Ad5-nCoV boosted vaccine and reinfection-induced memory T/B cell responses and humoral immunity to SARS-CoV-2: based on two prospective cohorts.

AbstractHere, we regularly followed SARS-CoV-2 infected cohorts to investigate the combined effects of neutralizing antibodies (NAbs) and B and T cell profiles during the convalescent period. Ten participants infected with SARS-CoV-2 in December 2022 were selected to assess the effects of an inhaled adenovirus type 5 vectored COVID-19 vaccine (Ad5-nCoV) booster on B cells and humoral immunity. To evaluate T cell responses, eight primary and 20 reinfection participants were included. Blood samples from all 38 participants were collected at 1-, 2-, and 6-months post-infection. The assays included single B cell technology, activation-induced marker (AIM) assays, and pseudovirus neutralization. In the first cohort, eighteen monoclonal antibodies (mAbs) with neutralizing activity from memory B cells (MBC) against SARS-CoV-2 mutants were obtained by high throughput single-B-cell cloning method, which lasted from 1- month to 6- month post infection. The overall number of mAbs from MBC in the inhaled Ad5-nCoV-boosted immunization group was higher than that in the non-boosted immunization group at 2-, and 6-months post-infection. In the second cohort, circulating T follicular helper cells (cTfh) and AIM + CD4 + T cells increased over time in the reinfection group (P < 0.05). The serum NAb levels against XBB.1.22, EG.5.1, and JN.1 in the primary infection group tended to increase from the post 1-month to 2-month infection (P < 0.05). In both cohorts, serum NAb titers showed significant immune escape, while cTfh and AIM + CD4 + T cells in the second cohort essentially showed no immune escape to new strains (including XBB, EG.5) during the six-month follow-up period. AIM + CD4 + T cells against BA.5 and EG.5 were strongly negatively correlated with the time to viral clearance in the reinfected group after months of 6M infection. The broader significance of this study was to comprehensively assess the ability of the SARS-CoV-2 boosted immunization and reinfection-induced generation of T/B cell immune memories in preventing reinfection.

Impact of dexmedetomidine-assisted anesthesia in elderly patients undergoing radical resection of colon cancer.

BACKGROUND: Radical resection of colon cancer under general anesthesia is one of the main treatment methods for this malignancy. However, due to the physiological characteristics of elderly patients, the safety of perioperative anesthesia needs special attention. As an α2-adrenergic receptor agonist, dexmedetomidine (Dex) has attracted much attention from anesthesiologists due to its stabilizing effect on heart rate and blood pressure, inhibitory effect on inflammation, and sedative and analgesic effects. Its application in general anesthesia may have a positive impact on the quality of anesthesia and postoperative recovery in elderly patients undergoing radical resection of colon cancer. AIM: To investigate the anesthetic effects of Dex during radical surgery for colon cancer under general anesthesia in elderly patients. METHODS: A total of 165 colon cancer patients who underwent radical surgery for colon cancer under general anesthesia at Qingdao University Affiliated Haici Hospital, Qingdao, China were recruited and divided into two groups: A and B. In group A, Dex was administered 30 min before surgery, while group B received an equivalent amount of normal saline. The hemodynamic changes, pulmonary compliance, airway pressure, inflammatory factors, confusion assessment method scores, Ramsay Sedation-Agitation Scale scores, and cellular immune function indicators were compared between the two groups. RESULTS: Group A showed less intraoperative hemodynamic fluctuations, better pulmonary compliance, and lower airway resistance compared with group B. Twelve hours after the surgery, the serum levels of TLR-2, TLR-4, IL-6, and TNF-α in group A were significantly lower than those of group B (P < 0.05). After extubation, the Ramsay Sedation-Agitation Scale score of group A patients was significantly higher than that of group B patients, indicating a higher level of sedation. The incidence of delirium was significantly lower in group A than in group B (P < 0.05). CONCLUSION: The use of Dex as an adjunct to general anesthesia for radical surgery in elderly patients with colon cancer results in better effectiveness of anesthesia.

Pentachlorophenol impairs the antimicrobic capability of blood clam via undermining humoral immunity and disrupting humoral-cellular crosstalk.

Due to past massive usage and persistent nature, pentachlorophenol (PCP) residues are prevalent in environments, posing a potential threat to various organisms such as sessile filter-feeding bivalves. Although humoral immunity and its crosstalk with cellular one are crucial for the maintaining of robust antimicrobic capability, little is known about the impacts of PCP on these critical processes in bivalve mollusks. In this study, pathogenic bacterial challenge and plasma antimicrobic capability assays were carried out to assess the toxic effects of PCP on the immunity of a common bivalve species, blood clam (Tegillarca granosa). Moreover, the impacts of PCP-exposure on the capabilities of pathogen recognition, hemocyte recruitment, and pathogen degradation were analyzed as well. Furthermore, the activation status of downstream immune-related signalling pathways upon PCP exposure was also assessed. Data obtained illustrated that 28-day treatment with environmentally realistic levels of PCP resulted in evident declines in the survival rates of blood clam upon Vibrio challenge along with markedly weakened plasma antimicrobic capability. Additionally, the levels of lectin and peptidoglycan-recognition proteins (PGRPs) in plasma as well as the expression of pattern recognition receptors (PRRs) in hemocytes were found to be significantly inhibited by PCP-exposure. Moreover, along with the downregulation of immune-related signalling pathway, markedly fewer chemokines (interleukin 8 (IL-8), IL-17, and tumor necrosis factor α (TNF-α)) in plasma and significantly suppressed chemotactic activity of hemocytes were also observed in PCP-exposed blood clams. Furthermore, compared to that of the control, blood clams treated with PCP had markedly lower levels of antimicrobic active substances, lysozyme (LZM) and antimicrobial peptides (AMP), in their plasma. In general, the results of this study suggest that PCP exposure could significantly impair the antimicrobic capability of blood clam via undermining humoral immunity and disrupting humoral-cellular crosstalk.

Recombinant outer membrane protein Lipl41 from Leptospira interrogans robust immune responses in mice model.

Background and Objectives: Leptospirosis is an infectious zoonotic disease that can result in severe complications. It is widespread, especially in hot and humid climates such as the northern region of Iran. The immune responses to leptospirosis are multifaceted. Lipl41 is an outer membrane protein that is expressed during infection and is highly conserved among pathogenic species. This makes it a good candidate for diagnosis and induction of specific immune responses. The aim of the present study was to evaluate immune responses against recombinant Lipl41 in mice. Materials and Methods: After immunizing of different groups of mice with recombinant Lipl41 (rLipl41), the levels of specific antibodies and cytokine profiles interferon-gamma/interleukin-4 (IFN-γ/IL-4) were measured. Results: The results revealed that rLipl41 showed a significant increase in antibody levels compared with the control groups (P< 0.05). Although the level of IL-4 in the groups that received Lipl41 was similar to that in the other control groups, the IFN-γ levels showed a significant increase (P<0.05). Conclusion: It has been concluded that recombinant Lipl41 protein could strongly stimulate specific immune responses and be considered a potential candidate for vaccine development and diagnostic research.

Development of Influenza-Specific CD4 T Cell-Mediated Immunity in Children Following Inactivated Influenza Vaccination.

BACKGROUND: While both cellular and humoral immunity are important in immunologic protection against influenza, how the influenza-specific CD4 T cell response is established in response to early vaccination remains inadequately understood. In this study, we sought to understand how the CD4 T cell response to IIV is established and develops throughout early childhood. METHODS: Influenza-specific CD4 T cell responses were quantified following IIV over two influenza seasons in 47 vaccinated children between 6 months and 8 years of age who had no documented history of natural influenza infection during the study. PBMCs were stimulated with peptide pools encompassing the translated regions of the pH1, H3, HAB, and NP proteins and CD4 T cell responses were assessed via multiparameter flow cytometry. RESULTS: There was boosting of H3- and HAB-specific CD4 T cells but not cells specific for the pH1 HA protein post-vaccination. A positive correlation between age and the magnitude of the influenza-specific CD4 T cell response was seen, with an overall greater magnitude of IFNγ-producing cells in subjects ≥3 years of age. Changes in CD4 T cell functionality were also noted in older compared to younger children, with increases in CD4 T cells producing IFNγ and TNF or IL-2 as well as IFNγ alone. CONCLUSIONS: IIV elicits a CD4 T cell response to H3 and HAB, with increases in the magnitude of the CD4 T cell response and changes in cellular functionality throughout childhood. This suggests that repeated influenza vaccination contributes to the development of anti-influenza CD4 T cell memory in children.

Cellular immune response to a single dose of live attenuated hepatitis a virus vaccine in obese children and adolescents.

Background: Limited data are currently available regarding the cellular immune response to a live attenuated hepatitis A virus (HAV) vaccine, especially in children with obesity. The objective of this retrospective cohort study was to compare the activation of antigen-specific interferon (IFN)-γ+ T cells in obese children and adolescents with healthy individuals before and after immunization with a single dose of live attenuated HAV vaccine. Methods: Blood samples were obtained from the 2021 study by Dumrisilp et al. investigating the immunogenicity of the live attenuated hepatitis A vaccine in children and young adults. Prior to enrollment, all 212 subjects had never received any HAV vaccine and tested negative for anti-HAV antibodies. The participants were vaccinated with a freeze-dried, live attenuated HAV vaccine of the H2 strain. In this study, we analyzed the stored peripheral blood mononuclear cells (PBMCs) obtained from a subgroup of 30 obese subjects and 30 normal-weight healthy controls of the same age and sex. PBMCs were collected before and 8-9 weeks after HAV vaccination for further analysis. These cells were stimulated with a recombinant antigen derived from HAV-VP3, and the immune response was evaluated using the IFN-γ enzyme-linked immunospot (ELISpot) assay. Results: The between-group analysis indicated that the T-cell response of obese participants was comparable to that of normal-weight controls both before and after vaccination. The change in IFN-γ production from before to after vaccination in the obese group was not significantly different from that of the control group. Additionally, in the obese group, no correlation was found between IFN-γ production and clinical characteristics such as sex, body mass index, waist circumference, and acanthosis nigricans. Conclusion: Testing for cellular immune response provides a comprehensive understanding of the overall immune response to vaccination. This study, the first to explore this significant aspect, suggests that obesity does not affect the short-term cellular immune response to live attenuated HAV vaccination.

Ethoxyquin mediates lung fibrosis and cellular immunity in BLM-CIA mice by inhibiting HSP90.

BACKGROUND: Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are characterized by severe pulmonary fibrosis and immune dysregulation. Heat shock protein 90 (HSP90) is involved in the progression of pulmonary fibrosis and the immune response. OBJECTIVES: This study aimed to explore whether HSP90 regulates the development of RA-ILD and its underlying mechanism. MATERIAL AND METHODS: In vivo, collagen-induced arthritis (CIA)-mice were treated with bleomycin (BLM) to establish an arthritic mouse model of pulmonary fibrosis. In vitro, human lung fibroblast 1 (HLF1) was exposed to transforming growth factor beta 1 (TGF-ß1) to simulate an RA-ILD model. The RA-ILD models were treated with the HSP90 inhibitor ethoxyquin (EQ) to explore the potential mechanism of HSP90 in RA-ILD. Histopathological analysis was performed, and pulmonary fibrosis was evaluated. The differentiation of M1/M2 macrophages and Th1/Th17/Treg cells was assessed. The role of the TGF-ß/Smad2/3 pathway in EQ-mediated RA-ILD progression was also explored. RESULTS: HSP90α and HSP90ß were upregulated in the RA-ILD models. Ethoxyquin mitigated arthritis in BLM-CIA mice, and reduced the expression of alpha-smooth muscle actin (α-SMA), collagen I (Col-1) and fibronectin (FN), as well as hydroxyproline content, thereby relieving pulmonary fibrosis. In addition, EQ increased M1 macrophages and inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-α) levels; conversely, EQ decreased M2 macrophages and vascular endothelial growth factor (VEGF)-A and TGF-ß1 contents. It also decreased Th17 (interleukin (IL)-17) while increasing Th1 (interferon gamma (IFN-γ)) and Treg (Foxp3), and restricted the expression of transforming growth factor beta type receptor I and II (TGF-ßRI and TGF-ßRII) and the phosphorylation of Smad2 and Smad3. CONCLUSIONS: This study revealed that EQ regulated pulmonary fibrosis and cellular immunity by inhibiting HSP90, appearing to act through the TGF-ß/Smad2/3 pathway. These findings suggest that EQ holds potential as a therapeutic agent for treating RA-ILD.

A Longitudinal Analysis of Memory Immune Responses in Convalescent Crimean-Congo Hemorrhagic Fever Survivors in Uganda.

Evaluating the adaptive immune responses to natural infection with Crimean-Congo hemorrhagic fever (CCHF) virus (CCHFV) in human survivors is critical to the development of medical countermeasures. However, the correlates of protection are unknown. As the most prevalent tick-borne human hemorrhagic fever virus with case fatality rates of 5%-30% and worldwide distribution, there is an urgent need to fill these knowledge gaps. Here, we describe adaptive immune responses in a cohort of Ugandan CCHF survivors via serial sampling over 6 years. We demonstrate persistent antibodies after infection and cross-neutralization against various clades of authentic CCHFV, as well as potent effector function. Moreover, we show for the first time persistent, polyfunctional antigen-specific memory T-cell responses to multiple CCHFV proteins up to 9 years after infection. Together, this data provides immunological benchmarks for evaluating CCHFV medical countermeasures and information that can be leveraged toward vaccine immunogen design and viral target identification for monoclonal antibody therapies.

Kinetics of humoral and cellular immune responses 5 months post-COVID-19 booster dose by immune response groups at the peak immunity phase: An observational historical cohort study using the Fukushima vaccination community survey.

Background: Understanding the waning of immunity after booster vaccinations is important to identify which immune-low populations should be prioritized. Methods: We investigated longitudinal cellular and humoral immunity after the third vaccine dose in both high- and low-cellular and humoral immunity groups at the peak immunity phase after the booster vaccination in a large community-based cohort. Blood samples were collected from 1045 participants at peak (T1: median 54 days post-third dose) and decay (T2: median 145 days post-third dose) phases to assess IgG(S), neutralizing activity, and ELISpot responses. Participants were categorized into high/low ELISpot/IgG(S) groups at T1. Cellular and humoral responses were tracked for approximately five months after the third vaccination. Results: In total, 983 participants were included in the cohort. IgG(S) geometric mean fold change between timepoints revealed greater waning in the >79 years age group (T2/T1 fold change: 0.27) and higher IgG(S) fold change in the low-ELISpot group at T1 (T2/T1 fold change: 0.32-0.33) than in the other groups, although ELISpot geometric mean remained stable. Conclusions: Antibody level of those who did not respond well to third dose vaccination waned rapidly than those who responded well. Evidence-based vaccine strategies are essential in preventing potential health issues caused by vaccines, including side-effects.

Production of recombinant cytokines and polyclonal antibodies for analysis of cellular immune response in golden Syrian hamster.

BACKGROUND: The development of therapies and vaccines for various diseases often necessitates the analysis of cellular immunity. However, unlike other rodents, the limited availability of reagents for Syrian hamsters restricts immunological analysis, particularly in the determination of serum effector molecules such as cytokines. In this study, we aim to produce and characterize the cytokines IFN-γ, TGF-ß, IL-6, IL-10, and TNF-α from Syrian hamsters in recombinant form and to generate polyclonal antibodies against them in rats. METHODS AND RESULTS: Cytokine transcript sequences were cloned into expression vectors in E. coli. Recombinant proteins were produced, purified through affinity chromatography, and characterized by Western blot using an anti-6xHis monoclonal antibody. Rats were immunized with the recombinant proteins to generate polyclonal antibodies (pAbs). These pAbs were characterized by Western blot and titrated by indirect ELISA. The recombinant cytokines rTNF-α, rIL-10, rIFN-γ, rTGF-ß, and rIL-6 were produced and specifically recognized at their expected molecular weights of 22.3 kDa, 19.8 kDa, 18.9 kDa, 11.8 kDa, and 22.9 kDa. pAbs were produced and demonstrated the ability to specifically recognize their target proteins with titers of 409,600 (rIL-10), 204,800 (rTNF-α), 102,400 (rIL-10), 51,200 (rTGF-ß), and 25,600 (rIFN-É£). CONCLUSIONS: The reagents produced represent a starting point for developing immunoassays to detect hamster cytokines, facilitating the analysis of cellular immunity in this biomodel.

Predictors of prognosis in Alzheimer's disease: The role of cognitive dysfunction, immune abnormalities, and advanced neuroimaging.

Alzheimer's disease (AD) is a grave illness that results in cognitive and social issues. A recent study examined the association between neuroimaging results, cognitive dysfunction, atypical cellular immune function, and poor prognostic factors in AD patients who demonstrated poor prognosis. Poor prognosis was associated with abnormal cellular immune function, extrapyramidal symptoms, altered consciousness, abnormal electroencephalogram, modified Rankin scale, increased neutrophil lymphocyte ratio, and severe pneumonia. The impaired cellular immune function characterized by a reduction in the blood T lymphocytes' proportion predicted poor prognosis as an independent risk factor in AD. Early initiation and maintenance of AD medications is associated with better outcomes.

Fullerene Derivatives for Tumor Treatment: Mechanisms and Application.

Fullerenes hold tremendous potential as alternatives to conventional chemotherapy or radiotherapy for tumor treatment due to their abilities to photodynamically kill tumor cells, destroy the tumor vasculature, inhibit tumor metastasis and activate anti-tumor immune responses, while protecting normal tissue through antioxidative effects. The symmetrical hollow molecular structures of fullerenes with abundant C=C bonds allow versatile chemical modification with diverse functional groups, metal clusters and biomacromolecules to synthesize a wide range of fullerene derivatives with increased water solubility, improved biocompatibility, enhanced photodynamic properties and stronger targeting abilities. This review introduces the anti-tumor mechanisms of fullerenes and summarizes the most recent works on the functionalization of fullerenes and the application of fullerene derivatives in tumor treatment. This review aims to serve as a valuable reference for further development and clinical application of anti-tumor fullerene derivatives.

Asian Flush Gene Variant Enhances Cellular Immunogenicity of COVID-19 Vaccine: Prospective Observation in the Japanese General Population.

We previously reported a reduced humoral immune response to the COVID-19 vaccines. Subsequently, we observed a lower susceptibility to COVID-19 in individuals carrying the ALDH2 rs671 variant through a web-based retrospective survey. Based on these findings, we hypothesized that rs671 variant was beneficial for cellular immunity against COVID-19. Using the IFN-γ enzyme-linked immunospot (ELISPOT) assay, we assessed cellular immunity before and after COVID-19 vaccination in two subcohorts of a previously reported cohort. Subcohort 1 (26 participants) had six repeated observations at baseline after one to three doses, whereas subcohort 2 (19 participants) had two observations before and after the third dose. ELISPOT counts at six months after the second dose increased from baseline in carriers of the rs671 variant but not in non-carriers. A positive effect of rs671 on ELISPOT counts was estimated using a mixed model (183 observations from 45 participants), including the random effect of subcohort, repeated measures, and fixed effects of vaccine type, age, sex, height, lifestyle, steroid use, and allergic disease. There was no association between ELISPOT counts and specific IgG levels, suggesting a limitation in estimating protective potential by humoral response. Our sequential observational studies suggest a beneficial effect of the rs671 variant in SARS-CoV-2 infection via enhanced cellular immune response, providing a potential basis for optimizing preventive measures and drug development.

Physiological responses of the stingless bee Partamona helleri to oral exposure to three agrochemicals: impact on antioxidant enzymes and hemocyte count.

Agrochemicals pose significant threats to the survival of bees, yet the physiological impacts of sublethal doses on stingless bees remain poorly understood. This study investigated the effects of acute oral exposure to three commercial formulations of agrochemicals [CuSO4 (leaf fertilizer), glyphosate (herbicide), and spinosad (bioinsecticide)] on antioxidant enzymes, malondialdehyde content (MDA), nitric oxide (NO) levels, and total hemocyte count (THC) in the stingless bee Partamona helleri. Foragers were exposed to lethal concentrations aimed to kill 5% (LC5) of CuSO4 (120 µg mL-1) or spinosad (0.85 µg mL-1) over a 24-h period. Glyphosate-exposed bees received the recommended label concentration (7400 µg mL-1), as they exhibited 100% survival after exposure. Ingestion of CuSO4 or glyphosate-treated diets by bees was reduced. Levels of NO and catalase (CAT) remained unaffected at 0 h or 24 h post-exposure. Superoxide dismutase (SOD) activity was higher at 0 h compared to 24 h, although insignificantly so when compared to the control. Exposure to CuSO4 reduced glutathione S-transferase (GST) activity at 0 h but increased it after 24 h, for both CuSO4 and glyphosate. MDA levels decreased after 0 h exposure to CuSO4 or spinosad but increased after 24 h exposure to all tested agrochemicals. THC showed no difference among glyphosate or spinosad compared to the control or across time. However, CuSO4 exposure significantly increased THC. These findings shed light on the physiological responses of stingless bees to agrochemicals, crucial for understanding their overall health.

Unique Lessons From the Natural Progression of Rejection in Human Uterine Allografts.

INTRODUCTION: Uterus transplantation (UTx) is a novel treatment for absolute uterine infertility. Acute T cell-mediated rejection (TCMR) can be monitored only through serial cervical biopsies. METHODS: This study, the first of its kind in human transplantation, evaluated clinical, serological, and pathophysiological manifestations of allograft rejection from immunosuppression withdrawal (ISW) to graft hysterectomy (Hx). RESULTS: Following live birth, immunosuppression was abruptly withdrawn from six living-donor UTx recipients. ISW occurred at a median of 7.4 weeks before graft Hx. Post-ISW signs of rejection included: (1) discoloration of the cervix; (2) increased uterine size compared to day of ISW; (3) serological evidence of eosinophilia and progressive development of donor-specific antibodies (DSA) or child-specific antibodies (CSA); (4) histopathological evidence of TCMR in cervical biopsies preceding the development of antibodies in serum; and (5) C4d deposition in tissue before formation of DSA or CSA in all but two recipients. At graft Hx, endometrial glands were preferentially targeted for destruction over stroma while parametrial arteries displayed variable arteritis and fibrointimal hyperplasia. CONCLUSION: Recognition of the progression of uterine allograft rejection may be important for other human organ recipients and drive research on modulation of immunosuppression and the paradoxical relationship between adaptive cellular and humoral immunity in natural pregnancies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02656550.

Chlorantraniliprole Enhances Cellular Immunity in Larvae of Spodoptera frugiperda (Smith) (Lepidoptera: Noctuidae).

The innate immunity of insects encompasses cellular and humoral defense mechanisms and constitutes the primary defense against invading microbial pathogens. Cellular immunity (phagocytosis, nodulation, and encapsulation) is primarily mediated by hemocytes. Plasmatocytes and granulocytes play an important role and require changes in the cytoskeletons of hemocytes. However, research investigating the immunological impacts of insecticides on the fall armyworm (FAW), Spodoptera frugiperda, remains scarce. Therefore, we conducted a study to investigate the effects of chlorantraniliprole exposure on cellular immunity in FAW larvae. Our findings revealed the presence of five types of hemocytes in the larvae: prohemocytes, plasmatocytes, granulocytes, oenocytoids, and spherulocytes. The LD10, LD20, and LD30 of chlorantraniliprole affected both the morphology and total count of some hemocytes in the larvae. Moreover, larvae exposed to chlorantraniliprole showed increased phagocytosis, nodulation, and encapsulation. To determine the mechanism of the enhanced cellular immunity, we studied plasmatocytes in the spread state and the cytoskeleton in hemocytes. It was found that the spreading ratio of plasmatocytes and the areas of the cytoskeletons in hemocytes were increased after chlorantraniliprole treatment. These results suggest that exposure to chlorantraniliprole results in an enhanced immune response function in FAW larvae, which may be mediated by cytoskeletal changes and plasmatocyte spreading. Consequently, this study provides valuable insights into the cellular immune response of FAW larvae to insecticide exposure.

Manganese-Modified Aluminum Adjuvant Enhances both Humoral and Cellular Immune Responses.

Aluminum adjuvants remain the most commonly used vaccine adjuvants. Being rather effective in triggering humoral immunity, however, aluminum adjuvants usually show limited abilities in activating cellular immunities. Herein, by adding manganese ions during the preparation of aluminum adjuvant, a manganese-modified aluminum (Mn-Al) adjuvant is obtained, which can effectively stimulate both humoral and cellular immune responses. Such Mn-Al adjuvant can enhance antigen adsorption and promote antigen internalization by dendritic cells (DCs). Subsequently, the released Mn2+ can activate the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway to further promote DC activation. When combines with the model antigen ovalbumin (OVA), the Mn-Al-adjuvantes vaccine can induce high levels of antigen-specific antibody titers and high proportions of antigen-specific cytotoxic T cells in vivo. Moreover, the Mn-Al-adjuvanted vaccine elicited stronger antigen-specific humoral and cellular immune responses than high-dose of the aluminum-based adjuvant. Additionally, immunization of mice with OVA in the presence of the Mn-Al adjuvant significantly inhibited the growth of B16-OVA tumors. Furthermore, when formulated with human papillomavirus antigens, Mn-Al-adjuvanted vaccines show better in vivo vaccination performance than aluminum-adjuvanted vaccines. Therefore, the manganese-modified aluminum adjuvant may thus become a new vaccine adjuvant with the potential to replace conventional aluminum adjuvants.

Exploring T-Cell Immunity to Hepatitis C Virus: Insights from Different Vaccine and Antigen Presentation Strategies.

The hepatitis C virus (HCV) is responsible for approximately 50 million infections worldwide. Effective drug treatments while available face access barriers, and vaccine development is hampered by viral hypervariability and immune evasion mechanisms. The CD4+ and CD8+ T-cell responses targeting HCV non-structural (NS) proteins have shown a role in the viral clearance. In this paper, we reviewed the studies exploring the relationship between HCV structural and NS proteins and their effects in contributing to the elicitation of an effective T-cell immune response. The use of different vaccine platforms, such as viral vectors and virus-like particles, underscores their versability and efficacy for vaccine development. Diverse HCV antigens demonstrated immunogenicity, eliciting a robust immune response, positioning them as promising vaccine candidates for protein/peptide-, DNA-, or RNA-based vaccines. Moreover, adjuvant selection plays a pivotal role in modulating the immune response. This review emphasizes the importance of HCV proteins and vaccination strategies in vaccine development. In particular, the NS proteins are the main focus, given their pivotal role in T-cell-mediated immunity and their sequence conservation, making them valuable vaccine targets.

MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC. DESIGN: To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice. RESULTS: Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP1A to repress H3K9me3-marked endogenous retroelements. The derepression of retrotransposons induced by MED12 loss triggered cytosolic nucleic acid sensing and subsequent activation of type I interferon pathways, ultimately leading to robust inflamed TME . Moreover, we uncovered a negative correlation between MED12 expression and immune resposne pathways, retrotransposon levels as well as the prognosis of patients with PDAC undergoing ICB therapy. CONCLUSION: In summary, our findings underscore the pivotal role of MED12 in remodelling immnue TME through the epigenetic silencing of retrotransposons, offering a potential therapeutic target for enhancing tumour immunogenicity and overcoming immunotherapy resistance in PDAC.

Effects of a supplemented diet containing 7 probiotic strains (Honeybeeotic) on honeybee physiology and immune response: analysis of hemolymph cytology, phenoloxidase activity, and gut microbiome.

BACKGROUND: In this study, a probiotic mixture (Honeybeeotic) consisting of seven bacterial strains isolated from a unique population of honeybees (Apis mellifera ligustica) was used. That honeybee population was located in the Roti Abbey locality of the Marche Region in Italy, an area isolated from human activities, and genetic contamination from other honeybee populations. The aim was to investigate the effects of this probiotic mixture on the innate immunity and intestinal microbiome of healthy common honeybees in two hives of the same apiary. Hive A received a diet of 50% glucose syrup, while hive B received the same syrup supplemented with the probiotics, both administered daily for 1 month. To determine whether the probiotic altered the immune response, phenoloxidase activity and hemolymph cellular subtype count were investigated. Additionally, metagenomic approaches were used to analyze the effects on gut microbiota composition and function, considering the critical role the gut microbiota plays in modulating host physiology. RESULTS: The results revealed differences in hemocyte populations between the two hives, as hive A exhibited higher counts of oenocytoids and granulocytes. These findings indicated that the dietary supplementation with the probiotic mixture was safe and well-tolerated. Furthermore, phenoloxidase activity significantly decreased in hive B (1.75 ± 0.19 U/mg) compared to hive A (3.62 ± 0.44 U/mg, p < 0.005), suggesting an improved state of well-being in the honeybees, as they did not require activation of immune defense mechanisms. Regarding the microbiome composition, the probiotic modulated the gut microbiota in hive B compared to the control, retaining core microbiota components while causing both positive and negative variations. Notably, several genes, particularly KEGG genes involved in amino acid metabolism, carbohydrate metabolism, and branched-chain amino acid (BCAA) transport, were more abundant in the probiotic-fed group, suggesting an effective nutritional supplement for the host. CONCLUSIONS: This study advocated that feeding with this probiotic mixture induces beneficial immunological effects and promoted a balanced gut microbiota with enhanced metabolic activities related to digestion. The use of highly selected probiotics was shown to contribute to the overall well-being of the honeybees, improving their immune response and gut health.