Immune responses in neonates

Basha, Saleem; Surendran, Naveen; Pichichero, Michael E.

doi:10.1586/1744666x.2014.942288

Cited by 395 publications

(373 citation statements)

References 142 publications

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“…In addition, Torin2-treated mice did not show any alteration in terms of systemic growth as compared with untreated mice. It is worth investigating the potential effect of Torin2 on the immune system and inflammation, as neonatal mice are considered immunodeviant (36). Survival data showed significantly decreased survival in the CQ-treated group; conversely, the Torin2-treated group had 100% survival upon exposure to hyperoxia ( Figure 4F).…”

Section: Original Researchmentioning

confidence: 99%

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Sureshbabu

Syed

Das

et al. 2016

Am J Respir Cell Mol Biol

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Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor 1/2 , limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomalassociated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.Keywords: cell death; oxygen; newborn; pulmonary; bronchopulmonary dysplasia Premature infants provided with supplemental oxygen are at higher risk for developing a chronic respiratory disease, bronchopulmonary dysplasia (BPD) (1). BPD occurs in developing lungs resulting in impaired alveolarization and dysregulated vascularization-the pathologic hallmarks (2). Premature infants diagnosed with BPD have diminished pulmonary function and reduced lung capacity as they grow older and up to adulthood (3). This disease represents a common yet complicated clinical issue associated with significant long-term morbidity and mortality (2, 3). Pulmonary-specific oxygen toxicity is This work was supported in part by National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) grants HL63039 (G.P.) and HL116632 (A.R.), by the Sigrid Jusélius Foundation (S.A.), and by NHLBI/NIH grant HL85103 (V.B.).Author Contributions: Concept and design-A.S. and V.B.; acquisition of data-A.S., M.S., P.D., C.J., G.P., A.R., S.A., R.J.H., and V.B.; data analysis and interpretation-A.S., M.S., P.D., C.J., G.P., A.R., S...

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Section: Original Researchmentioning

confidence: 99%

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Sureshbabu

Syed

Das

et al. 2016

Am J Respir Cell Mol Biol

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“…For example, recruitment of T cell help to B cells is hampered as a result of low MHC II and reduced antigen processing and presentation [11]. In addition, decreased dendritic cell maturation contributes to poor CD4 + T cell generation necessary to support antibody responses [4, 12, 13]. Finally, neonates demonstrate impairment in the CD40-CD40L pathway which plays a critical role in regulating B cells differentiation and function [14, 15].…”

Section: Introductionmentioning

confidence: 99%

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Holbrook

D’Agostino

Aycock

et al. 2017

Vaccine

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Generation of a potent antibody response that can be sustained over time is highly challenging in young infants. Our previous studies using a nursery-reared nonhuman primate model identified R848 conjugated to inactivated influenza virus as a highly immunogenic vaccine for neonates. Here we determined the effectiveness of this vaccine in mother-reared infants as well as its ability to promote improved responses at 6 months compared to vaccination in the absence of R848. In agreement with our nursery study, R848 conjugated to influenza virus induced a higher antibody response in neonates compared to the non-adjuvanted vaccine. Further, the increase in the response relative to that induced by the non-adjuvanted vaccine was maintained at 6 months suggesting the increased antibody secreting cells that resulted from inclusion of conjugated R848 production were capable of surviving long term. There was no significant difference in quality of antibody (i.e. neutralization or affinity), suggesting the beneficial effect of conjugated R848 during vaccination of neonates with inactivated influenza virus is likely manifest during the early generation of antibody secreting cells.

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“…This may be related to the natural dampening of the Th-1 associated immune response. Following from that, neonatal T cells exhibit similar or even stronger Th-1 immune responses to certain vaccines, such as the BCG vaccination, compared to adult responses [2]. It has been speculated that the expected drop in the polarized type-1 immune responses reflects the generalized hypofunction of inflammatory and immune mechanisms in a number of protective systems, which significantly increases the risk of infection in this exposed population.…”

Section: Letter To the Editormentioning

confidence: 99%

“…It has been speculated that the expected drop in the polarized type-1 immune responses reflects the generalized hypofunction of inflammatory and immune mechanisms in a number of protective systems, which significantly increases the risk of infection in this exposed population. However, during development the neonatal immune system is constantly maturing, since it is a continuous process where both accelerated and retarded development is deleterious [2].…”

Section: Letter To the Editormentioning

confidence: 99%

Notes for the Immune Responses in Neonates: Commonly Expected Dampening of the Type-1 Associated Immunity during BCG Vaccination

Antas

Lima²,

Pedro³

et al. 2015

J Anc Dis Prev Rem

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Immune responses in neonates

Cited by 395 publications

References 142 publications

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Inhibition of Regulatory-Associated Protein of Mechanistic Target of Rapamycin Prevents Hyperoxia-Induced Lung Injury by Enhancing Autophagy and Reducing Apoptosis in Neonatal Mice

Adjuvanting an inactivated influenza vaccine with conjugated R848 improves the level of antibody present at 6 months in a nonhuman primate neonate model

Notes for the Immune Responses in Neonates: Commonly Expected Dampening of the Type-1 Associated Immunity during BCG Vaccination

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