Cited by 8 publications

(9 citation statements)

References 15 publications

(10 reference statements)

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“…Iron overload due to multiple pre-transplant red blood cell transfusion has been described to have negative impact on alloSCT outcome (7,8,11,13). Second, ferritin levels are very high during severe graft-versus-host disease and during macrophage activation syndromes after alloSCT (12). Third, ferritin is an acute phase protein that is regularly elevated during acute and chronic infections (24,25).…”

Section: Discussionmentioning

confidence: 99%

“…Primary endpoint was the incidence of acute GVHD. Acute GVHD was picked as a primary endpoint because of our previous observation on a correlation of maximum Ferritin levels after alloSCT with acute GVHD severity (12). Secondary endpoints were relapse incidence (RI), non-relapse mortality (NRM), overall survival (OS), progression free survival (PFS), and the incidence of chronic GVHD.…”

Section: Endpoints and Statistical Analysesmentioning

confidence: 99%

“…Mortality in the first months/years after alloSCT is mainly due to leukemia relapse, infections or graft-versus-host disease (GVHD). In all these clinical situations serum ferritin, an acute phase and iron binding protein, has been demonstrated to be elevated (6)(7)(8)(9)(10)(11)(12)(13). Based on this background results, several retrospective studies and metaanalyses have suggested that serum ferritin may be of use as a biomarker during alloSCT (7,(14)(15)(16)(17)(18).…”

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confidence: 97%

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Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT – A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party

et al. 2020

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Frontiers in Immunology | www.frontiersin.org April 2020 | Volume 11 | Article 586 Penack et al. Ferritin and alloSCT Outcomehigher infection-related mortality in the high ferritin group (HR = 3.9, CI = 1.6-9.7, p = 0.003). Acute and chronic GVHD incidence or severity were not associated to serum ferritin levels. We conclude that ferritin levels can serve as routine laboratory biomarker for mortality risk assessment before alloSCT.

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Section: Discussionmentioning

confidence: 99%

Section: Endpoints and Statistical Analysesmentioning

confidence: 99%

mentioning

confidence: 97%

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Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT – A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party

et al. 2020

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“…57 Detected differences in VEGF levels may occur due to different posttransplant time points of determination, different measurement assays, VEGF sources (eg, serum in patients vs organ biopsies in our study), or varying GVHD progression. For example, severe course of GVHD was found associated with activation and infiltration of macrophages, [58][59][60][61] which are known to be a source of VEGF. [62][63][64] The clinical setting in GVHD is variable due to different drug applications, particularly preexisting diseases or treatments, which modify a growth factor pathway in many ways.…”

Section: Discussionmentioning

confidence: 99%

Initiation of Acute Graft-Versus-Host Disease By Angiogenesis

Riesner

Shi

Jacobi

et al. 2016

Blood

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Angiogenesis and inflammation are two closely related processes and inhibition of angiogenesis can ameliorate inflammatory diseases by reducing the recruitment of tissue infiltrating leukocytes. However, there is limited evidence on initial mechanisms of both processes and it is unknown if angiogenesis contributes to initiation of inflammation or is a mere consequence of inflammation. Recent research showed that graft-versus-host disease (GVHD) is associated to angiogenesis making the endothelium a potential new therapeutic target during allogeneic stem cell transplantation (bone marrow transplantation, allo-BMT). We studied kinetics and quantity of angiogenesis and leukocyte infiltration in murine acute GVHD models (LP/J→B6, B6→Balb/c, B6→BDF and 129S2/Sv→B6) by assessing CD31, CD4, CD8, CD11b by immune staining and FACS analysis. In GVHD target organs colon, skin and liver, we found significant increased vascular density and endothelial cell (EC) number but no leukocyte infiltration as early as day+2 after BMT (Fig. 1a,b). Leukocyte infiltration occurred secondary to angiogenesis at day+7 or later. No angiogenesis and inflammation occurred in the non-acute GVHD target organs joints, cardiac and skeletal muscle (Fig. 1c) suggesting a previously unrecognized role of the endothelium in GVHD organ tropism. Similar analyses in a standard model for inflammatory bowel disease, the 3% dextran sulfate sodium-induced (DSS) colitis, confirmed that angiogenesis preceded leukocyte infiltration in colon (d+1 vs. d+3) implicating that the significance of our results surpasses the field of transplantation biology. We aimed at identifying pathways that are relevant for initiation of angiogenesis during GVHD and first investigated the Vegfa/VEGFR1+2 axis. Based on our previous observation demonstrating a reduction of GVHD due to inhibition of neovascularization by anti-VE-cadherin antibodies (Penack et al, JNCI 2010), we performed therapeutic interventions with monoclonal blocking antibodies. Anti-VEGFR1+2 (DC101+MFI, Imclone) and anti-Vegfa (B20-4.1.1, Genentech) did not lead to GVHD reduction (Fig. 1d). Furthermore, we found no consistent upregulation of Vegfa and VEGFR2 expression levels in GVHD target organs during initiation of GVHD or later time points (Fig. 1e) suggesting that the Vefga/VEGFR2 pathway is not a major mechanism for initiation of angiogenesis in GVHD target organs. We next assessed known endothelial activation signs and performed qPCR analysis of adhesion molecules Icam1, Vcam1, E- and P-selectin (Fif. 1f) as well as immune staining of MHC-II (Fig. 1g). We confirmed previous knowledge that endothelial cells upregulate adhesion molecules and MHC-II during established GVHD. In sharp contrast, adhesion molecules and MHC-II were downregulated or not changed during the initiation of angiogenesis at day+2. This suggests that alternative pathways are important during initial angiogenesis in early GVHD. To identify alternative pathways during initial angiogenesis in an unbiased approach, we performed microarray analyses of FACS-sorted colon ECs (Fig. 2a) and LC-MS/MS proteome analyses of MACS-isolated liver ECs (Fig. 2c) at day+2 after allo-BMT vs. syn-BMT. Strikingly, we detected substantial metabolic and cytoskeletal changes in ECs of allo-BMT recipients (Fig. 2b,d). Recently, metabolic processes have been shown to be associated with cytoskeletal remodeling during EC migration and angiogenesis (Uebelhoer et al., J Vasc Res 2016). Accordingly, measuring single-cell mechanical characteristics with Real-Time deformabiliy cytometry (Otto et al., Nature Methods 2015) revealed profoundly higher deformation (D = 0.0547 ± 0.0011) and overall softening of ECs from allo-BMT recipients (Fig. 2e) indicating to enhanced EC migration and proliferation. We demonstrate that angiogenesis initiates GVHD in target organs and is restricted to target organs. Our findings implicate that endothelial biology plays a major role in GVHD organ tropism and disease development. We revealed novel genes and proteins regulating migration and proliferation of EC in initial angiogenesis during GVHD. Our study amends the knowledge on the interplay between the vasculature and inflammation opening a new window to develop therapeutic strategies targeting the endothelium. Disclosures No relevant conflicts of interest to declare.

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“…A retrospective paediatric study found serum ferritin levels of >10,000 µg/mL 90% sensitive and 96% specific for HLH, but its utility in the adult post-HSCT setting has not been validated (16). Serum ferritin > 10,000 µg/mL has been associated with poor survival in patients with GVHD, but this study did not investigate if these patients had sHLH/MAS (17). There is evidence that ferritin levels are not strongly associated with presence of GVHD, so may prove a useful biomarker allowing differentiation from sHLH/MAS (18,19).…”

Section: Background Review: Shlh/mas In Relation To Hsct and Car-t Cementioning

confidence: 91%

Diagnosis and Management of Secondary HLH/MAS Following HSCT and CAR-T Cell Therapy in Adults; A Review of the Literature and a Survey of Practice Within EBMT Centres on Behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP)

et al. 2020

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Organ siderosis and hemophagocytosis during acute graft-versus-host disease

Cited by 8 publications

References 15 publications

Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT – A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party

Association of Serum Ferritin Levels Before Start of Conditioning With Mortality After alloSCT – A Prospective, Non-interventional Study of the EBMT Transplant Complications Working Party

Initiation of Acute Graft-Versus-Host Disease By Angiogenesis

Diagnosis and Management of Secondary HLH/MAS Following HSCT and CAR-T Cell Therapy in Adults; A Review of the Literature and a Survey of Practice Within EBMT Centres on Behalf of the Autoimmune Diseases Working Party (ADWP) and Transplant Complications Working Party (TCWP)

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