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Therapeutic IL-2/JES6 treatment. Sensitized and repeatedly challenged mice were treated with IL-2/JES6 either four or 72 h before the final allergen challenge. (A) Hypothermia and diarrhea following allergen challenges, before IL-2/JES6 administration. (B) Rectal temperature curve (left) and maximal temperature drop (right) of mice treated with IL-2/JES6 4 h before allergen challenge. (C) Rectal temperature curve (left) and maximal temperature drop (right) of mice treated with IL-2/JES6 at 72 h before allergen challenge. (D) Total IgE, ovalbumin (OVA)-specific IgE and IgG1 and MMCP-1 in serum measured by ELISA (after challenge 13, 72 h after the last IL-2/JES6 treatment). Data depicted represent mean ± SEM (A: n = 35, (B–D) n = 7 8). *p < 0.05, **p < 0.01, ****p < 0.0001 (Student’s t-test).
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Food allergies are common, costly and potentially life-threatening disorders. They are driven by Th2, but inhibited by Th1 reactions. There is also evidence indicating that IL-2 agonist treatment inhibits allergic sensitization through expansion of regulatory T cells. Here, we tested the impact of an IL-2 agonist in a novel model for food allergy t...
Citations
... Contrastingly, Th1 reaction and the prototypic cytokine interferon (IFN)-γ could counterbalance Th2 responses, thus reducing the generation of IL-4 and IgE and ultimately inhibiting allergic sensitization. 13 Regulating Th1/Th2 balance exerts certain roles in mitigating allergic inflammatory responses in ovalbumin-elicited AR mice. 14 From the aforementioned research, we can learn the paramount significance of the Th1/Th2 balance in AR. ...
Objective:
Allergic rhinitis (AR) is a prevailing immune disorder affecting the nasal mucosa. B-cell lymphoma 6 (BCL6) imposes essential roles in immunity. This study probed into the serum expression of BCL6 and its effect on AR diagnosis and patients' quality of life (QOL).
Methods:
A total of 113 patients with AR including 38 cases with mild AR (MAR) and 75 cases with moderate-severe AR (MSAR) were enrolled, with 101 healthy people enrolled as control. Serum expression of BCL6 was detected by RT-qPCR and the diagnostic efficacy of BCL6 for AR was analyzed using the receiver operating characteristic curve. The proportion of T helper-1/2 (Th1/Th2) cells in CD4+ T cells in peripheral blood mononuclear cells was detected using flow cytometry. The correlation between BCL6 and Th1/Th2 cells and the effects of BCL6 expression on patients' QOL were assessed by Pearson analysis and Mini-RQLQ questionnaire.
Results:
BCL6 was downregulated in patients with AR, serum BCL6 level < 0.8450 had certain auxiliary diagnostic values for AR, and serum BCL6 level < 0.5400 could assist the diagnosis of AR severity. Th1 cell proportion in CD4+ T cells was decreased, whereas Th2 cell proportion was increased with AR severity. BCL6 was positively-linked with Th1 cells but inversely-correlated with Th2 cells in patients with AR. Patients with AR with low BCL6 expression had a poorer QOL compared with high BCL6 expression. The domains most affected by BCL6 expression were practical problems, nasal symptoms, and lacrimation.
Conclusion:
Serum BCL6 is downregulated and low BCL6 expression greatly deteriorates QOL in patients with AR.
... Diarrhea and allergen-induced temperature drop are associated with low allergen-specific IgG1 to IgE ratios To investigate the development of allergen-specific antibodies and murine food allergy, mice were sensitized to hen's egg by intratracheal treatment with egg white (EW)/egg yolk plasma (EYP) followed by repeated oral gavage (o.g.) with EW and EYP 39 . Starting at week four, mice were examined for diarrhea and hypothermia in response to o.g. ...
... Egg allergens were prepared and food allergy to hen's egg was induced as described previously 39 . Briefly: EW and EY were separated and prepared as described. ...
Mutated and unmutated IgE and IgG play different and partly opposing roles in allergy development, but the mechanisms controlling their relative production are incompletely understood. Here, we analyzed the IgE-response in murine food allergy. Deep sequencing of the complementary-determining region (CDR) repertoires indicated that an ongoing unmutated extrafollicular IgE response coexists with a germinal center response, even after long-lasting allergen challenges. Despite overall IgG1-dominance, a significant proportion of clonotypes contained several-fold more IgE than IgG1. Clonotypes with differential bias to either IgE or IgG1 showed distinct hypermutation and clonal expansion. Hypermutation rates were associated with different physiochemical binding properties of individual B-cell receptors (BCR). Increasing BCR signaling strength inhibited class switching from IgG1 to IgE in vitro, preferentially constraining IgE formation. These data indicate that antigen-binding properties of individual BCRs determine differential IgE hypermutation and IgE versus IgG1 production on the level of single B-cell clones.
... In the control group we observed an elevation in both IFNg and IL-10, which is typically associated with the suppression of Th2 re-sponses. Here we hypothesize that IFNg may be acting as an enhancer of mast cell degranulation 56 and IL-10 may be proinflammatory under certain conditions, as it was shown to play a critical role in the development of Th2 responses in an allergic dermatitis mouse model. 57 Immune tolerance in the context of hepatic AAV gene delivery is predicated on a number of variables including, but not limited to, the AAV capsid, promoter, and transgene product expression levels. ...
Immunotherapies for patients with food allergy have shown some success in limiting allergic responses. However, these approaches require lengthy protocols with repeated allergen dosing and patients can relapse following discontinuation of treatment. The purpose of this study was to test if a single dose of an adeno-associated virus (AAV) vector can safely prevent and treat egg allergy in a mouse model. AAV vectors expressing ovalbumin (OVA) under an ubiquitous or liver-specific promoter were injected prior to or after epicutaneous sensitization with OVA. Mice treated with either AAV8-OVA vector were completely protected from allergy sensitization. These animals had a significant reduction in anaphylaxis mediated by a reduction in OVA specific IgE titers. In mice with established OVA allergy, allergic responses were mitigated only in mice treated with an AAV8-OVA vector expressing OVA from an ubiquitous promoter. In conclusion, an AAV vector with a liver specific promoter was more effective for allergy prevention, but higher OVA levels were necessary for reducing symptoms in preexisiting allergy. Overall, our AAV gene immunotherapy resulted in an expansion of OVA specific FoxP3⁺ CD4⁺ T cells, an increase in the regulatory cytokine IL-10, and a reduction in the IgE promoting cytokine IL-13 .
... IL-2 and IFN-γ support Th1 cell proliferation and antagonize the effects of IL-4 and TNF-α. 25 All this conforms with the findings of this study: the Tα1 group had lower sputum supernatant levels of IL-4 and TNF-α but higher sputum supernatant levels of IL-2 and IFN-γ compared with the control group. Previous studies have also shown that Tα1 can reduce liver inflammation and reduce hepatocyte apoptosis by down-regulating TNF-α and up-regulating IL-10. ...
Objective:
To observe the clinical efficacy of thymosin alpha 1 (Tα1) combined with multi-modality chemotherapy in patients with pulmonary tuberculosis (PTB) complicated with diabetes and discuss the effects of such combination therapy on lymphocyte subsets and sputum levels of cytokines.
Methods:
A total of 120 patients with PTB complicated with diabetes admitted to the Affiliated Hospital of North China University of Science and Technology from January 2017 to January 2018 were included in this study and randomly divided into an experimental group (Tα1 group, n=60) and a control group (n=60). Clinical efficacy and adverse drug reactions were observed and compared between the two groups. Blood samples were collected for lymphocyte (NK cell and T cell subsets) levels by flow cytometry, and sputum samples were collected for cytokine (IL-2, IFN-γ, IL-4 and TNF-α) levels by ELISA.
Results:
Two groups showed no statistically significant difference in sputum culture-negative conversion rate, chest lesion absorption rate, and cavity closure rate (P>0.05) after 6 months of treatment. However, after 12 months, the sputum culture-negative conversion rate, chest lesion absorption rate, and cavity closure rate in the Tα1 group increased compared with the control group, and the differences were statistically significant (P<0.05). There was a significant increase in CD3+, CD4+, NK-cells lymphocytes after six months in the Tα1 group than in the control group, whereas the CD8+, Th17, Treg lymphocytes in the Tα1 group were substantially lower than in the control group, with the differences showing statistical significance (P<0.05, respectively). After six months of treatment, the sputum supernatant levels of interleukin-4 (IL-4) and tumor necrosis factor α (TNF-α) in the Tα1 group were lower than in the control group, whereas the sputum supernatant levels of interleukin-2 (IL-2) and interferon gamma (IFN-γ) in the Tα1 group were higher than in the control group, and the differences were statistically significant (P<0.05, respectively). There was no statistically significant difference in the incidence of adverse reactions between the two groups (P>0.05).
Conclusion:
Tα1 combined with multi-modality chemotherapy has a visible curative effect on PTB patients with diabetes as it can regulate immune function and reduce the levels of inflammatory cytokines. As a safe combination therapy, it seems promising for further use in clinical practice.
Casein (CN) is the primary allergenic protein in cow’s milk, contributing to the worldwide escalating prevalence of food allergy. However, there remains limited knowledge regarding the effect of structural modifications on CN allergenicity. Herein, we prepared three modified CN (mCN), including sodium dodecyl sulfate and dithiothreitol-induced linear CN (LCN), transglutaminase-crosslinked CN (TCN), and glucose-glycated CN (GCN). The electrophoresis results indicated widespread protein aggregation among mCN, causing variations in their molecular weights. The unique internal and external structural characteristics of mCN were substantiated by disparities in surface microstructure, alterations in the secondary structure, variations in free amino acid contents, and modifications in functional molecular groups. Despite the lower digestibility of TCN and GCN compared to LCN, they significantly suppressed the IL-8 production in Caco-2 cells without significantly promoting their proliferation. Moreover, GCN showed the weakest capacity to induce LAD2 cell degranulation. Despite the therapeutic effect of TCN, GCN-treated mice displayed the most prominent attenuation of allergic reactions and a remarkably restored Th1/Th2 imbalance, while LCN administration resulted in severe allergic phenotypes and endotypes in both cellular and murine models. This study highlighted the detrimental impact of linear modifications and underscored the significance of glycation in relation to CN allergenicity.
Purpose: Serum electrolyte imbalances are highly prevalent in COVID-19 patients. However, their associations with COVID-19 outcomes are inconsistent, and of unknown prognostic value. We aim to systematically clarify the associations and prognostic accuracy of electrolyte imbalances (sodium, calcium, potassium, magnesium, chloride and phosphate) in predicting poor COVID-19 clinical outcome.
Methods: PubMed, Embase and Cochrane Library were searched. Odds of poor clinical outcome (a composite of mortality, intensive-care unit (ICU) admission, need for respiratory support and acute respiratory distress syndrome) were pooled using mixed-effects models. The associated prognostic sensitivity, positive and negative likelihood ratios (LR + , LR-) and predictive values (PPV, NPV; assuming 25% pre-test probability), and area under the curve (AUC) were computed.
Results: We included 28 observational studies from 953 records with low to moderate risk-of-bias. Hyponatremia (OR = 2.08, 95% CI = 1.48–2.94, I2 = 93%, N = 8), hypernatremia (OR = 4.32, 95% CI = 3.17–5.88, I2 = 45%, N = 7) and hypocalcemia (OR = 3.31, 95% CI = 2.24–4.88, I2 = 25%, N = 6) were associated with poor COVID-19 outcome. These associations remained significant on adjustment for covariates such as demographics and comorbidities. Hypernatremia was 97% specific in predicting poor outcome (LR + 4.0, PPV = 55%, AUC = 0.80) despite no differences in CRP and IL-6 levels between hypernatremic and normonatremic patients. Hypocalcemia was 76% sensitive in predicting poor outcome (LR- 0.44, NPV = 87%, AUC = 0.71). Overall quality of evidence ranged from very low to moderate.
Conclusion: Hyponatremia, hypernatremia and hypocalcemia are associated with poor COVID-19 clinical outcome. Hypernatremia is 97% specific for a poor outcome, and the association is independent of inflammatory marker levels. Further studies should evaluate if correcting these imbalances help improve clinical outcome.
Research into food allergy continues to rapidly evolve, accompanying and driving real changes in the clinical approach to these diseases. The past year has seen the roll out of the first treatment approved for active management of food allergy, more data on alternative methods of treatment, the continued evolution of strategies for prevention of food allergy, a renewed interest in phenotyping food allergy subtypes and, importantly, key new insights into the pathophysiology of food allergy. We expect that in the coming years, the therapies that are in pre-clinical or early clinical evaluation now will make their way to the clinic, finally allowing the possibility of safe and effective treatments for food allergy.
The year 2020 is characterised by the COVID-19 pandemic that has quelled more than half a million lives in recent months. We are still coping with the negative repercussions of COVID-19 pandemic in 2021, in which the 2nd wave in India resulted in a high fatality rate. Regardless of emergency vaccine approvals and subsequent meteoric global vaccination drives in some countries, hospitalisations for COVID-19 will continue to occur due to the propensity of mutation in SARS-CoV-2 virus. The immune response plays a vital role in the control and resolution of infectious diseases. However, an impaired immune response is responsible for the severity of the respiratory distress in many diseases. The severe COVID-19 infection persuaded cytokine storm that has been linked with acute respiratory distress syndrome (ARDS), culminates into vital organ failures and eventual death. Thus, safe and effective therapeutics to treat hospitalised patients remains a significant unmet
clinical need. In that state, any clue of possible treatments, which save patients life, can be treasured for this time point. Many cohorts and clinical trial studies demonstrated that timely administration of immunomodulatory drugs on severe COVID-19 patients may mitigate the disease severity, hospital stay and mortality. This article addresses the severity and risk factors of hypercytokinemia in COVID-19 patients, with special emphasis on prospective immunomodulatory therapies.
