Gene expression profile of cytokines in patients with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation with reduced conditioning

Poloni, Antonella; Emanuelli, Monica; Trappolini, Silvia; Mancini, Stefania; Pozzi, Valentina; Costantini, Benedetta; Serrani, Federica; Berardinelli, Eleonora; Renzi, E.; Olivieri, Attilio; Leoni, Pietro

doi:10.1016/j.cyto.2010.12.008

Cited by 12 publications

(5 citation statements)

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“…Interferon alpha-1/13 (IFNα1/13), interferon alpha-2 (IFNα2), interferon beta (IFNβ) [72], interferon gamma (IFNγ) [73] and tumor necrosis factor alpha (TNFα) [74] were detected. IFN-I stimulated genes, MxA [75] and TRIM22 [76], were detected to confirm pDCs depletion effect on type I IFN production.…”

Section: Methodsmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

et al. 2014

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The role of plasmacytoid dendritic cells (pDC) in human immunodeficiency virus type 1 (HIV-1) infection and pathogenesis remains unclear. HIV-1 infection in the humanized mouse model leads to persistent HIV-1 infection and immunopathogenesis, including type I interferons (IFN-I) induction, immune-activation and depletion of human leukocytes, including CD4 T cells. We developed a monoclonal antibody that specifically depletes human pDC in all lymphoid organs in humanized mice. When pDC were depleted prior to HIV-1 infection, the induction of IFN-I and interferon-stimulated genes (ISGs) were abolished during acute HIV-1 infection with either a highly pathogenic CCR5/CXCR4-dual tropic HIV-1 or a standard CCR5-tropic HIV-1 isolate. Consistent with the anti-viral role of IFN-I, HIV-1 replication was significantly up-regulated in pDC-depleted mice. Interestingly, the cell death induced by the highly pathogenic HIV-1 isolate was severely reduced in pDC-depleted mice. During chronic HIV-1 infection, depletion of pDC also severely reduced the induction of IFN-I and ISGs, associated with elevated HIV-1 replication. Surprisingly, HIV-1 induced depletion of human immune cells including T cells in lymphoid organs, but not the blood, was reduced in spite of the increased viral replication. The increased cell number in lymphoid organs was associated with a reduced level of HIV-induced cell death in human leukocytes including CD4 T cells. We conclude that pDC play opposing roles in suppressing HIV-1 replication and in promoting HIV-1 induced immunopathogenesis. These findings suggest that pDC-depletion and IFN-I blockade will provide novel strategies for treating those HIV-1 immune non-responsive patients with persistent immune activation despite effective anti-retrovirus treatment.

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Section: Methodsmentioning

confidence: 99%

Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

et al. 2014

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“…In one study it was observed that NF-jB activation induced by LTa occurred in a monophasic manner, whereas TNF activated NF-jB in a biphasic manner [32]. Despite data suggesting that LTa is a weaker ligand for TNFR1, other evidence shows that LTa, but not TNF and LTb, has crucial roles in the initiation and development of some inflammatory diseases, such as rheumatoid arthritis [36,37], graft versus host disease, and the graft versus leukaemia effect [38,39], and also lymphangiogenesis in inflammation [40], via TNFR1 signalling.…”

Section: Introductionmentioning

confidence: 99%

Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor

et al. 2013

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Both of the TNF superfamily ligands, TNF and LTa, can bind and signal through TNFR1 and TNFR2, yet mice mutant for each have different phenotypes. Part of this difference is because LTa but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LTb to activate LTbR, which is consistent with the similar phenotypes of the LTa and LTbR deficient mice. However, it has also been reported that the LTa 3 homotrimer signals differently than TNF through TNFR1, and has unique roles in initiation and exacerbation of some inflammatory diseases. Our modeling of the TNF/TNFR1 interface compared to the LTa 3 /TNFR1 structure revealed some differences that could affect signalling by the two ligands. To determine whether there were any functional differences in the ability of TNF and LTa 3 to induce TNFR1-dependent apoptosis or necroptosis, and if there were different requirements for cIAPs and Sharpin to transmit the TNFR1 signal, we compared the ability of cells to respond to TNF and LTa 3 . Contrary to our hypothesis, we were unable to discover differences in signalling by TNFR1 in response to TNF and LTa 3 . Our results imply that the reasons for the conservation of LTa are most likely due either to differential regulation, the ability to signal through Herpes Virus Entry Mediator or the ability of LTa to form heterotrimers with LTb. Structured digital abstractLT alpha physically interacts with RIPK1 and cIAP1 by tandem affinity purification (View interaction) TNF and TNF bind by blue native page (View interaction) LT alpha and LT alpha bind by blue native page (View interaction) TNF physically interacts with cIAP1 and RIPK1 by tandem affinity purification (View interaction) Abbreviations BMDM, bone marrow-derived macrophage; cIAP, cellular inhibitor of apoptosis; ERK, extracellular signal-regulated kinase; GFP, green fluorescent protein; HVEM, herpes virus entry mediator; IjBa, inhibitor of jBa; JNK, c-Jun N-terminal kinase; LTa, lymphotoxin a; LTb, lymphotoxin b; LTbR, lymphotoxin b receptor; LUBAC, linear ubiquitin assembly complex; MAPK, mitogen-activated protein kinase; MDF, mouse dermal fibroblast; MEF, mouse embryonic fibroblast; MLKL, mixed lineage kinase domain-like; Nec-1, necrostatin-1; NF-jB, nuclear factor-jB; PDB, Protein Data Bank; PI, propidium iodide; QVD, quinolyl-valyl-O-methylaspartyl-(2,6-difluorophenoxy)-methyl ketone; RIPK, receptor interacting protein kinase; TNFR, tumour necrosis factor receptor.; TNF, tumour necrosis factor.

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“…The top candidate was lymphotoxin beta receptor or TNFR superfamily, member 3 ( LTBR ) with P = 1.73 × 10 −13 (Figure 1). Concordantly, it was recently reported that the expression of LTBR is elevated in patients with cGVHD + as compared to cGVHD − , and that the application of lymphotoxin beta receptor-immunoglobulin fusion protein in mouse model of cGVHD is beneficial [8,9]. …”

Section: Resultsmentioning

confidence: 88%

Combined meta-analysis of systemic effects of allogeneic stem cell transplantation and systemic sclerosis

et al. 2014

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BackgroundChronic graft-versus-host disease (cGVHD) is a major factor of morbidity and mortality for allogeneic stem cell transplantation (aSCT). The skin and internal organ involvement is the most common systemic complication of cGVHD and closely resembles systemic sclerosis (SSc). Circulating lymphocytes characterize the autoimmune nature of both conditions. Therefore we hypothesized that the common clinical manifestation (systemic organ and skin injury) and the common underlying players (lymphocytes) justify the combined meta-analysis of these diseases.ResultsThe aSCT and SSc datasets were uploaded from Gene Expression Omnibus (GEO), a public functional genomics data repository. The available microarray studies of peripheral blood mononuclear cells (PBMCs) and isolated lymphocytes were limited to well established microarray platforms (Affymetrix, Agilent, Canvac, and Illumina) and experimental settings with ≥10 patients per group. The resulting pools of data were merged by unique gene identifier and analyzed by the expression genome-wide association studies (eGWAS) coupled with the subtraction of the cGVHD+ and cGVHD− molecular signatures. The eGWAS was applied to 47 and 50 lymphocyte profiles from aSCT and SSc patients, respectively. The identified 35 candidates were represented by 8 known cGVHD genes (including CXCR4, LTBR and PML) and 28 new candidate genes (including SEPX1 and DNJGB1). The further mutual subtraction of cGVHD+ and cGVHD− candidates and pathway analysis identified a list of 25 genes. Seven of these genes belong to the fibroblast development and function pathway, consisting of the well known cGVHD genes CCND1, JUN, and FOS, and the new molecular targets MMP2, FOSB, TNFAIP8, and DUSP1. These genes become primary candidates for a potential link of systemic effects of cGVHD and SSc.ConclusionsWe designed a new approach for meta-analysis by combining data from different diseases using common clinical manifestation as a linker. This allowed us to power up the insufficient standalone meta-analysis of aSCT microarray studies, by adding SSc samples to the data pool. This new method has successfully identified novel molecular targets for systemic effects of both aSCT and SSc. We believe that this approach is generalizable and can be applied to an array of diseases with common clinical manifestations.

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Gene expression profile of cytokines in patients with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation with reduced conditioning

Cited by 12 publications

References 28 publications

Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

Plasmacytoid Dendritic Cells Suppress HIV-1 Replication but Contribute to HIV-1 Induced Immunopathogenesis in Humanized Mice

Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor

Combined meta-analysis of systemic effects of allogeneic stem cell transplantation and systemic sclerosis

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