Serological responses to vaccination in children exposed in utero to ustekinumab or vedolizumab: cross-sectional analysis of a prospective multicentre cohort.

Evidence on serological responses to vaccination in children exposed to ustekinumab (UST) or vedolizumab (VDZ) in utero is lacking. This multicentre prospective study aimed to assess the impact of prenatal exposure to UST or VDZ due to maternal inflammatory bowel disease (IBD) on serological responses to vaccination and other immunological parameters in exposed children. Children aged ≥ 1 year who were exposed in utero to UST or VDZ and completed at least 1-year of mandatory vaccination were included. We assessed the serological response to vaccination (non-live: tetanus, diphtheria, and Haemophilus influenzae B; live: mumps, rubella, and measles), whole blood count, and immunoglobulin levels. The control group comprised unexposed children born to mothers without IBD. A total of 23 children (median age, 25 months) exposed to UST (n = 13) or VDZ (n = 10) and 10 controls (median age, 37 months) were included. The serological response to vaccination was comparable between the UST and VDZ groups and controls, with an adequate serological response rate of ≥ 80%. Only children exposed to UST showed a slightly reduced serological response to mumps (67% vs. 86% in controls), whereas all children exposed to VDZ showed an adequate response. The majority of the exposed children had normal levels of individual immunoglobulin classes, similar to the controls. No severe pathology was observed in any of the children.Conclusion: Despite the limited sample size, our findings suggest that in utero exposure to VDZ or UST does not significantly impair the vaccine response or broader immunological parameters in exposed children.

Simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupts immune cell homeostasis.

ORMDL3 is a prominent member of a family of highly conserved endoplasmic reticulum resident proteins, ORMs (ORM1 and ORM2) in yeast, dORMDL in Drosophila and ORMDLs (ORMDL1, ORMDL2, and ORMDL3) in mammals. ORMDL3 mediates feedback inhibition of de novo sphingolipid synthesis. Expression levels of ORMDL3 are associated with the development of inflammatory and autoimmune diseases including asthma, systemic lupus erythematosus, type 1 diabetes mellitus and others. It has been shown that simultaneous deletions of other ORMDL family members could potentiate ORMDL3-induced phenotypes. To understand the complex function of ORMDL proteins in immunity in vivo, we analyzed mice with single or double deletions of Ormdl genes. In contrast to other single and double knockouts, simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupted blood homeostasis and reduced immune cell content in peripheral blood and spleens of mice. The reduced number of splenocytes was not caused by aberrant immune cell homing. A competitive bone marrow transplantation assay showed that the development of Ormdl1-/-/Ormdl3-/- B cells was dependent on lymphocyte intrinsic factors. Highly increased sphingolipid production was observed in the spleens and bone marrow of Ormdl1-/-/Ormdl3-/- mice. Slight, yet significant, increase in some sphingolipid species was also observed in the spleens of Ormdl3-/- mice and in the bone marrow of both, Ormdl1-/- and Ormdl3-/- single knockout mice. Taken together, our results demonstrate that the physiological expression of ORMDL proteins is critical for the proper development and circulation of lymphocytes. We also show cell-type specific roles of individual ORMDL family members in the production of different sphingolipid species.

Chronic inflammation decreases HSC fitness by activating the druggable Jak/Stat3 signaling pathway.

Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.

Improved hematopoietic stem cell transplantation upon inhibition of natural killer cell-derived interferon-gamma.

Hematopoietic stem cell transplantation (HSCT) is a frequent therapeutic approach to restore hematopoiesis in patients with hematologic diseases. Patients receive a hematopoietic stem cell (HSC)-enriched donor cell infusion also containing immune cells, which may have a beneficial effect by eliminating residual neoplastic cells. However, the effect that donor innate immune cells may have on the donor HSCs has not been deeply explored. Here, we evaluate the influence of donor natural killer (NK) cells on HSC fate, concluded that NK cells negatively affect HSC frequency and function, and identified interferon-gamma (IFNγ) as a potential mediator. Interestingly, improved HSC fitness was achieved by NK cell depletion from murine and human donor infusions or by blocking IFNγ activity. Thus, our data suggest that suppression of inflammatory signals generated by donor innate immune cells can enhance engraftment and hematopoietic reconstitution during HSCT, which is particularly critical when limited HSC numbers are available and the risk of engraftment failure is high.

Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy.

Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (i) impairment of iron-sulfur [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (ii) inhibition of mitochondrial respiration leading to mitochondrial reactive oxygen species production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (iii) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of deferoxamine represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anticancer drug via mitochondrial targeting. SIGNIFICANCE: These findings show that targeting the iron chelator deferoxamine to mitochondria impairs mitochondrial respiration and biogenesis of [Fe-S] clusters/heme in cancer cells, which suppresses proliferation and migration and induces cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2289/F1.large.jpg.

Safety of Anti-TNF-Alpha Therapy During Pregnancy on Long-term Outcome of Exposed Children: A Controlled, Multicenter Observation.

BACKGROUND: Evidence of the impact of in utero exposure to anti-tumor necrosis factor (TNF)-alpha on long-term childhood development is limited. The aim was to assess the impact of in utero exposure to anti-TNF-alpha due to mothers' inflammatory bowel disease (IBD) on long-term postnatal development of exposed children. METHODS: We included consecutive children (≥12 months of age) born to mothers with IBD (2007-2016) treated with anti-TNF-alpha during pregnancy in 3 centers in the Czech Republic. A control group was comprised of unexposed children of non-IBD mothers undergoing mandatory check-ups at general pediatricians' offices. Data on perinatal period, psychomotor development, vaccination, infections, antibiotics, and allergy were collected by treating pediatricians using a predefined questionnaire. RESULTS: Seventy-two exposed and 69 unexposed children were included (median age, 35 and 50 months, respectively). Exposed children had growth and psychomotor development similar to controls. There was no significant difference in infectious complications within the first year of life (23.9% vs 17.4%; P = 0.36) or during the whole follow-up between exposed infants and controls (P = 0.32). Concomitant immunosuppressants during pregnancy and anti-TNF-alpha levels in cord blood were not associated with elevated infection rate within the first year of life (P > 0.05). Over 95% of exposed children had adequate serologic response to vaccination, except for haemophilus and mumps vaccines. Clinically manifested allergy was similar between the groups (P = 0.98). CONCLUSIONS: Anti-TNF-alpha exposure in utero does not seem to have a negative impact on postnatal development of children with regard to infectious complications, allergy, growth, or psychomotor development when compared with unexposed children of non-IBD women.

Paediatric Home Parenteral Nutrition in the Czech Republic and Its Development: Multicentre Retrospective Study 1995-2011.

BACKGROUND: Treatment quality and outcomes of paediatric home parenteral nutrition (HPN) program during its development in the Czech Republic. METHODS: A retrospective study of patients receiving HPN from May 1995 till June 2011. RESULTS: Sixty-six patients were treated in 8 centres. In 48 patients, long-term PN began in the first year of life and in 35 of them in the first month. Sixty children had gastrointestinal and 6 had non-gastrointestinal disease. In a majority of the patients, the Broviac catheter was used. Thirty-two (48.5%) patients were weaned from PN after 1-117 months, 21 (32.8%) continued on HPN after 7-183 months, and 13 (19.7%) patients died, all on PN. The mortality in patients with primary gastrointestinal disease was significantly lower than in patients with non-gastrointestinal disease. Thirty-one paediatric patients were receiving HPN for 14,480 catheter days in 2009-2010. Fourteen patients had 23 Catheter Related Blood Stream Infections (CRBSI) episodes. The incidence of CRBSI in 2009-2010 was 1.58/1,000 catheter days. CONCLUSION: Submitted data showed that even in the absence of expert centres, patient care may achieve results comparable to countries with well-developed HPN program. A majority of Czech HPN patients are at present treated in specialized centres, following the most desirable pattern of care.