The diagnostic accuracy of ARFI liver and spleen was comparable to TE and Fibrotest for the detection of complications in patients with cirrhosis.

In a clinical phase I/II trial, pediatric patients with high-risk malignancies were treated with ex vivo IL-2-stimulated donor natural killer (NK) cells after transplantation with haploidentical stem cells. To evaluate the potential negative effects of the immunosuppressive drug mycophenolate mofetil (MMF) used for immunotherapy, the functionality and signaling of ex vivo NK cells was investigated. Our results show that during NK cell expansion, long-term (9 days) incubation with mycophenolic acid (MPA), the active metabolite of MMF, in therapeutically relevant concentrations led to the severe inhibition of NK cell proliferation. This correlated with a significantly reduced cytokine/chemokine secretion and the inhibited acquisition of surface receptors regarding cytotoxicity (e.g., NKp30, NKp44, NKp46, NKG2D), adhesion/migration (e.g., ICAM-1/CD54, LFA-1/CD11a, CD62L, CXCR3) and activation (e.g., CD25). Moreover, MPA prevented phosphorylation of the central signaling molecules STAT-3/-4/-5, AKT and ERK1/2. In contrast, short-term (24 h) MPA incubation of IL-2-stimulated NK cells had no or only marginal effects on the activated NK cell phenotype, including receptor expression, cytokine/chemokine secretion and intracellular signaling. Further, short-term MPA incubation only moderately affected the highly cytotoxic activity of previously IL-2-stimulated NK cells. In conclusion, while long-term MPA incubation significantly compromised ex vivo NK cell functionality, previously IL-2-activated NK cells seemed to be rather resistant to short-term MPA treatment. This finding supports the use of IL-2-activated NK cells as immunotherapy, especially for patients treated with MMF after haploidentical stem cell transplantation.

Unlike the mechanism reported in other malignancies, NKG2D-mediated cytotoxicity does not constitute the major killing mechanism of CIK cells against NB.

No abstract

To elucidate cross-sectional patterns and longitudinal changes of oral and stool microbiota in multiple sclerosis (MS) patients and the effect of B-cell depletion. We conducted an observational, longitudinal clinical cohort study analysing four timepoints over 12 months in 36 MS patients, of whom 22 initiated B-cell depleting therapy with ocrelizumab and a healthy control group. For microbiota analysis of the oral cavity and the gut, provided stool and oral swab samples underwent 16S rDNA sequencing and subsequent bioinformatic analyses. Oral microbiota-patterns exhibited a reduced alpha-diversity and unique differential microbiota changes compared to stool such as increased levels of Proteobacteria and decreased abundance of Actinobacteria. Following B-cell depletion, we observed increased alpha-diversity in the gut and the oral cavity as well as a long-term sustained reduction of pro-inflammatory Gram-negative bacteria (e.g., Escherichia/Shigella). MS patients have altered stool and oral microbiota diversity patterns compared to healthy controls, which are most pronounced in patients with higher disease activity and disability. Therapeutic B-cell depletion is associated with persisting regression of these changes. Whether these microbial changes are unspecific side-effects of B-cell depletion or indirectly modulate MS disease activity and progression is currently unknown and necessitates further investigations.

BackgroundCytokine-induced-killer (CIK) cells are a promising immunotherapeutic approach for impending relapse following hematopoietic stem cell transplantation (HSCT). However, there is a high risk for treatment failure associated with severe graft versus host disease (GvHD) necessitating pharmaceutical intervention post-transplant. Whether immunosuppression with mycophenolate mofetil (MMF) or Ciclosporin A (CsA) influences the cytotoxic effect of CIK cell immunotherapy is still an open issue.MethodsCIK cells were generated from PBMC as previously described followed by co-incubation with mycophenolic acid (MPA) or CsA. Proliferation, cytotoxicity and receptor expression were investigated following short- (24 h), intermediate- (3 days) and long-term (7 days) MPA incubation with the intention to simulate the in vivo situation when CIK cells were given to a patient with relevant MPA/CsA plasma levels.ResultsShort-term MPA treatment led to unchanged proliferation capacity and barely had any effect on viability and cytotoxic capability in vitro. The composition of CIK cells with respect to T-, NK-like T- and NK cells remained stable. Intermediate MPA treatment lacked effects on NKG2D, FasL and TRAIL receptor expression, while an influence on proliferation and viability was detectable. Furthermore, long-term treatment significantly impaired proliferation, restricted viability and drastically reduced migration-relevant receptors accompanied by an alteration in the CD4/CD8 ratio. CD3+CD56+ cells upregulated receptors relevant for CIK cell killing and migration, whereas T cells showed the most interference through significant reductions in receptor expression. Interestingly, CsA treatment had no significant influence on CIK cell viability and the cytotoxic potential against K562.ConclusionsOur data indicate that if immunosuppressant therapy is indispensable, efficacy of CIK cells is maintained at least short-term, although more frequent dosing might be necessary.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1024-4) contains supplementary material, which is available to authorized users.

Objective: To elucidate cross-sectional patterns and longitudinal changes of oral and stool microbiota in multiple sclerosis (MS) patients and the effect of B-cell depletion.Methods: We conducted an observational, longitudinal clinical cohort study analysing four timepoints over 12 months in 36 MS patients, of whom 22 initiated B-cell depleting therapy with ocrelizumab and a healthy control group. For microbiota analysis of the oral cavity and the gut, provided stool and oral swab samples underwent 16S rDNA sequencing and subsequent bioinformatic analyses. Results: Oral microbiota-patterns exhibited a reduced alpha-diversity and unique differential microbiota changes compared to stool such as increased levels of Proteobacteria and decreased abundance of Actinobacteria. Following B-cell depletion, we observed increased alpha-diversity in the gut and the oral cavity as well as a long-term sustained reduction of pro-inflammatory Gram-negative bacteria (e.g., Escherichia/Shigella).Conclusion: MS patients have altered stool and oral microbiota diversity patterns compared to healthy controls, which are most pronounced in patients with higher disease activity and disability. Therapeutic B-cell depletion is associated with persisting regression of these changes. Whether these microbial changes are unspecific side-effects of B-cell depletion or indirectly modulate MS disease activity and progression is currently unknown and necessitates further investigations.

ZusammenfassungMultiple Sklerose (MS) ist eine chronisch entzündliche Autoimmunerkrankung des zentralen Nervensystems mit hoher Prävalenz. Mehrere Studien zeigen die deutlich erhöhte Häufigkeit sowohl von Frakturen als auch einer Osteoporose bei MS-Erkrankten: So besteht ein in mehreren Studien gezeigtes knapp 3-fach erhöhtes Hüftfrakturrisiko bei MS-Patienten, die Prävalenz von Osteopenie und Osteoporoserate ist bis zu 10-fach gegenüber der Normalbevölkerung erhöht. Der deutlichste Zusammenhang besteht zwischen dem Osteoporoserisiko und -ausmaß und dem Grad der Immobilität, aber auch die entzündliche Krankheitspathologie sowie Lebensstilfaktoren wie Vitamin D, Rauchen, sowie hormonelle Dysregulationen, Begleiterkrankungen und Medikamente tragen grundsätzlich und kumulativ zum erhöhten Osteoporose- und Frakturrisiko bei. Das deutlich erhöhte Osteoporose und Frakturrisiko wird im klinischen Alltag von MS-Patienten nur selten thematisiert, obwohl schon früh eine negative Beeinträchtigung des Knochenstoffwechsels vorliegt. Frakturrisiko und Osteoporose sind daher eine bisher unterschätzte Problematik bei MS-Erkrankten, die in einem präventiven Ansatz früh von den Behandlern thematisiert werden sollte. Ausgleich einer Vitamin D-Defizienz und vor allem ein Erhalt der Mobilität sind die am besten durch Daten belegten präventiven Maßnahmen zur Vermeidung einer fortschreitenden Osteoporose und zur Reduktion des Frakturrisikos.