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See detailScreening transplant donors for HTLV-1 and -2
Gallo, Robert; Willems, Luc ULg; Hasegawa, 4 Hideki et al

in Blood (2016), 128(26),

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See detailHost Interleukin 6 and Indoleamine 2,3 Dioxygenase Regulate Inflammation in the Brain during Graft Versus Host Disease
Belle, Ludovic ULg; Koester, E; Hansen, E et al

in Blood (2016, December), 128

Graft versus host disease (GVHD) commonly induces pathological damage in peripheral target organs such as the skin, liver and gastrointestinal tract leading to well characterized organ-specific clinical ... [more ▼]

Graft versus host disease (GVHD) commonly induces pathological damage in peripheral target organs such as the skin, liver and gastrointestinal tract leading to well characterized organ-specific clinical manifestations. A number of studies, however, have shown that patients with GVHD can also have behavioral and mood alterations that can affect overall cognitive function and lead to significant impairments in quality of life. The extent to which GVHD contributes to cognitive dysfunction and induces inflammation within the central nervous system (CNS), however, has not been critically examined. To address this question, we conducted studies using two well-defined murine GVHD models [C57BL/6(H-2b)→Balb/c (H-2d) and B10.BR(H-2k)→B6 (H-2b)]. We observed that there was a significant increase in the number of donor-derived CD4+ and CD8+ T cells in the brains of GVHD recipients early (days 7 -14) and late (day 42) post transplantation compared to BM controls. Histological studies revealed activated microglial cells and CD3+ T cell infiltration in the periventricular regions of brains in GVHD recipients that were not present in BM animals. Real time q-PCR analysis also demonstrated significant increases in IFN-γ, TNF-α, and IL-6 mRNA expression indicative of a proinflammatory state. Notably, GVHD animals exhibited behavioral changes in the forced swim test and elevated plus maze which are validated assays of stress coping and anxiety, respectively. Since IL-6, in particular, plays a pivotal role in GVHD pathogenesis in murine models and humans, we examined whether blockade of IL-6 signaling altered neuroinflammation. Animals treated with an anti-IL-6R antibody had a significant reduction in the number of donor-derived CD4+ and CD8+T cells in the brain compared to isotype control-treated mice. Anti-IL-6R treatment of GVHD mice also resulted in significant reductions in IFN-γ, TNF-α, and IL-6 mRNA and normalized behavior in the forced swim test, indicative of a decreased inflammatory response. Since IL-6 is produced by a wide variety of cells, including microglial and T cells, both donor and recipient cells have the potential to modulate GVHD severity within the CNS. To define whether donor or host IL-6 production was most critical for inducing neuroinflammation, experiments were conducted employing IL-6-/- mice as either donors or recipients. Whereas the absence of IL-6 in donor-derived cells had no impact on the degree of inflammation within the CNS, recipient animals that lacked IL-6 had a significant decrease in the number of donor-derived T cells which accumulated in the brain as well as a marked reduction in inflammatory cytokines, indicating that host IL-6 production was critical. To define the downstream pathways of IL-6-mediated CNS inflammation, we examined the role of indoleamine 2,3-dioxygenase (IDO) since IL-6 has been shown to upregulate IDO-1 expression under inflammatory conditions. We observed that IDO-1 mRNA levels were significantly increased in the brains of GVHD animals, and that blockade of IL-6 signaling resulted in a marked decrease in IDO mRNA levels. Additionally, transplantation studies using IDO-/- mice revealed that host, but not donor, IDO production was required for maximal inflammatory effects. Serotoninergic projections to the prefrontal cortex (PFC), in particular, are sensitive to inflammation and contribute to stress coping behavior. Therefore, to further interrogate this pathway, we performed quantitative mass spectrometry of brain extracts from the PFC. We found that tryptophan and 5HT concentrations were not different between BM and GVHD groups. However, there was an increase in the IDO product, kynurenic acid, in GVHD recipients consistent with an increase in brain IDO expression. To provide additional support for the premise that IL-6 effects were mediated through the IDO pathway, recipient mice were treated with either 1-methyltryptophan (1-MT), a completive inhibitor of IDO, or a vehicle control. GVHD mice treated with 1-MT had decreased accumulation of T cells in the brain and normal behavior in the forced swim test, demonstrating that inhibition of IDO abrogated CNS inflammation and behavioral changes in the presence of intact IL-6 signaling. In summary, these studies demonstrate that host IL-6 and IDO regulate inflammation and adversely impact behavioral function within the brain during GVHD through the tryptophan metabolic pathway. [less ▲]

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See detailBlockade of Interleukin 27 Signaling Attenuates Graft Versus Host Disease By Augmenting CD4+ and CD8+ Regulatory T Cell Reconstitution
Belle, Ludovic ULg; Agle, Kimberlee; Zhou, Vivian et al

in Blood (2016), 128

Reestablishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft-versus-host disease (GVHD), and recalibrate the effector and regulatory arms of the immune system ... [more ▼]

Reestablishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft-versus-host disease (GVHD), and recalibrate the effector and regulatory arms of the immune system. However, clinically feasible, cost-effective strategies that do not require extensive ex vivo cellular manipulation have remained elusive. In the current study, we demonstrate that inhibition of the interleukin-27p28 (IL-27p28) signaling pathway through antibody blockade or genetic ablation prevented lethal GVHD in multiple murine transplant models. Moreover, protection from GVHD was attributable to augmented global reconstitution of CD4+ natural regulatory T cells (nTregs), CD4+ induced Tregs (iTregs), and CD8+ iTregs, and was more potent than temporally concordant blockade of IL-6 signaling. Inhibition of IL-27p28 also enhanced the suppressive capacity of adoptively transferred CD4+ nTregs by increasing the stability of Foxp3 expression. Notably, blockade of IL-27p28 signaling reduced T-cell–derived-IL-10 production in conventional T cells; however, there was no corresponding effect in CD4+ or CD8+ Tregs, indicating that IL-27 inhibition had differential effects on IL-10 production and preserved a mechanistic pathway by which Tregs are known to suppress GVHD. Targeting of IL-27 therefore represents a novel strategy for the in vivo expansion of Tregs and subsequent prevention of GVHD without the requirement for ex vivo cellular manipulation, and provides additional support for the critical proinflammatory role that members of the IL-6 and IL-12 cytokine families play in GVHD biology. [less ▲]

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See detailActivating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell–derived lymphomas
Vallois, David; Dobay, Maria Pamela D.; Morin, Ryan D. et al

in Blood (2016), 128

Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood ... [more ▼]

Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n 5 72) or other TFH-derived PTCL (n 5 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-kB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlationwithpresenting clinical featuresnor significantimpacton survivalwasobserved, thepresenceofTCR-relatedmutations correlated with early disease progression. Thus, targeting of TCR-related eventsmay hold promise for the treatment of TFH-derived lymphomas. [less ▲]

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See detailImpact of Age and Treatment Group in Childhood High Hyperdiploid Low Risk B-Cell Acute Lymphoblastic Leukemia (ALL): Results of the CLG-EORTC 58951 Study
Clement, Laura; Suciu, Stefan; Luquet, Isabelle et al

in Blood (2016)

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See detailTreatment of Multiple Myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group
Sonneveld, Pieter; Avet-Loiseau, Hervé; Lonial, Sagar et al

in Blood (2016), 127(24), 2955-62

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See detailBlockade of Interleukin 27 Signaling Attenuates Graft Versus Host Disease By Augmenting CD4+ and CD8+ Regulatory T Cell Reconstitution
Belle, Ludovic ULg; Agle, K; Zhou, V et al

in Blood (2015, December), 126

The interleukin-6 (IL-6) cytokine superfamily (i.e. IL-6, IL-12, and IL-23) plays a major role in the modulation of inflammatory and regulatory pathways during graft versus host disease (GVHD). IL-27, a ... [more ▼]

The interleukin-6 (IL-6) cytokine superfamily (i.e. IL-6, IL-12, and IL-23) plays a major role in the modulation of inflammatory and regulatory pathways during graft versus host disease (GVHD). IL-27, a recently discovered member of this family, is a heterodimeric cytokine that is composed of the p28 and EBI3 subunits and signals through a heterodimeric receptor composed of WSX-1 and gp130. Notably, IL-6 also uses gp130 as a signaling component which biologically links IL-27 and IL-6. IL-27 has been shown to have opposing proinflammatory and immunoregulatory effects, but its role in GVHD is not well understood. To define the functional significance of IL-27, lethally irradiated Balb/c (H-2d) mice were transplanted with C57BL/6J (H-2b) BM and spleen cells, and then treated with an anti-IL-27p28-specific antibody on days 0 and +6. p28 antibody-treated animals had significantly improved weight recovery and overall survival (47% versus 0% survival at day 60, p=0.002), as well as reduced numbers of proinflammatory CD4+ and CD8+ IFN-γ+ T cells in GVHD target organs, when compared to isotype control antibody-treated mice. A similar outcome was observed in an MHC-matched, minor antigen disparate model (B6→Balb.B), indicating that this was not a strain-specific phenomenon. Given the similarities between IL-6 and IL-27, we examined whether blockade of IL-27 promoted regulatory T cell (Treg) reconstitution as has been observed with inhibition of IL-6 signaling. Recipients transplanted with BM grafts from B6 Foxp3EGFP reporter animals and treated with p28 antibody had a significant increase in the number of CD4+ nTregs, CD4+ iTregs and CD8+ iTregs in GVHD target organs, indicating that blockade of IL-27 augmented global Treg reconstitution. In fact, inhibition of IL-27 was more effective at augmenting Treg reconstitution than comparable antibody blockade of IL-6. To further elucidate the role of IL-27, we employed transgenic IL-27−/− and IL-27R−/− animals to dissect the relevant contributions of donor and recipient populations. Paradoxically, we observed that transplantation with IL-27−/− donor grafts exacerbated GVHD mortality and augmented accumulation of proinflammatory T cells, whereas transplantation of recipient IL-27−/− mice with wild type grafts had no effect on transplant outcomes. This discordance between antibody-based and genetic studies was unexpected and led us to consider whether there were steady state alterations in T cells from IL-27−/− animals that biased these cells towards a proinflammatory phenotype. To that end, we observed that naive CD8+ T cells from IL-27−/− mice had greater IFN-γ production than wild type cells after in vitro polyclonal stimulation and CD4+ nTregs from these animals had diminished expression of CXCR3 which is critical for Treg trafficking into inflamed tissue sites. Thus, the lack of endogenous IL-27 resulted in intrinsic immune dysregulation which led to an exacerbation of GVHD after transfer of these T cells into recipients. To resolve this paradox, we employed IL-27R−/− (WSX-1−/−) mice and demonstrated that mice transplanted with IL-27R−/− grafts had enhanced weight recovery and survival providing confirmation that blockade of IL-27 signaling reduced GVHD. In addition, using IL-27R−/− Foxp3EGFP reporter mice, we observed increased frequencies and numbers of CD4+ and CD8+ Foxp3+ T cells in mice reconstituted with IL-27R−/− grafts, confirming results observed with p28 antibody blockade. Since IL-10 is a mechanism by which CD4+ Tregs suppress GVHD and IL-27 has been shown to enhance T cell-derived IL-10 secretion in nontransplant models, we examined whether IL-27 blockade adversely affected IL-10 production by Tregs. Recipients transplanted with marrow grafts from IL-10.BitFoxp3EGFP dual reporter animals and treated with p28 antibody had a significant reduction in the frequency of IL-10-producing conventional CD4+ and CD8+ T cells in GVHD target organs. Notably, however, there was no difference in the frequency of CD4+ Foxp3+ IL-10+ T cells, indicating that blockade of IL-27 signaling preferentially affected conventional T cells and had no adverse effect on CD4+ Foxp3+ T cell-derived IL-10 production. In summary, these studies demonstrate that blockade of IL-27 signaling potently augments Treg reconstitution leading to a reduction in the severity of GVHD and may therefore represent a novel strategy to reduce mortality from this disease in man. [less ▲]

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See detailOutcome and risk factor analysis of molecular subgroups in cytogenetically normal AML treated by allogeneic transplantation
SCHMID, Christoph; LABOPIN, Myriam; SOCIE, Gerard et al

in Blood (2015)

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) can be subdivided by molecular mutations. However, data on the influence of combinations of different aberrations on outcome after ... [more ▼]

Patients with cytogenetically normal acute myeloid leukemia (CN-AML) can be subdivided by molecular mutations. However, data on the influence of combinations of different aberrations on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) is limited. Therefore, we performed a retrospective registry analysis on 702 adults with CNAML undergoing HSCT in first complete remission (CR). Patients were grouped according to presence or absence of NPM1 mutations (NPM1mut) and FLT3 internal tandem duplications (FLT3-ITD). Double negative patients were evaluated for mutations of the CCAAT/enhancer binding protein α gene (CEBPα). The influence of genotypes on relapse, non-relapse mortality, leukemia-free survival (LFS) and overall survival (OS), and a prognostic classification combining NPM1/FLT3-ITD profile and classical risk factors were calculated. 2y-OS from HSCT was 81±5% in NPM1mut/FLT3wt (n=68), 75±3% in NPM1wt/FLT3wt (n=290), 66±3% in NPM1mut/FLT3-ITD (n=269) and 54±7% in NPM1wt/FLT3-ITD (n=75; p=0.003). Analysis of CEBPα among patients with NPM1wt/FLT3wt revealed excellent results both in patients with CEBPα mut (n=13, 2y-OS:100%), and with a triple negative genotype (n=138, 2y-OS:77±3%). In a Cox-model of predefined factors, older age, presence of FLT3-ITD and >1 course of chemotherapy to reach CR were associated with inferior outcome. 2y-OS/LFS were 88±3%/79±4% in patients without any, 77±2%/73±3% with one, and 53±4%/50±4 with>=2 risk factors (p=0.002 for LFS, p=0.003 for OS). Hence, FLT3-ITD proofed to be the decisive molecular marker for outcome after HSCT for CN-AML in CR1, regardless of NPM1 mutational status, variations of transplant protocols, or development of GvHD. Age, FLT3-ITD and response to induction chemotherapy allow for a prognostic risk classification. [less ▲]

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See detailFlow Cytometry Assessment of CD34+ Viability in Thawed Cord Blood Units: A Multi-Center Eurocord and Netcord Study
SACCARDI, RICCARDO; AZQUETA, Carmen; BALLERINI, Lara et al

in Blood (2014), 124

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See detailRIC allo-SCT with Flu/Bu in comparaison to Flu/Mel for AML results in similar overall survival: a report from the ALWP of the EBMT
BARON, Frédéric ULg; LABOPIN, Myriam; PENIKET, Andrew et al

in Blood (2014, December), 124(21), 545

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