Respiratory Virus Infections in Hematopoietic Cell Transplant Recipients

Highly immunocompromised pediatric and adult hematopoietic cell transplant (HCT) recipients frequently experience respiratory infections caused by viruses that are less virulent in immunocompetent individuals. Most of these infections, with the exception of rhinovirus as well as adenovirus and parainfluenza virus in tropical areas, are seasonal variable and occur before and after HCT. Infectious disease management includes sampling of respiratory specimens from nasopharyngeal washes or swabs as well as sputum and tracheal or tracheobronchial lavages. These are subjected to improved diagnostic tools including multiplex PCR assays that are routinely used allowing for expedient detection of all respiratory viruses. Disease progression along with high mortality is frequently associated with respiratory syncytial virus, parainfluenza virus, influenza virus, and metapneumovirus infections. In this review, we discuss clinical findings and the appropriate use of diagnostic measures. Additionally, we also discuss treatment options and suggest new drug formulations that might prove useful in treating respiratory viral infections. Finally, we shed light on the role of the state of immune reconstitution and on the use of immunosuppressive drugs on the outcome of infection

A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm requiring hematopoietic stem cell transplantation (HSCT) in most cases. We retrospectively analyzed 119 JMML patients who underwent first allogeneic HSCT between 2002 and 2021. The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95%CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatmentrelated mortality (TRM) of 9.0% (95%CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95%CI: 65.7-82.4) and 66.4% (95%CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT >6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with three or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%. Our study demonstrates improved transplant outcomes compared to prior published data, which can be attributed to the synergistic impacts of a low TRM and a reduced yet still substantial relapse incidence. By integrating genetic information with clinical and hematological features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit novel therapeutic agents and post-transplant strategies

Respiratory Virus Infections in Hematopoietic Cell Transplant Recipients

Highly immunocompromised pediatric and adult hematopoietic cell transplant (HCT) recipients frequently experience respiratory infections caused by viruses that are less virulent in immunocompetent individuals. Most of these infections, with the exception of rhinovirus as well as adenovirus and parainfluenza virus in tropical areas, are seasonal variable and occur before and after HCT. Infectious disease management includes sampling of respiratory specimens from nasopharyngeal washes or swabs as well as sputum and tracheal or tracheobronchial lavages. These are subjected to improved diagnostic tools including multiplex PCR assays that are routinely used allowing for expedient detection of all respiratory viruses. Disease progression along with high mortality is frequently associated with respiratory syncytial virus, parainfluenza virus, influenza virus, and metapneumovirus infections. In this review, we discuss clinical findings and the appropriate use of diagnostic measures. Additionally, we also discuss treatment options and suggest new drug formulations that might prove useful in treating respiratory viral infections. Finally, we shed light on the role of the state of immune reconstitution and on the use of immunosuppressive drugs on the outcome of infection.Peer Reviewe

Immunorégulation de la maladie du Greffon contre l’Hôte (GVH) par les cellules souches mésenchymateuses de la gelée de Wharton : études in vitro et in vivo sur un modèle de GVH chez la souris NSG

Wharton's Jelly Mesenchymal Stem Cells (WJ-MSC) are pluripotent stromal cells derived from umbilical cords. In our study, WJ-MSCs produced at clinical grade at the University Hospital of Nancy have an anti-proliferative potential of variable intensity on T lymphocytes (LTs). Pre-incubation of WJ-MSCs with IFN-γ (WJ-MSC-IFN) for 48 h increases their anti-proliferative potential in vitro. We showed that this effect was related to an increase in indoleamine2,3-dioxygenase (IDO) activity by WJ-MSCs. We also observed that independently of IFN activation and of IDO, WJ-MSCs can transfer mitochondrial material to activated LTs. This transfer is contact-dependent, as is the immunosuppressive action of WJ-MSCs. After mitochondrial transfer, activated T cells having received mitochondria proliferate significantly less than those that had not received mitochondria. IDO inhibition restores the proliferative capacity of LTs, whether or not they have received mitochondria. The analysis of the metabolic pathways of LTs in the presence of WJ-MSCs revealed a modulation of T cell metabolism characterized by a decrease in aerobic glycolysis and an increase in oxidative phosphorylation, a phenomenon reversed by IDO inhibition. Finally, we have shown in a mouse model of graft versus host disease (GVHD), that 3 sequential injections of WJ-MSC-IFN (at D7, D14 and D21 post-transplantation) allow to reduce the clinical and histological signs of GVHD and increase mouse survival. This protective effect against GVHD was not related to a lower proliferation of LTs, nor to the induction of regulatory T cells. The “homing” studies of WJ-MSCs have shown their presence in the lung and at a lower rate in the skin 24 hours after administration, then they become undetectable. Their contact with LTs is nevertheless transiently possible in these organs after each administration. Altogether, our results suggest that WJ-MSC-IFN inhibit LT activation via complementary mechanisms involving IDO production and mitochondrial transfer modulating T cell metabolism. The results of the preclinical study led us to develop of a phase I clinical trial of several administrations of WJ-MSC for the prevention of GvHD.Les Cellules Souches Mésenchymateuses de gelée de Wharton (CSM-GW) sont des cellules stromales pluripotentes issues de cordons ombilicaux. Dans notre étude, les CSM-GW produites à grade clinique au CHRU de Nancy ont un potentiel anti-prolifératif d’intensité variable selon le cordon source sur les lymphocytes T (LT). La pré-incubation des CSM-GW par IFN-γ (CSM-GW-IFN) pendant 48h augmente leur potentiel anti-prolifératif in vitro. Nous montrons que cet effet est lié à l’augmentation de l’activité de l’indoleamine2,3-dioxygénase (IDO) des CSM-GW-IFN. Nous avons également observé que, indépendamment de l’activation par IFN et d’IDO, les CSM-GW sont capables de transférer du matériel mitochondrial vers les LT activés. Ce transfert est contact dépendant, tout comme l’action immunosuppressive des CSM-GW. Après transfert mitochondrial, les LT activés ayant reçu des mitochondries prolifèrent significativement moins que ceux n’ayant pas reçu de mitochondries. L’inhibition d’IDO restaure la capacité proliférative des LT, qu’ils aient ou non reçu des mitochondries. L’analyse des voies métaboliques des LT activés en présence de CSM-GW, a révélé une modulation du métabolisme des LT caractérisée par une diminution de la glycolyse aérobie et une augmentation de la phosphorylation oxydative, phénomène reversé par l’inhibition d’IDO. Nous avons enfin montré dans un modèle murin de maladie du greffon contre l’hôte (GVH), que 3 injections de CSM-GW-IFN séquentielles (J7, J14 et J21 post-greffe) permettaient de réduire les signes cliniques et histologiques de GVH et d’augmenter la survie des souris. Cet effet protecteur vis-à-vis de la GVH n’était pas lié à une prolifération moindre des lymphocytes T dans le sang, ni à l’induction de T régulateurs. Les études de « homing » des CSM-GW ont permis de les détecter dans les poumons et à moindre taux dans la peau 24H après l’administration puis elles deviennent indétectables. Leur contact avec les lymphocytes T est néanmoins transitoirement possible dans ces organes après chaque administration. Au total, nos résultats suggèrent que les CSM-GW-IFN inhibent l’activation des LT via des mécanismes complémentaires impliquant la production d’IDO et le transfert de mitochondries qui vont moduler le métabolisme des LT activés. Les résultats de l’étude préclinique nous ont conduit au développement d’une étude clinique de phase I d’injections de CSM-GW en prévention de la GVH chez l’homme

Impact of Wharton Jelly Mesenchymal Stem Cells on Graft versus Host Disease

Les Cellules Souches Mésenchymateuses de gelée de Wharton (CSM-GW) sont des cellules stromales pluripotentes issues de cordons ombilicaux. Dans notre étude, les CSM-GW produites à grade clinique au CHRU de Nancy ont un potentiel anti-prolifératif d’intensité variable selon le cordon source sur les lymphocytes T (LT). La pré-incubation des CSM-GW par IFN-γ (CSM-GW-IFN) pendant 48h augmente leur potentiel anti-prolifératif in vitro. Nous montrons que cet effet est lié à l’augmentation de l’activité de l’indoleamine2,3-dioxygénase (IDO) des CSM-GW-IFN. Nous avons également observé que, indépendamment de l’activation par IFN et d’IDO, les CSM-GW sont capables de transférer du matériel mitochondrial vers les LT activés. Ce transfert est contact dépendant, tout comme l’action immunosuppressive des CSM-GW. Après transfert mitochondrial, les LT activés ayant reçu des mitochondries prolifèrent significativement moins que ceux n’ayant pas reçu de mitochondries. L’inhibition d’IDO restaure la capacité proliférative des LT, qu’ils aient ou non reçu des mitochondries. L’analyse des voies métaboliques des LT activés en présence de CSM-GW, a révélé une modulation du métabolisme des LT caractérisée par une diminution de la glycolyse aérobie et une augmentation de la phosphorylation oxydative, phénomène reversé par l’inhibition d’IDO. Nous avons enfin montré dans un modèle murin de maladie du greffon contre l’hôte (GVH), que 3 injections de CSM-GW-IFN séquentielles (J7, J14 et J21 post-greffe) permettaient de réduire les signes cliniques et histologiques de GVH et d’augmenter la survie des souris. Cet effet protecteur vis-à-vis de la GVH n’était pas lié à une prolifération moindre des lymphocytes T dans le sang, ni à l’induction de T régulateurs. Les études de « homing » des CSM-GW ont permis de les détecter dans les poumons et à moindre taux dans la peau 24H après l’administration puis elles deviennent indétectables. Leur contact avec les lymphocytes T est néanmoins transitoirement possible dans ces organes après chaque administration. Au total, nos résultats suggèrent que les CSM-GW-IFN inhibent l’activation des LT via des mécanismes complémentaires impliquant la production d’IDO et le transfert de mitochondries qui vont moduler le métabolisme des LT activés. Les résultats de l’étude préclinique nous ont conduit au développement d’une étude clinique de phase I d’injections de CSM-GW en prévention de la GVH chez l’homme.Wharton's Jelly Mesenchymal Stem Cells (WJ-MSC) are pluripotent stromal cells derived from umbilical cords. In our study, WJ-MSCs produced at clinical grade at the University Hospital of Nancy have an anti-proliferative potential of variable intensity on T lymphocytes (LTs). Pre-incubation of WJ-MSCs with IFN-γ (WJ-MSC-IFN) for 48 h increases their anti-proliferative potential in vitro. We showed that this effect was related to an increase in indoleamine2,3-dioxygenase (IDO) activity by WJ-MSCs. We also observed that independently of IFN activation and of IDO, WJ-MSCs can transfer mitochondrial material to activated LTs. This transfer is contact-dependent, as is the immunosuppressive action of WJ-MSCs. After mitochondrial transfer, activated T cells having received mitochondria proliferate significantly less than those that had not received mitochondria. IDO inhibition restores the proliferative capacity of LTs, whether or not they have received mitochondria. The analysis of the metabolic pathways of LTs in the presence of WJ-MSCs revealed a modulation of T cell metabolism characterized by a decrease in aerobic glycolysis and an increase in oxidative phosphorylation, a phenomenon reversed by IDO inhibition. Finally, we have shown in a mouse model of graft versus host disease (GVHD), that 3 sequential injections of WJ-MSC-IFN (at D7, D14 and D21 post-transplantation) allow to reduce the clinical and histological signs of GVHD and increase mouse survival. This protective effect against GVHD was not related to a lower proliferation of LTs, nor to the induction of regulatory T cells. The “homing” studies of WJ-MSCs have shown their presence in the lung and at a lower rate in the skin 24 hours after administration, then they become undetectable. Their contact with LTs is nevertheless transiently possible in these organs after each administration. Altogether, our results suggest that WJ-MSC-IFN inhibit LT activation via complementary mechanisms involving IDO production and mitochondrial transfer modulating T cell metabolism. The results of the preclinical study led us to develop of a phase I clinical trial of several administrations of WJ-MSC for the prevention of GvHD

Shifting Paradigms: The Case of Autologous Reconstitution after an Upfront Matched Unrelated Hematopoietic Cell Transplantation for Severe Acquired Aplastic Anemia in a Child

During the last few years, the therapeutic landscape of idiopathic aplastic anemia (IAA) has been profoundly revolutionized by the increased use of alternative transplant procedures, such that today hematopoietic cell transplantation (HCT) from a matched unrelated donor (MUD) has been suggested as a possible first line strategy in pediatric patients with severe IAA, in the absence of a matched related donor. However, in this particular context, outcomes and early and long-term toxicities remain to be determined, as compared to non-transplant procedures. While prospective trials are ongoing, we report here the case of a 12-year-old boy with IAA, receiving an upfront bone marrow HCT from a MUD, who experienced early graft rejection associated with autologous hematological recovery, which could induce remission of his hemopathy. This case offers the opportunity to discuss the challenges associated with these new transplant paradigms and provides a brief review of the literature regarding the issue of autologous recoveries after allogeneic HCT in IAA

Long-term Adverse Effects of Acute Myeloid Leukemia Treatment on Odontogenesis in a Child

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Water pumping in mantle shear zones

International audienceWater plays an important role in geological processes. Providing constraints on what may influence the distribution of aqueous fluids is thus crucial to understanding how water impacts Earth's geodynamics. Here we demonstrate that ductile flow exerts a dynamic control on water-rich fluid circulation in mantle shear zones. Based on amphibole distribution and using dislocation slip-systems as a proxy for syn-tectonic water content in olivine, we highlight fluid accumulation around fine-grained layers dominated by grain-size-sensitive creep. This fluid aggregation correlates with dislocation creep-accommodated strain that localizes in water-rich layers. We also give evidence of cracking induced by fluid pressure where the highest amount of water is expected. These results emphasize long-term fluid pumping attributed to creep cavitation and associated phase nucleation during grain size reduction. Considering the ubiquitous process of grain size reduction during strain localization, our findings shed light on multiple fluid reservoirs in the crust and mantle

Enhanced Cytotoxic Activity of Ex Vivo-differentiated Human Natural Killer Cells in the Presence of HOXB4

International audienceWe have previously shown that human umbilical cord blood CD34 progenitor cells undergo in vitro differentiation into functional natural killer (NK) cells and that their coculture in the presence of HOXB4-transduced stromal MS-5 cells resulted in an increase in differentiated NK number. The present study was conducted to compare the stromal effect on NK lytic potential in the presence and absence of HOXB4. Our results provide evidence that HOXB4-transduced MS-5 cells as compared with transduced GFP (+) MS-5 cells induced highly differentiated cytotoxic NK cells. Importantly, this difference was not because of the expression of activating NK receptors but was associated with an increased induction of granzyme B degranulation in response to stimulation with NK cell susceptible targets. DNA microarray-based global transcriptional profiling confirmed the upregulation of granzyme B. These findings provide further evidence that HOXB4 is a crucial regulator of NK function and that its use in generating functional NK cells with increased lytic potential may be significant for cancer immunotherapy