Stress can impair T cell-mediated immunity. To determine if infants with high stress responses had deficits in T-cell mediated immunity, we examined the association of pain-induced cortisol responsiveness with thymic function and vaccine responses in infants. This study was performed among 306 (male = 153 and female = 153) participants of a randomized, controlled trial examining the effect of neonatal vitamin A supplementation on immune function in Bangladesh (NCT01583972). Salivary cortisol was measured before and 20 min after a needle stick (vaccination) at 6 weeks of age. The thymic index (TI) was determined by ultrasonography at 1, 6, 10 and 15 weeks. T-cell receptor excision circle and blood T-cell concentrations were measured at 6 and 15 weeks. Responses to Bacillus Calmette–Guérin (BCG), tetanus toxoid, hepatitis B virus and oral poliovirus vaccination were assayed at 6 and 15 weeks. Cortisol responsiveness was negatively associated with TI at all ages (p p = .0035) and 15 weeks (p = .0083), and was negatively associated with the delayed-type hypersensitivity (DTH) skin test response to BCG vaccination at 15 weeks (p = .034) in both sexes. Infants with a higher cortisol response to pain have differences in the T-cell compartment and a lower DTH response to vaccination. Sex differences in the immune system were seen as early as 6 weeks of age in these healthy infants.
Stress can impair T cell-mediated immunity. To determine if infants with high stress responses had deficits in T-cell mediated immunity, we examined the association of pain-induced cortisol responsiveness with thymic function and vaccine responses in infants. This study was performed among 306 (male = 153 and female = 153) participants of a randomized, controlled trial examining the effect of neonatal vitamin A supplementation on immune function in Bangladesh (NCT01583972). Salivary cortisol was measured before and 20 min after a needle stick (vaccination) at 6 weeks of age. The thymic index (TI) was determined by ultrasonography at 1, 6, 10 and 15 weeks. T-cell receptor excision circle and blood T-cell concentrations were measured at 6 and 15 weeks. Responses to Bacillus Calmette–Guérin (BCG), tetanus toxoid, hepatitis B virus and oral poliovirus vaccination were assayed at 6 and 15 weeks. Cortisol responsiveness was negatively associated with TI at all ages (p < .01) in boys only, was negatively associated with naïve helper T-cell concentrations in both sexes at both 6 (p = .0035) and 15 weeks (p = .0083), and was negatively associated with the delayed-type hypersensitivity (DTH) skin test response to BCG vaccination at 15 weeks (p = .034) in both sexes. Infants with a higher cortisol response to pain have differences in the T-cell compartment and a lower DTH response to vaccination. Sex differences in the immune system were seen as early as 6 weeks of age in these healthy infants.
Age-appropriate vaccination is crucial for infants, protecting them from vaccine-preventable diseases. Delaying in starting initial immunization may result in incomplete or non-vaccination in early life. However, limited vaccine coverage data are available regarding the starting age of vaccination. In this study, we determined the factors associated with the delay in infant immunization. We carried out a cross-sectional study at three maternal-child health clinics in Dhaka city. Mothers visited these clinics for their infant immunization were surveyed with structured questionnaires. A multivariate logistic regression model was used to estimate the significant influencing factors on untimely vaccination. A total of 548 mother-infant pairs were surveyed. 46.5% of mothers did not receive Tetanus (TT) vaccines, and mothers who had a previous pregnancy were less likely to receive TT-vaccine (p < .01). 41.2% of infants did not receive BCG vaccines within 1-week of birth. Mothers working outside the home showed a negative impact on BCG vaccination (p < .05). Among the infants' born in-clinic facilities, 39% were BCG unvaccinated, and 69% had c-section delivery. The median age of infants for starting vaccination was 6.57 wks (95% CI: 6.43–7.14); however, 17.3% infants received vaccination at ≥8 wks of age. Mother's schooling-years and infant normal body-weight positively associated with vaccination at <8 wks, whereas sickness after birth increased the age to start vaccination program recommended at 6 wks. Our analysis suggests the need for specific interventions based on potential maternal determinants, such as educating mothers about the timing and the importance of infant immunization, and addressing programmatic barriers to timely vaccination among infants in Bangladesh.
Stress can impair T cell-mediated immunity. To determine if infants with high stress responses had deficits in T-cell mediated immunity, we examined the association of pain-induced cortisol responsiveness with thymic function and vaccine responses in infants. This study was performed among 306 (male = 153 and female = 153) participants of a randomized, controlled trial examining the effect of neonatal vitamin A supplementation on immune function in Bangladesh (NCT01583972). Salivary cortisol was measured before and 20 min after a needle stick (vaccination) at 6 weeks of age. The thymic index (TI) was determined by ultrasonography at 1, 6, 10 and 15 weeks. T-cell receptor excision circle and blood T-cell concentrations were measured at 6 and 15 weeks. Responses to Bacillus Calmette–Guérin (BCG), tetanus toxoid, hepatitis B virus and oral poliovirus vaccination were assayed at 6 and 15 weeks. Cortisol responsiveness was negatively associated with TI at all ages (p p = .0035) and 15 weeks (p = .0083), and was negatively associated with the delayed-type hypersensitivity (DTH) skin test response to BCG vaccination at 15 weeks (p = .034) in both sexes. Infants with a higher cortisol response to pain have differences in the T-cell compartment and a lower DTH response to vaccination. Sex differences in the immune system were seen as early as 6 weeks of age in these healthy infants.
Milk exosomes (MEs) and their microRNA cargos constitute novel bioactive food compounds, and bovine MEs (BMEs) are being considered for use in drug delivery. The internalization of MEs by macrophages and degradation in lysosomes (in all cells) limit biological activities. Here, we determined whether BMEs internalized by murine bone marrow-derived macrophages (BMDMs) retrofuse with the intralumenal membrane in the multivesicular body (MVB) for subsequent release into the extracellular space or whether BMEs are destined for degradation in lysosomes. BMDMs were treated with HiLyte™ Fluor 750 hydrazide-labeled BMEs, washed, and the release of BMEs into the extracellular space was assessed by quantifying HiLyte™ fluorescence in culture media and exosomes purified from BMDM media (BMDM-Exo). The lysosomal localization of BMEs in BMDMs was assessed by confocal microscopy analysis of pH-sensitive pHrodo red-labeled BME in lysosomes counterstained with LysoTracker™ Green DND-26 (LysT) and confocal microscopy analysis of pHrodo red signals in the presence of the autophagy inhibitor, bafilomycin A1 (Baf A1). Parametric and non-parametric tests were used for statistical analyses; P < 0.05 was considered statistically significant. HiLyte™ signal was not detected in BMDM culture media and BMDM-Exo (P > 0.05 compared to untreated control). Treatment with Baf A1, resulted in an 84% decrease in pHrodo-BME signal in BMDMs (P < 0.05), and pHrodo-BMEs were found to co-localize with LysT in BMDMs. The retrofusion of BME-derived intralumenal MVBs and secretion of BME into the extracellular space is quantitatively minor in BMDMs. The majority of BMEs localizes to lysosomes for degradation in BMDMs. NIH P20GM10432, NIFA 2016–67,001-25,301 and 2022–67,021-36,407, and USDA (Hatch, and W-4002); all to J. Zempleni. J. Zempleni is a consultant for PureTech Health, Inc.
Bovine milk exosomes (BMEs) are promising candidates for delivering drugs to brain tumors because they are scalable, bioavailable after oral administration, and cross the blood-brain barrier. The use of BMEs in drug delivery is limited by their rapid elimination by macrophages. The objectives of this study were to identify the BME transporter and assess BME transport kinetics in murine bone marrow-derived macrophages (BMDMs) as a first step toward developing strategies that decrease the elimination of drug-loaded BMEs. BMEs were isolated by differential centrifugation from skim milk. For transport studies, proteins and lipids on the BME surface were labeled with HiLyte™ Fluor 750 hydrazide and PKH26, respectively, and RNAs in BMEs were labeled with Exo-Red; unlabeled BMEs were used to assess background noise. Bone marrow cells were isolated from the femur and tibia of both C57BL/6J and scavenger receptor A-I/II knockout mice and differentiated ex vivo into BMDMs for use in transport studies. ANOVA, Dunnett's and Kruskal-Wallis test, Dunn's post-hoc test, unpaired t-test, and two-tailed Mann–Whitney U tests were used for statistical analysis; P < 0.05 was considered statistically significant. The uptake of BME was not saturated at the highest concentration used (4.3 × 1011 BMEs/mL) and the longest incubation time (53 h) tested. Chemical inhibition of phagocytosis by cytochalasin D led to a 69 ± 18% decrease in BME uptake compared to solvent controls (P ˂ 0.05), whereas inhibition of macropinocytosis, caveolar-dependent endocytosis, and endocytosis of clathrin-coated vesicles had no significant effect on BME uptake (11%-33% decrease compared to controls; P > 0.05). Treatment with inhibitors of class A scavenger receptor (CASR), fucoidan and dextran sulfate caused a 70 ± 8.1% and 70 ± 18% decrease (P ˂ 0.05), respectively, in BME uptake. The role of CASR in BME uptake was confirmed by using a genetics approach: the uptake of BMEs by BMDMs from scavenger receptor A-I/II knockout mice decreased by 58 ± 23% compared to BMDMs from wild-type mice (P ˂ 0.05). BME uptake is facilitated by CASR in BMDMs and uptake cannot be saturated under physiological conditions. NIH 1P20GM104320, and NIFA 2016–67,001-25,301 and 2020–67,017-30,834, USDA Hatch-1,011,996, and USDA W4002 (all to J.Z.). J.Z is a consultant for PureTech Health, Inc.
Exosomes are natural nanoparticles that originate in the endocytic system. Exosomes play an important role in cell-to-cell communication by transferring RNAs, lipids, and proteins from donor cells to recipient cells or by binding to receptors on the recipient cell surface. The concentration of exosomes and the diversity of cargos are high in milk. Exosomes and their cargos resist degradation in the gastrointestinal tract and during processing of milk in dairy plants. They are absorbed and accumulate in tissues following oral administrations, cross the blood-brain barrier, and dietary depletion and supplementation elicit phenotypes. These features have sparked the interest of the nutrition and pharmacology communities for exploring milk exosomes as novel bioactive food compounds and for delivering drugs to diseased tissues. This review discusses the current knowledgebase, uncertainties, and controversies in these lines of scholarly endeavor and health research.
Bovine milk exosomes (BMEs) are being explored in drug delivery despite their rapid elimination by macrophages. We aimed at identifying the BME transporter in murine bone marrow-derived macrophages (BMDMs). Fluorophore-labeled BMEs were used in transport studies in BMDMs from C57BL/6J and class A scavenger receptor type 1/2 (CASR-1/2) knockout mice and tissue accumulation in macrophage-depleted C57BL/6J mice. Parametric and nonparametric statistics tests for pairwise and multiple comparisons were used. Chemical inhibitors of phagocytosis by cytochalasin D led to a 69 ± 18% decrease in BME uptake compared with controls (P < 0.05), whereas inhibitors of endocytic pathways other than phagocytosis had a modest effect on uptake (P > 0.05). Inhibitors of class A scavenger receptors (CASRs) including CASR-1/2 caused a 70% decrease in BME uptake (P < 0.05). The uptake of BMEs by BMDMs from CASR-1/2 knockout mice was smaller by 58 ± 23% compared with wild-type controls (P < 0.05). Macrophage depletion by clodronate caused a more than 44% decrease in BME uptake in the spleen and lungs (P < 0.05), whereas the decrease observed in liver was not statistically significant. In conclusion, CASR-1/2 facilitates the uptake of BMEs in BMDMs and C57BL/6J mice.
The intestinal microbiome in early infancy affects immunologic development and thus may affect vaccine memory, though few prospective studies have examined such associations. We examined the association of Bifidobacterium levels in early infancy with memory responses to early vaccination measured at 2 years of age.In this prospective observational study, we examined the association of Bifidobacterium abundance in the stool of healthy infants at 6 to 15 weeks of age, near the time of vaccination, with T-cell and antibody responses measured at 6 weeks, 15 weeks, and 2 years of age. Infants were vaccinated with Bacillus Calmette-Guérin (BCG) (at birth), oral polio virus (at birth and at 6, 10, and 14 weeks), tetanus toxoid (TT) (at 6, 10, and 14 weeks), and hepatitis B virus (at 6, 10, and 14 weeks). Fecal Bifidobacterium was measured at 6, 11, and 15 weeks. Bifidobacterium species and subspecies were measured at 6 weeks.Mean Bifidobacterium abundance in early infancy was positively associated with the CD4 T-cell responses to BCG, TT, and hepatitis B virus at 15 weeks, with CD4 responses to BCG and TT at 2 years, and with plasma TT-specific immunoglobulin G and stool polio-specific immunoglobulin A at 2 years. Similar associations were seen for the predominant subspecies, Bifidobacterium longum subspecies infantis.Bifidobacterium abundance in early infancy may increase protective efficacy of vaccines by enhancing immunologic memory. This hypothesis could be tested in clinical trials of interventions to optimize Bifidobacterium abundance in appropriate populations.
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