Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness

Chronic viral infections are associated with hematopoietic suppression, bone marrow (BM) failure, and hematopoietic stem cell (HSC) exhaustion. However, how persistent viral challenge and inflammatory responses target BM tissues and perturb hematopoietic competence remains poorly understood. Here, we combine functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus leads to (1) long-lasting decimation of the BM stromal network of mesenchymal CXCL12-abundant reticular cells, (2) proinflammatory transcriptional remodeling of remaining components of this key niche subset, and (3) durable functional defects and decreased competitive fitness in HSCs. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined antibody-mediated inhibition of type I and II IFN pathways completely preempts degeneration of CARc and protects HSCs from chronic dysfunction. Hence, viral infections and ensuing immune reactions durably impact BM homeostasis by persistently decreasing the competitive fitness of HSCs and disrupting essential stromal-derived, hematopoietic-supporting cues

Rezensionen

Rezension zu: 1) Bender Walter/Zech, Rainer (Hrsg.): ... denn sie wissen, was sie tun! Auf dem Weg zur selbstreflexiven Organisation. Fallstudien zur Qualitätsentwicklung. Schriftenreihe für kritische Sozialforschung und Bildungsarbeit, Bd. 12. Hannover: Espressum Verl. 2007. ISBN 978-3-89069-014-8. 2) Göhlich, Michael; Wulf, Christoph; Zirfas, Jörg (Hrsg.): Pädagogische Theorien des Lernens. Weinheim: Beltz 2007. ISBN 978-3-407-32072-8. 3) Göhlich, Michael; König, Eckard; Schwarzer, Christine (Hrsg.): Beratung, Macht und organisationales Lernen. Wiesbaden: VS Verl. f. Sozialwiss. 2007. ISBN 978-3-531-15360-5. 4) Heimbach-Steins, Marianne; Kruip, Gerhard; Kunze, Axel Bernd: Das Menschenrecht auf Bildung und seine Umsetzung in Deutschland. Diagnose – Reflexionen – Perspektiven. Bielefeld: W. Bertelsmann 2007. ISBN 978-3-7639-3542-0. 5) Pallasch, Waldemar; Hameyer, Uwe: Lerncoaching - theoretische Grundlage und Praxisbeispiele zu einer didaktischen Herausforderung. Weinheim: Juventa 2008. ISBN 978-3-7799-2136-3. 6) Tippelt, Rudolf; Reich, Jutta; Hippel, Aiga v.; Barz, Heiner; Baum, Dajana: Weiterbildung und soziale Milieus in Deutschland. Bd. 3, Milieumarketing implementieren. Bielefeld: W. Bertelsmann 2008. ISBN 978-3-7639-1943-7. 7) Tödt, Katia: Lernerorientierte Qualitätstestierung für Bildungsveranstaltungen (LQB). Bielefeld: W. Bertelsmann 2008. ISBN 978-3-7639-3625-0. 8) Walber, Markus: Selbststeuerung im Lernprozess und Erkenntniskonstruktion: eine empirische Studie in der Weiterbildung. Münster: Waxmann 2007. ISBN 978-3-8309-1888-2. 9) Weil, Markus: Weiterbildungskooperation in KMU: eine Perspektive für berufs- und wirtschaftspädagogische Konzepte. Bern: h.e.p. Verl. 2006. ISBN 3-03905-234-9

Antibody Response to SARS-CoV-2 Vaccination in Patients following Allogeneic Hematopoietic Cell Transplantation

Vaccines against SARS-CoV-2 have been rapidly approved. Although pivotal studies were conducted in healthy volunteers, little information is available on the safety and efficacy of mRNA vaccines in immunocompromised patients, including recipients of allogeneic hematopoietic cell transplantation (allo-HCT). Here we used a novel assay to analyze patient- and transplantation-related factors and their influence on immune responses to SARS-CoV-2 vaccination over an extended period (up to 6 months) in a large and homogenous group of allo-HCT recipients at a single center in Switzerland. We examined longitudinal antibody responses to SARS-CoV-2 vaccination with BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna) in 110 allo-HCT recipients and 86 healthy controls. Seroprofiling recording IgG, IgA, and IgM reactivity against SARS-CoV-2 antigens (receptor-binding domain, spike glycoprotein subunits S1 and S2, and nucleocapsid protein) was performed before vaccination, before the second dose, and at 1, 3, and 6 months after the second dose. Patients were stratified to 3 groups: 3 to 6 months post-allo-HCT, 6 to 12 months post-allo-HCT, and >12 months post-allo-HCT. Patients in the 3 to 6 months and 6 to 12 months post-allo-HCT groups developed significantly lower antibody titers after vaccination compared with patients in the >12 months post-allo-HCT group and healthy controls (P 65 years (P = .030), those receiving immunosuppression for prevention or treatment of graft-versus-host disease (GVHD) (P = .033), and patients with relapsed disease (P = .014) displayed low humoral immune responses to the vaccine. In contrast, the intensity of the conditioning regimen, underlying disease (myeloid/lymphoid/other), and presence of chronic GVHD had no impact on antibody levels. Antibody titers achieved the highest levels at 1 month after the second dose of the vaccine but waned substantially in all transplantation groups and healthy controls over time. This analysis of long-term vaccine antibody response is of critical importance to allo-HCT recipients and transplant physicians to guide treatment decisions regarding revaccination and social behavior during the SARS-CoV-2 pandemic. Keywords: Allogeneic hematopoietic cell transplantation; SARS-CoV-2; Vaccinatio

Antibody response to a third SARS-CoV-2 vaccine dose in recipients of an allogeneic haematopoietic cell transplantation

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies. Keywords: allogeneic haematopoietic cell transplantation; severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2); vaccine respons

Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response

BACKGROUNDNeutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated. METHODSWe conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7-11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends. RESULTSIn this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusion-related adverse events and low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (P = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio, 3.0; 95% CI, 1.1-8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1-11; P = 0.034). CONCLUSIONOur data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies. TRIAL REGISTRATIONClinicalTrials.gov NCT04869072. FUNDINGThis study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program "Comprehensive Genomic Pathogen Detection" of the University of Zurich

Was macht ein Coach? Nur ein Modetrend oder ernstzunehmendes Tätigkeitsfeld?

Coaching ist mittlerweile in verschiedensten Bereichen zum Thema geworden. Allein die Vielfalt der Begriffe, die jüngste Veröffentlichungen tragen, ist enorm. Gibt man „Coaching" als Stichwort in das „ Verzeichnis lieferbarer Bücher" ein, findet man aktuell u.a. Muskel-Coaching, Seelen-Coaching, Kleine-Kerle-Coaching, 30-Tage-Coaching, Spirituelles Coaching und vieles mehr. Was dahinter steckt ist oft nicht eindeutig zu erkennen, jedoch wird in der exponentiell gestiegenen Verwendung des Begriffs deutlich, dass Coaching als Mittel der Wahl, wenn nicht gar als Allheilmittel angepriesen wird und einem Bedürfnis nach Begleitung und Beratung in verschiedensten Lebensbereichen Rechnung getragen wird und in unserer Arbeits- und Lebenswelt als so notwendig erscheint. Sieht man jedoch einmal ab von diesem fast inflationären Gebrauch des Begriffes „Coaching", so verbirgt sich dahinter ein ernstzunehmendes Arbeitsfeld, welches aktuell auch auf einer Professionalisierungsebene diskutiert wird. Das Bemühen, Standards zu schaffen und Transparenz herzustellen, um Qualität zu sichern und auch die Weiterentwicklung des Feldes voranzutreiben wird zunehmend lauter. Die Fragen nach den Kompetenzen, Grenzen, Ausbildungsvoraussetzungen, einer Zertifizierung und auch die Frage nach dem Wert eines Coachings stellen dabei zentrale Aspekte der Diskussion dar. (DIPF/Orig.

Differential dynamics of HIV infection in humanized MISTRG versus MITRG mice

Humanized mice are a powerful tool to study HIV in vivo. The recently generated mouse strains MITRG and MISTRG, which differ in human SIRPα expression, support an improved human myeloid lineage development from human hematopoietic stem and progenitor cells. The rationale of the study was the characterization of the two mouse strains during an HIV infection with CCR5- and CXCR4-tropic viruses. Upon HIV infection, we observed HIV dissemination and sustained viral load over 20 wk in peripheral blood in both reconstituted mouse strains. However, HIV RNA levels were significantly lower in MITRG mice compared with MISTRG mice during the first 8 wk postinfection. HIV-infected MISTRG mice showed lymphocyte activation and changes in lymphocyte subsets in blood and spleen, recapitulating hallmarks of HIV infection in humans. Depletion of murine tissue-resident macrophages in MITRG mice led to significantly elevated viral loads, and lymphocyte levels were similar to those in HIV-infected MISTRG mice. Depletion of CD8+ T cells in MISTRG mice before HIV infection resulted in substantially decreased CD4+ T cell levels, indicating functionality of human CD8+ T cells; depletion of CD4+CD8+ thymocytes may have contributed, in part, to the latter finding. In summary, MITRG and MISTRG mice represent novel HIV mouse models, despite differential HIV dynamics

Modelling of a genetically diverse evolution of Systemic Mastocytosis with Chronic Myelomonocytic Leukemia (SM-CMML) by next generation sequencing

BACKGROUND Systemic mastocytosis (SM) is a heterogenous, clonal mast cell (MC) proliferation, rarely associated with clonal hematologic non-mast cell lineage disease (SM-AHNMD). KIT (D816V) is regarded as driver-mutation in SM-AHNMD. METHODS DNA isolated from peripheral blood (PB) of an SM-CMML patient was investigated with targeted next generation sequencing. Variants were verified by Sanger sequencing and further characterized in the SM part of the bone marrow trephine (BMT), normal tissue, and FACS sorted PB cell subpopulations. FINDINGS Low coverage deep-sequencing (mean 10x) on a GS 454 Junior revealed two as yet unreported SNVs (CBFA2T3 and CLTCL1), both germ-line mutations. High coverage (mean 1674x) targeted re-sequencing on an Ion Proton revealed 177 variants in coding regions. Excluding SNPs, the final list comprised 11 variants. Among these, TET2 (p.Thr1027fs, p.Cys1263Ser) and RUNX1 (p.Asn109Ser) were identified in in the peripheral blood and the SM part of BMT, but not in normal tissue. Furthermore, Sanger sequencing of PB cells revealed similar signal intensities for both TET2 mutations in FACS sorted CD34+ precursor cells and CD16+ granulocytes comparable to signals in the SM part of BMT. In contrast, RUNX1 exhibited a double intensity in CD34+ cells compared to the SM part of BMT and a homozygous variant signal in granulocytes. Both TET2 and RUNX1 mutations were not detectable in B- and T-cells. CONCLUSION We present a heterozygous triple-mutation pattern (KIT, TET2, RUNX1) in mast cells (SM disease part) with additional LOH of RUNX1 in granulocytes (CMML disease part). These identified mutations allow a more detailed insight into a multistep pathogenesis which suggests a common tumor progenitor in SM-CMML