The intestinal mucosa is lined by epithelial cells, which are key cells to sustain gut homeostasis. Food allergy is an immune-mediated adverse reaction to food, likely due to defective regulatory ...circuits.
is a non-pathogenic bacterium with immunomodulatory properties. We hypothesize that the anti-inflammatory effect of dead
.
on activated epithelial cells modulates milk allergy through the restoration of tolerance in a mouse model. Epithelial cells (Caco-2 and enterocytes from mouse gut) and macrophages were stimulated with
.
and induction of luciferase under the NF-κB promoter, ROS and cytokines production were studied. Balb/c mice were mucosally sensitized with cow´s milk proteins plus cholera toxin and orally challenged with the allergen to evidence hypersensitivity symptoms. After that, mice were orally administered with heat-killed
.
as treatment and then challenged with the allergen. The therapeutic efficacy was
(clinical score and cutaneous test) and
(serum specific antibodies and cytokines-ELISA, and cell analysis-flow cytometry) evaluated. Heat-killed
.
modulated the induction of pro-inflammatory chemokines, with an increase in anti-inflammatory cytokines by intestinal epithelial cells and by macrophages with decreased OX40L expression.
, oral administration of
.
increased the frequency of lamina propria CD4
CD25
FoxP3
T cells, and clinical signs were lower in
.
-treated mice compared with milk-sensitized animals.
depletion of Tregs (anti-CD25) abrogated
.
immunomodulation. In conclusion, these bacteria suppressed the intestinal inflammatory immune response to reverse food allergy.
Background
IgE‐mediated food allergy remains a significant and growing worldwide problem. Sublingual immunotherapy (SLIT) shows an excellent safety profile for food allergy, but the clinical efficacy ...needs to be improved. This study assessed the effects of the Toll‐like receptor 4 agonist outer membrane protein (Omp) 16 from Brucella abortus combined with cow´s milk proteins (CMP) through the sublingual route to modulate cow's milk allergy in an experimental model.
Methods
Mice sensitized with cholera toxin and CMP were orally challenged with the allergen to elicit hypersensitivity reactions. Then, mice were treated with a very low amount of CMP along with Omp16 as a mucosal adjuvant, and finally, animals were re‐exposed to CMP. Systemic and mucosal immune parameters were assessed in vivo and in vitro.
Results
We found that the sublingual administration of Omp16 + CMP induced a buccal Th1 immune response that modulated the intestinal allergic response with the suppression of symptoms, reduction of IgE and IL‐5, and up‐regulation of IgG2a and IFN‐γ. The adoptive transfer of submandibular IFN‐γ‐producing α4β7+CD4+ and CD8+ cells conferred protection against allergic sensitization. The use of Omp16 + CMP promoted enhanced protection compared to CMP alone.
Conclusion
In conclusion, Omp16 represents a promising mucosal adjuvant that can be used to improve the clinical and immune efficacy of SLIT for food allergy.
•Latex peptidases were able to perform total hydrolysis of caseins.•On the other hand, whey proteins were more resistant to proteolysis.•Heat pretreatment of the whey proteins enhanced the degree of ...hydrolysis.•In vivo tests showed that latex peptidases reduced antigenicity and allergenicity.•Results were similar to a commercial partially hydrolyzed formula.
The present study evaluated four laticifer fluids as a novel source of peptidases capable of hydrolyzing proteins in cow’s milk. The latex peptidases from Calotropis procera (CpLP), Cryptostegia grandiflora (CgLP), and Carica papaya (CapLP) were able to perform total hydrolysis of caseins after 30 min at pH 6.5, as confirmed by a significant reduction in the residual antigenicity. Casein hydrolysis by Plumeria rubra latex peptidases (PrLP) was negligible. Moreover, whey proteins were more resistant to proteolysis by latex peptidases; however, heat pretreatment of the whey proteins enhanced the degree of hydrolysis and reduced the residual antigenicity of the hydrolysates. The in vivo assays show that the cow’s milk proteins hydrolysed by CgLP and CapLP exhibited no immune reactions in mice allergic to cow’s milk, similar to a commercial partially hydrolysed formula. Thus, these peptidases are promising enzymes for the development of novel hypoallergenic formulas for children with a milk allergy.
This work aimed to evaluate the effect of carbonylation induced by tetracyclines, β-lactams, fluoroquinolones, and pyrethroids in caseins of bovine origin on their immunoreactivity and allergenicity. ...Using a spectrophotometric method, ELISA, dot-blot, and an IgE-mediated milk allergy mouse model, we confirmed that antibiotics and pesticides at their maximum residue limit, promoted the in vitro carbonylation of caseins (among 5.0 ± 0.01 and 67.5 ± 0.70 nmol of carbonyl/mg of protein); furthermore, carbonylations greater than 19 nmol significantly increase the in vitro IgE immunoreactivity of caseins (average OD among 0.63-1.50) regarding the negative control (average OD: 0.56). On the other hand, sensitized mice exposed to oxidized caseins showed increased clinical scores (2-5), positive skin tests, and footpad swelling (0.28-0.59 mm) compared to the negative control (1-2; negative skin tests; 0.1 mm, respectively), denoting increased allergenicity. These results suggest that casein carbonylation increases their IgE immunoreactivity and allergenicity, a fact that could be explained by the resistance to the digestion promoted by carbonylation and by conformational changes in the random coil casein structure, which can expose cryptic epitopes or neoepitopes.
Patients with inborn errors of immunity (IEI) in Argentina were encouraged to receive licensed Sputnik, AstraZeneca, Sinopharm, Moderna, and Pfizer vaccines, even though most of the data of humoral ...and cellular responses combination on available vaccines comes from trials conducted in healthy individuals. We aimed to evaluate the safety and immunogenicity of the different vaccines in IEI patients in Argentina.
The study cohort included adults and pediatric IEI patients (
n
= 118) and age-matched healthy controls (HC) (
n
= 37). B cell response was evaluated by measuring IgG anti-spike/receptor binding domain (S/RBD) and anti-nucleocapsid(N) antibodies by ELISA. Neutralization antibodies were also assessed with an alpha-S protein-expressing pseudo-virus assay. The T cell response was analyzed by IFN-γ secretion on S- or N-stimulated PBMC by ELISPOT and the frequency of S-specific circulating T follicular-helper cells (TFH) was evaluated by flow cytometry.
No moderate/severe vaccine-associated adverse events were observed. Anti-S/RBD titers showed significant differences in both pediatric and adult IEI patients versus the age-matched HC cohort (
p
< 0.05). Neutralizing antibodies were also significantly lower in the patient cohort than in age-matched HC (
p
< 0.01). Positive S-specific IFN-γ response was observed in 84.5% of IEI patients and 82.1% presented S-specific TFH cells. Moderna vaccines, which were mainly administered in the pediatric population, elicited a stronger humoral response in IEI patients, both in antibody titer and neutralization capacity, but the cellular immune response was similar between vaccine platforms. No difference in humoral response was observed between vaccinated patients with and without previous SARS-CoV-2 infection.
In conclusion, COVID-19 vaccines showed safety in IEI patients and, although immunogenicity was lower than HC, they showed specific anti-S/RBD IgG, neutralizing antibody titers, and T cell-dependent cellular immunity with IFN-γ secreting cells. These findings may guide the recommendation for a vaccination with all the available vaccines in IEI patients to prevent COVID-19 disease.
Designing effective drug nanocarriers that are easy to synthesize, robust, and nontoxic is a significant challenge in nanomedicine. Polyamine-multivalent molecule nanocomplexes are promising drug ...carriers due to their simple and all-aqueous manufacturing process. However, these systems can present issues of colloidal instability over time and cellular toxicity due to the cationic polymer. In this study, we finely modulate the formation parameters of poly(allylamine-tripolyphosphate) complexes to jointly optimize the robustness and safety. Polyallylamine was ionically assembled with tripolyphosphate anions to form liquid-like nanocomplexes with a size of around 200 nm and a zeta potential of −30 mV. We found that nanocomplexes exhibit tremendous long-term stability (9 months of storage) in colloidal dispersion and that they are suitable as protein-loading agents. Moreover, the formation of nanocomplexes induced by tripolyphosphate anions produces a switch-off in the toxicity of the system by altering the overall charge from positive to negative. In addition, we demonstrate that nanocomplexes can be internalized by bone-marrow-derived macrophage cells. Altogether, these nanocomplexes have attractive and promising properties as delivery nanoplatforms for potential therapies based on the immune system activation.
Patients with oncohematological or primary hematological diseases have a higher risk of developing severe forms of COVID-19 and their evolution is unfavorable. General care and immunization with ...vaccines is the current form of protection for these patients. The presence of post-vaccination IgG antibodies was analyzed in 73 oncohematological adult patients or with immune diseases treated at a regional hospital in Argentina. The patients were immunized with the Sputnik V, AstraZeneca or Sinopharm vaccine. 69% were evaluated after one dose and the rest after two. We observed that 65% of the patients achieved IgG seroconversion. In the analysis of the variables that influenced seroconversion with achieved levels >65% were: age <60 years: 67%; no chemotherapy treatment at the time of analysis: 69%; complete remission of the disease: 67%; two doses: 68% and history of COVID-19 infection prior to vaccination: 83%. However, none of these variables showed a statistically significant difference in a univariate analysis. The anti-SARS-Cov2 vaccination in these patients showed a significant tendency to seroconversion, the main factor being COVID-19 infection prior to vaccination.
Los pacientes (pac) oncohematológicos o con hemopatías primarias presentan un riesgo mayor de desarrollar formas graves de COVID-19 y su evolución es desfavorable. Los cuidados generales y la inmunización con vacunas es la forma actual de protección para estos pacientes. Se analizó la presencia de anticuerpos IgG post vacunación en 73 pacientes adultos oncohematológicos o con hemopatías inmunes atendidos en un hospital regional de Argentina. Los pacientes fueron inmunizados con la vacuna Sputnik V, AstraZeneca o Sinopharm. El 69% fue evaluado luego de una dosis y el resto después de dos. Observamos que el 65% de los pacientes logró seroconversión IgG. En el análisis de las variables que influyeron en la seroconversión y que lograron niveles >65% fueron: edad <60 años: 67%; sin tratamiento de quimioterapia al momento del análisis: 69%;remisión completa de la enfermedad: 67%; 2 dosis: 68% y antecedente de haber padecido COVID-19 previo a la vacunación: 83%. Sin embargo, ninguna de las variables presentó diferencia estadísticamente significativa en un análisis univariable. La vacunación anti SARS-Cov2 en estos pacientes mostró una tendencia importante a la seroconversión, siendo el principal factor haber tenidoCOVID-19 previo a la vacunación.
Nivolumab was the first anti-programmed cell death 1 drug approved in Argentina for non–small-cell lung cancer treatment in the second-line setting.
The present study was a multicenter, ...observational, retrospective study of patients with progression to stage IV NSCLC during platinum-based chemotherapy who had received nivolumab monotherapy in a drug-expanded access program in Argentina.
The data from 109 patients were assessed retrospectively for safety and clinical outcomes. The follow-up period was 8.83 months (interquartile range, 3.4-12.67); 57.8% were men, 29.4% were current smokers, and 78.0% had a diagnosis of nonsquamous cell cancer. The median number of chemotherapy lines before nivolumab was 2 (range, 1-4). Also, 59.6% had received radiotherapy and 89% had received platinum-based chemotherapy. The drug-related toxicity rate was 78.9%, the grade 2-3 toxicity rate was 28.4%, and 33.9% of patients had required corticosteroids. The treatment response was evaluated in 104 patients. The best response was a complete response in 2 (2%), partial response in 28 (27%), stable disease in 33 (32%), and progressive disease in 41 (39%). Univariate analysis revealed that the absence of corticosteroid use (P = .034), toxicity grade 1-3 (P = .0025), and performance status of ≤ 1 (P = .049) were associated with longer disease-free survival, performance status of ≤ 1 (P < .001), and toxicity grade 1-3 (P = .001) were associated with longer overall survival. On multivariate Cox regression analysis, toxicity grade 1-3 (hazard ratio HR, 0.44; 95% confidence interval CI, 0.24-0.81; P = .008) and age ≤ 50 years (HR, 0.28; 95% CI, 0.13-0.61; P = .001) were associated with longer progression-free survival and corticosteroid use was associated with shorter progression-free survival (HR, 2.06; 95% CI, 1.22-3.48; P = .007).
The use of nivolumab in the real world setting in patients with heavily pretreated NSCLC was well tolerated and showed promising clinical efficacy. The performance status, use of corticosteroids, and immune-mediated toxicity seem to be the conditions that can affect the clinical outcomes.
The retrospective data from 109 patients with previously treated non–small-cell lung cancer in Argentina in a drug-expanded program were analyzed. The overall response rate was 28.57%, progression-free survival was 6.1 months, and overall survival was 12.1 months. Multivariate analysis revealed that grade 1-3 toxicity, younger age (≤ 50 years), and no concomitant corticosteroid use were associated with longer progression-free survival.
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