Th17 cell-mediated immune response in a subpopulation of dogs with idiopathic epilepsy

Background Canine idiopathic epilepsy (IE) is a common neurological disease with severe impact on the owner´s and the dog’s quality of life. A subpopulation of dogs with IE does not respond to antiseizure drugs (non-responder). Th17 cells (T helper cells) and their proinflammatory Interleukin-17 (IL-17) are part of the immune system and previous studies showed their involvement in the pathogenesis of several autoimmune diseases. Non-responder might have an abnormal immune response against structures of the central nervous system. To discover a new aetiology of canine IE and thereby optimising the therapy of intractable IE, this prospective study aimed to investigate Th17 cells and IL-17 in dogs with IE. The underlying hypothesis was that in some dogs with IE a Th17 cell-mediated immune response could be detectable. Methods 57 dogs with IE and 10 healthy dogs (control group, C) were enrolled in the study. EDTA blood was taken to measure Th17 cells by flow cytometry. IL-17 was measured in 35 cerebrospinal fluid (CSF) and 33 serum samples using an enzyme-linked immunosorbent assay (ELISA). It was investigated whether there was a significant increase of stimulated Th17 cells in blood samples or of IL-17 in serum and CSF samples of dogs with IE in comparison to C. Correlations between the amount of Th17 cells/μL or IL-17 and different clinical parameters e.g. seizure frequency, seizure type, seizure severity or treatment response were evaluated. Additionally, Th17 cells/μL were randomly controlled of 17 dogs with IE and were examined for changes over time and in relation to treatment response. Results Ten dogs with IE had strongly elevated stimulated Th17 cells/μL within the blood (>100 Th17 cells/μL). A slight positive correlation between stimulated Th17 cells/μL and seizure severity (p = 0.046; rSpear = 0.27) was proven in these dogs. In addition, 4/10 dogs with elevated Th17 levels experienced cluster seizures and status epilepticus in comparison to 9% of the dogs with non-elevated Th17 levels (<100 Th17 cells/μL). Dogs with IE had significantly higher IL-17 values in CSF and serum samples compared to C (p<0.001; p<0.002; respectively). Conclusion In single dogs with IE, strongly increased amounts of Th17 cells were detectable and dogs with elevated Th17 cells seemed to have a greater risk for experiencing a combination of cluster seizures and status epilepticus. Therefore, an underlying Th17-cell mediated immune response was suspected and hence anti-inflammatory drugs could be indicated in these single cases with intractable epilepsy.

Liposome-Mediated Delivery of MERS Antigen Induces Potent Humoral and Cell-Mediated Immune Response in Mice

The advancements in the field of nanotechnology have provided a great platform for the development of effective antiviral vaccines. Liposome-mediated delivery of antigens has been shown to induce the antigen-specific stimulation of the humoral and cell-mediated immune responses. Here, we prepared dried, reconstituted vesicles (DRVs) from DPPC liposomes and used them as the vaccine carrier system for the Middle East respiratory syndrome coronavirus papain-like protease (DRVs-MERS-CoV PLpro). MERS-CoV PLpro emulsified in the Incomplete Freund’s Adjuvant (IFA-MERS-CoV PLpro) was used as a control. Immunization of mice with DRVs-MERS-CoV PLpro did not induce any notable toxicity, as revealed by the levels of the serum alanine transaminase (ALT), aspartate transaminase (AST), blood urea nitrogen (BUN) and lactate dehydrogenase (LDH) in the blood of immunized mice. Immunization with DRVs-MERS-CoV PLpro induced greater antigen-specific antibody titer and switching of IgG1 isotyping to IgG2a as compared to immunization with IFA-MERS-CoV PLpro. Moreover, splenocytes from mice immunized with DRVs-MERS-CoV PLpro exhibited greater proliferation in response to antigen stimulation. Moreover, splenocytes from DRVs-MERS-CoV PLpro-immunized mice secreted significantly higher IFN-γ as compared to splenocytes from IFA-MERS-CoV PLpro mice. In summary, DRVs-MERS-CoV PLpro may prove to be an effective prophylactic formulation to prevent MERS-CoV infection.

Unravelling the Proteomics of HLA-B*57:01+ Antigen Presenting Cells during Abacavir Medication

Type B adverse drug reactions (ADRs) are unpredictable based on the drug’s pharmacology and represent a key challenge in pharmacovigilance. For human leukocyte antigen (HLA)-mediated type B ADRs, it is assumed that the protein/small-molecule interaction alters the biophysical and mechanistic properties of the antigen presenting cells. Sophisticated methods enabled the molecular appreciation of HLA-mediated ADRs; in several instances, the drug molecule occupies part of the HLA peptide binding groove and modifies the recruited peptide repertoire thereby causing a strong T-cell-mediated immune response that is resolved upon withdrawal of medication. The severe ADR in HLA-B*57:01+ patients treated with the antiretroviral drug abacavir (ABC) in anti-HIV therapy is an example of HLA-drug-T cell cooperation. However, the long-term damages of the HLA-B*57:01-expressing immune cells following ABC treatment remain unexplained. Utilizing full proteome sequencing following ABC treatment of HLA-B*57:01+ cells, we demonstrate stringent proteomic alteration of the HLA/drug presenting cells. The proteomic content indisputably reflects the cellular condition; this knowledge directs towards individual pharmacovigilance for the development of personalized and safe medication.

Safety and efficacy of the Novavax vaccine—a narrative review

Mass vaccination programs are a public health priority for managing the global coronavirus disease (COVID-19) pandemic. The NVX-CoV2373 vaccine is being developed by Novavax. It consists of a SARS-CoV-2 spike glycoprotein subunit (NVX-CoV2373), which has been shown to have structural stability with pH and temperature perturbations, and the saponin-based Matrix-M adjuvant, which is added to enhance the B- and T-cell-mediated immune response. Animal studies in mice, olive baboons, and cynomolgus macaques demonstrated the potential of this vaccine in protecting the respiratory tract against COVID-19. Subsequent phase 1 and 2 trials then confirmed its safety and the dose-sparing potential of Matrix-M. The results led to the use of a low dose (5 μg) of NVX-CoV2373 in phase 3 trials. In a phase 3 trial involving 14,039 participants, the vaccine efficacy rate was 89.7% (prevention of symptomatic infection). Local and systemic adverse events were mild and self-limiting; commonly reported symptoms included injection-site pain and tenderness, headache, myalgia, and fatigue. A subgroup study confirmed the safety and efficacy of co-administering the NVX-CoV2373 vaccine and the seasonal influenza vaccine. Overall, the vaccine has been found to be safe and effective, meeting the minimum vaccine efficacy rate of 50% to be considered for COVID-19 vaccine emergency use listing approval. Keywords: Clinical trials, COVID-19, COVID-19 vaccine, immunology

Designing multi-epitope based peptide vaccine targeting spike protein SARS-CoV-2 B1.1.529 (Omicron) variant using computational approaches.

Since the SARS-CoV-2 outbreak in 2019, millions of people have been infected with the virus, and due to its high human-to-human transmission rate, there is a need for a vaccine to protect people. Although some vaccines are in use, due to the high mutation rate in the SARS-CoV-2 multiple variants, the current vaccines may not be sufficient to immunize people against new variant threats. One of the emerging variants of concern is B1.1.529 (Omicron), which carries ~30 mutations in the Spike protein of SARS-CoV-2 is predicted to evade antibodies recognition even from vaccinated people. We used a structure-based approach along with an epitope prediction server to develop a Multi-Epitope based Subunit Vaccine (MESV) involving SARS-CoV-2 B1.1.529 variant spike glycoprotein. The predicted epitope with better antigenicity and non-toxicity were used for designing and predicting vaccine construct features and structure models. The MESV construct In-silico cloning in pET28a expression vector predicted the construct to be highly translational. The proposed MESV vaccine construct was also subjected to immune simulation prediction and was found to be highly antigenic and elicit a cell-mediated immune response. The proposed MESV in the present study has the potential to be evaluated further for vaccine production against the newly identified B1.1.529 (Omicron) variant of concern.

Nutritional Deficiencies in Celiac Disease: Current Perspectives

Gluten-induced T-cell-mediated immune response damages the villous structure that significantly affects the functioning of the small intestinal mucosa [...]

Low dose dexamethasone in combination with Remdesivir does not cause immune dysregulation

BackgroundThe administration of Remdesivir/Dexamethasone combination on T and B cell responses in patients with COVID-19 is sparse. To compare cell mediated immune response in patients treated with only Remdesivir and Remdesivir/dexamethasone combinationStudy DesignProspective, cohort studyMethodsRT-PCR positive SARS-CoV-2 patients (n=49) were enrolled. Patients not requiring O2-supplementation were on remdesivir and those requiring were on remdesivir/dexamethasone. Baseline parameters (complete blood picture, inflammatory markers), T and B cells (flow cytometry: day 5 and 30) and neutralizing antibodies (chemiluminescence: day 30) were estimated. Students “t’’ test was used to evaluate the differences.ResultsOf the 49 patients, 26 (Mean age-44.68±13.45) were treated with remdesivir and 23 (Mean age-48.33±14.76) with remdesivir/dexamethasone combination. While blood counts and immune cells increased, inflammatory markers decreased post treatment in both the groups. A significant increase in WBC (6357±981Vs10700±1363; p=0.01), absolute neutrophil counts (4578±711Vs8256±1323; p=0.01) with decrease in levels of CRP (31±7.1Vs10±4.2; p=0.01), D-Dimer (172.3±8Vs118.1±12; p=0.0005), IL6 (17.6±3.8Vs1.72±0.2; p=0.0001), CD4 cells (2681±86Vs1256±369; p=0.0003), CD8 cells (1749±88 Vs 1256±221; p=0.01) and neutralizing antibodies were seen post treatment in the combination group. Correction of hypoxia and maintenance of oxygen >95% was also noted. ConclusionRemdesivir/dexamethasone combination given to patients requiring oxygen supplementation is safe at 4-6mg/day and showed a marked decrease in inflammation and no immune dysregulation.

Wheat Breeding, Fertilizers, and Pesticides: Do They Contribute to the Increasing Immunogenic Properties of Modern Wheat?

Celiac disease (CD) is a small intestinal inflammatory condition where consumption of gluten induces a T-cell mediated immune response that damages the intestinal mucosa in susceptible individuals. CD affects at least 1% of the world’s population. The increasing prevalence of CD has been reported over the last few decades. However, the reason for this increase is not known so far. Certain factors such as increase in awareness and the development of advanced and highly sensitive diagnostic screening markers are considered significant factors for this increase. Wheat breeding strategies, fertilizers, and pesticides, particularly herbicides, are also thought to have a role in the increasing prevalence. However, less is known about this issue. In this review, we investigated the role of these agronomic practices in depth. Our literature-based results showed that wheat breeding, use of nitrogen-based fertilizers, and herbicides cannot be solely responsible for the increase in celiac prevalence. However, applying nitrogen fertilizers is associated with an increase in gluten in wheat, which increases the risk of developing celiac-specific symptoms in gluten-sensitive individuals. Additionally, clustered regularly interspaced short palindromic repeats (CRISPR) techniques can edit multiple gliadin genes, resulting in a low-immunogenic wheat variety that is safe for such individuals.

The Importance of RNA-Based Vaccines in the Fight against COVID-19: An Overview

In recent years, vaccine development using ribonucleic acid (RNA) has become the most promising and studied approach to produce safe and effective new vaccines, not only for prophylaxis but also as a treatment. The use of messenger RNA (mRNA) as an immunogenic has several advantages to vaccine development compared to other platforms, such as lower coast, the absence of cell cultures, and the possibility to combine different targets. During the COVID-19 pandemic, the use of mRNA as a vaccine became more relevant; two out of the four most widely applied vaccines against COVID-19 in the world are based on this platform. However, even though it presents advantages for vaccine application, mRNA technology faces several pivotal challenges to improve mRNA stability, delivery, and the potential to generate the related protein needed to induce a humoral- and T-cell-mediated immune response. The application of mRNA to vaccine development emerged as a powerful tool to fight against cancer and non-infectious and infectious diseases, for example, and represents a relevant research field for future decades. Based on these advantages, this review emphasizes mRNA and self-amplifying RNA (saRNA) for vaccine development, mainly to fight against COVID-19, together with the challenges related to this approach.

Successive Inoculations of Pigs with Porcine Reproductive and Respiratory Syndrome Virus 1 (PRRSV-1) and Swine H1N2 Influenza Virus Suggest a Mutual Interference between the Two Viral Infections

Porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza A virus (swIAV) are major pathogens of the porcine respiratory disease complex, but little is known on their interaction in super-infected pigs. In this study, we investigated clinical, virological and immunological outcomes of successive infections with PRRSV-1 and H1N2 swIAV. Twenty-four specific pathogen-free piglets were distributed into four groups and inoculated either with PRRSV at study day (SD) 0, or with swIAV at SD8, or with PRRSV and swIAV one week apart at SD0 and SD8, respectively, or mock-inoculated. In PRRSV/swIAV group, the clinical signs usually observed after swIAV infection were attenuated while higher levels of anti-swIAV antibodies were measured in lungs. Concurrently, PRRSV multiplication in lungs was significantly affected by swIAV infection, whereas the cell-mediated immune response specific to PRRSV was detected earlier in blood, as compared to PRRSV group. Moreover, levels of interferon (IFN)-α measured from SD9 in the blood of super-infected pigs were lower than those measured in the swIAV group, but higher than in the PRRSV group at the same time. Correlation analyses suggested an important role of IFN-α in the two-way interference highlighted between both viral infections.