Immune Restoration Research Articles

Monkeypox Presenting as a Hand Consult in the Emergency Department: Two Case Reports.

The ongoing outbreak of the monkeypox virus (now referred to as "mpox") was deemed a public health emergency by the World Health Organization in 2022. The United States now reports the highest number of mpox cases, with 29 980 cases and 21 deaths as of January 11, 2023. The most common presenting symptom is a pruritic, vesicular rash that commonly involves the hands. While covering hand call, our division has encountered 2 cases of mpox in the emergency department for which the chief complaint was a hand lesion. Because hand surgeons will be called upon to make an initial diagnosis, the purpose of these case reports is to describe the presentation, disease course, treatment, and outcomes of these mpox patients. These patients had both uncontrolled HIV as well as other sexually transmitted disease. Symptoms included painful vesicular hand lesions with ulceration and eventual central necrosis, followed by similar lesions on the face, trunk, and genital area. Diagnosis was made using nucleic acid amplification testing through polymerase chain reaction. The patients were treated with restoration of immunity through control of HIV as well as treatment of all secondary bacterial infections. One patient died in the hospital, and the other survived without any long-term defects.

Satisfaction and quality of life of patients treated with tobramycin-dexamethasone suspension in daytime surgery managed by integrated nursing model

Purpose: To investigate the effect of an integrated nursing model in day surgeries, treated with tobramycin-dexamethasone suspension, and its influence on patient satisfaction, quality of life, and indicators of immunity recovery.
 Methods: Ninety-eight patients with ophthalmic diseases admitted to Anhui No. 2 Provincial People’s Hospital, Anhui, China from January 2021 to June 2022 were scheduled for surgery and treated with tobramycin-dexamethasone. They were randomly divided into two groups (control and study groups, with 49 cases in each group). All patients received routine nursing intervention, and an integrated nursing model was applied to the study group on this basis. Improvement in ocular symptoms, SF-36, changes in immune-related lymphocyte subsets in peripheral blood, and nursing satisfaction were compared.
 Results: Ocular symptom score at 24 h after operation in the study group was lower than in control group (p < 0.05). The SF-36 scores (physical status, cognitive ability, social function, emotional and mental status), immune-related lymphocyte subsets, and overall satisfaction rate after intervention in the study group were higher than those in the control group (p < 0.05).
 Conclusion: Integrated nursing model achieves ideal nursing effect in day surgery managed with tobramycin-dexamethasone> It also facilitates the recovery of patient’s eyes and plays a significant role in improving the quality of life, restoration of immunity, and nursing satisfaction of patients. A multicenter investigation will, however, be required prior to its full-scale clinical application.

TREX1 531C/T Polymorphism and Autoantibodies Associated with the Immune Status of HIV-1-Infected Individuals.

Autoimmune diseases can develop during HIV-1 infection, mainly related to the individual's immune competence. The study investigated the association of the TREX1 531C/T polymorphism and antinuclear antibodies (ANA) in HIV-1 infection and the time of antiretroviral therapy (ART) used. Cross-sectional and longitudinal assessments were carried out in 150 individuals, divided into three groups: ART-naïve, 5 years and 10 years on ART; ART-naïve individuals were evaluated for 2 years after initiation of treatment. The individuals' blood samples were submitted to indirect immunofluorescence tests, real-time PCR and flow cytometry. The TREX1 531C/T polymorphism was associated with higher levels of TCD4+ lymphocytes and IFN-α in individuals with HIV-1. Individuals on ART had a higher frequency of ANA, higher levels of T CD4+ lymphocytes, a higher ratio of T CD4+/CD8+ lymphocytes and higher levels of IFN-α than therapy-naïve individuals (p < 0.05). The TREX1 531C/T polymorphism was associated with better maintenance of the immune status of individuals with HIV-1 and ANA with immune restoration in individuals on ART, indicating the need to identify individuals at risk of developing an autoimmune disease.

Anthocyanins as a factor in the alimentary restoration of cellular immunity in diet induced obesity in rats

The article presents the results of a study of the effect of anthocyanins on cellular immunity in rats on a model of alimentary obesity. The aim of the study was to study the effect of an anthocyanin- enriched diet on cellular immunity in diet induced obesity in rats. The study was carried out on male Wistar rats with an initial body weight of 108±2 g. The animals were randomized by body weight into 3 groups (8 pcs. in group). For 12 weeks, rats of the 1st (control) group received a complete modified diet of AIN93M; rats of the 2nd group consumed a high-calorie choline-deficient diet (HCChDD), the fat content of which was 45%, fructose – 20% of the energy value of the diet; rats of the 3rd group received HCChDD with the addition of standardized blueberry and blackcurrant extract (30% anthocyanins) at an average daily dose of 11 mg anthocyanins/kg body weight. The expression of differentiation markers of peripheral blood lymphocytes was carried out by flow cytofluorimetry. As a result of the study, it was found that in rats of the 2nd group with alimentary obesity, the relative content in the peripheral blood of T helpers (CD3+CD4+) was increased (p &lt; 0.05) (75.75±1.11% versus 70.07±0 49% – group 1, 72.14±0.91% – group 3) and reduced (p &lt; 0.05) content of T cytotoxic lymphocytes (CD3+CD8+) (22.54±1.14% versus 28.09±0.72% – 1st group, 26.07±0.87% – 3rd group). The CD3/CD4 ratio in rats of the 2nd group exceeded (p &lt; 0.05) this index in rats of the 1st and 3rd groups (3.44±0.25 versus 2.47±0.09 – 1st group, 2.79±0.13 – 3rd group). Enrichment of the HCChDD with the blueberry and blackcurrant extract led to the normalization of these parameters of cellular immunity. The number of B lymphocytes (CD45R+), Т lymphocytes (CD3+) and NK cells (CD161+) in the rat peripheral blood of all experimental groups had no statistically significant differences. The results of the study of cellular immunity in rats with alimentary obesity indicate the presence of metainflammation. The received data indicate the prospect of using biologically active substances.

Functional exhaustion of CD4&lt;sup&gt;+&lt;/sup&gt;T cells in HIV/HCV coinfected HAART-treated patients

Infection with hepatitis C virus (HCV) is common among HIV-positive patients, with up to 50% of them being coinfected in Russia. While highly active antiretroviral therapy (HAART) suppresses HIV replication and restores the immune system of HIV-infected subjects, HCV coinfection interferes with CD4+T cell regeneration and increases the risk of patients’ morbidity and mortality. During HAART, HIVinfection progression and the immune system restoration efficiency largely depend on immune activation and CD4+T cell exhaustion. This study determined the level of activation, exhaustion, and cytokine production in CD4+T cells obtained from the peripheral blood of HAART-treated HIV/HCV coinfected and HIV monoinfected subjects. The study comprised 11 HIV/HCV coinfected individuals and 10 HIV monoinfected patients receiving HAART for more than two years, with a control group of 10 volunteers without the signs of HIV or HCV infections. Compared with healthy controls, HIV/HCV coinfected patients had an increased frequency of activated CD38+HLA-DR+ CD4+T lymphocytes (p &lt; 0.05), a higher level of CD4+T cell exhaustion determined according to the TIGIT expression density per cell (p &lt; 0.05), and a greater proportion of interferon-gamma (IFNγ)-producing CD4+T lymphocytes following activation (p &lt; 0.05). The frequency of IFNγ-producing CD4+T cells in the donors’ blood positively correlated with the proportion of activated CD4+T cells (R = 0.514, p &lt; 0.01). Despite having a large number of IFNγ-producing CD4+T lymphocytes, the HIV/HCV coinfected patients’ average production of IFNγ by CD4+T cells was significantly lower than that in healthy controls (p &lt; 0.05). The IFNγ production in CD4+T lymphocytes did not depend on activation (p &gt; 0.05). However, a negative correlation was established between the IFNγ production and the level of CD4+T cell exhaustion (R = -0.400, p &lt; 0.05). The letter was also found to inversely correlate with the CD4+T cell counts in the donors’ peripheral blood (R = -0.598, p &lt; 0.01). These data suggest that HCV coinfection leads to pronounced functional exhaustion of CD4+T cells and may aggravate the course of HIVinfection in patients receiving HAART.

In HIV-infected patients, intestinal bacteria-derived products interfere with CD4&lt;sup&gt;+&lt;/sup&gt;T cell regeneration

Despite successful suppression of viral replication by antiretroviral drugs there is no significant increase in the number of peripheral CD4+T lymphocytes in some HIV-infected patients (immune nonresponse to therapy). One of the crucial factors for immunodeficiency aggravation is immune activation developing in response to the bacterial products entry into the bloodstream through the damaged intestinal barrier. Additionally, the intestinal microflora produces various solutes that accumulate in the blood and exhibit toxic properties. This work aimed to evaluate the effect of intestinal microbial products (para-cresol sulfate and indoxyl sulfate) on the number of CD4+T lymphocytes in HIV-infected patients receiving antiretroviral therapy. The object of the study was the peripheral blood of HIV-infected subjects with different immune system restoration efficiency during the therapy. Uninfected donors were enrolled as healthy controls. Plasma concentrations of IL-6 (p = 0.012), IP-10 (p = 0.0004), and sCD14 (p = 0.003) in HIV-infected immune nonresponders were increased compared with those in individuals with effective restoration of CD4+Tcells (immune responders). Although both groups of HIV-positive subjects did not differ in plasma lipopolysaccharide and I-FABP levels, para-cresol sulfate (p = 0.001) and indoxyl sulfate (p = 0.042) concentrations were increased in immune non-responders. In vitro experiments showed a negative dose-dependent effect of para-cresol sulfate and indoxyl sulfate on the viability and mitotic activity of CD4+T lymphocytes. Thus, in HIV-infected patients with impaired regeneration of CD4+T lymphocytes during antiretroviral therapy, a higher level of systemic inflammation is noted than in subjects responding to treatment with an increase in the number of CD4+T cells. The severity of the intestinal barrier damage and the load of bacterial components released into the bloodstream are approximately the same in HIV-infected individuals with different efficiency of immune recovery in response to treatment. Simultaneously, the blood plasma of immune non-responders is significantly enriched with microbial products of intestinal origin: para-cresol sulfate and indoxyl sulfate. The significant decrease in the proliferative capacity of CD4+T cells stimulated in vitro and the induction of their death in the presence of these toxins may be a reason for the ineffective restoration of the number of CD4+T lymphocytes in HIV-infected individuals receiving antiretroviral therapy.

The efficacy of branched-chain amino acid granules to restore phagocytic activity in cirrhosis patients, a randomized controlled trial.

Infection is a detrimental complication among cirrhotic patients, leading to major morbidity and mortality. Reduction in phagocytic activation, as part of immunoparesis, is a distinctive key component of cirrhosis-associated immune dysfunction (CAID) and predicts the development of infection. However, there are limited data on immunotherapeutic approaches to restore phagocytosis. We aimed to determine the effect of branched-chain amino acid (BCAA) granules on phagocytic activity in patients with CAID. In this double-blind randomized controlled trial, Participants were randomly assigned (1:1 ratio stratified by Child-Pugh status) to receive either BCAA granules or placebo. In the 3rd and 6th months, phagocytic activity was assessed by flow cytometry. The primary endpoint was the restoration of innate immunity at the 6th month, defined as ≥75% phagocytic activity; the secondary endpoints were the accretion of phagocytic activity and hospitalization due to infection. A total of 37 patients were included. There were no differences among the patients in the baseline characteristics and phagocytic activity. At the 6th month, a higher proportion of patients with phagocytic restoration was observed in the BCAA granule group compared to the placebo group (68 vs. 5.6%, p < 0.001). The mean phagocytic activity was 75.4 and 63.4% in the BCAA granule and placebo groups, respectively (p < 0.001). Progressive accretion of phagocytic activity was observed during the 3rd and 6th months. There was no difference in hospitalization due to infection (3 vs. 2 events, p = 0.487). Our results suggest that BCAA granules significantly restore phagocytic activity across various stages of cirrhosis. A longer follow-up period is required to demonstrate infection prevention.Clinical Trial Registration: www.clinicaltrials.in.th, TCTR20190830005.

Lenacapavir: A Novel Long-Acting Capsid Inhibitor for HIV.

To review the efficacy, safety, and role of lenacapavir (LEN) in the treatment of HIV-1 infection. A literature search was performed using PubMed and Google Scholar (through March 2023) with the search term LEN and GS-6207. Other resources included abstracts presented at recent conferences, the manufacturer's Web site, and prescribing information. All relevant articles, trial updates, and conference abstracts in the English language were included. Lenacapavir represents a new class of antiretrovirals (ARVs) with a novel mechanism of action as a capsid inhibitor and a unique twice-a-year subcutaneous administration schedule. Lenacapavir when combined with other ARVs has proven to benefit heavily treatment-experienced (HTE) patients with HIV-1 infection in achieving viral suppression and immune restoration. Lenacapavir is a new treatment option that patients who are HTE can consider adding as part of an ARV regimen. Lenacapavir is an effective and well-tolerated option for HTE patients which is a valuable addition to the arsenal of ARVs.

Impacts of plasma microbial lipopolysaccharide translocation on B cell perturbations and anti-CD4 autoantibody production in people with HIV on suppressive antiretroviral therapy

Background. Up to 20% of people with HIV (PWH) who undergo virologically suppressed antiretroviral therapy (ART) fail to experience complete immune restoration. We recently reported that plasma anti-CD4 IgG (antiCD4IgG) autoantibodies from immune non-responders specifically deplete CD4 + T cells via antibody-dependent cytotoxicity. However, the mechanism of antiCD4IgG production remains unclear.Methods. Blood samples were collected from 16 healthy individuals and 25 PWH on suppressive ART. IgG subclass, plasma lipopolysaccharide (LPS), and antiCD4IgG levels were measured by ELISA. Gene profiles in B cells were analyzed by microarray and quantitative PCR. Furthermore, a patient-derived antiCD4IgG–producing B cell line was generated and stimulated with LPS in vitro. B cell IgG class switch recombination (CSR) was evaluated in response to LPS in splenic B cells from C57/B6 mice in vitro.Results. Increased plasma anti-CD4 IgGs in PWH were predominantly IgG1 and associated with increased plasma LPS levels as well as B cell expression of TLR2, TLR4, and MyD88 mRNA in vivo. Furthermore, LPS stimulation induced antiCD4IgG production in the antiCD4IgG B cell line in vitro. Finally, LPS promoted CSR in vitro.Conclusion. Our findings suggest that persistent LPS translocation may promote anti-CD4 autoreactive B cell activation and antiCD4IgG production in PWH on ART, which may contribute to gradual CD4 + T cell depletion. This study suggests that reversing a compromised mucosal barrier could improve ART outcomes in PWH who fail to experience complete immune restoration.

OCCURRENCE OF HEPATITIS B, HEPATITIS C AND TREPONEMAL COINFECTION IN PEOPLE LIVING WITH HIV

Morbidity and mortality of HIV positive patients depends on their response to antiretroviral therapy. Early detection and treatment of co-infection may lead to better outcome as indicated by immune restoration. The present cross- sectional study was undertaken to assess occurrence of coinfections of HBV, HCV and Syphilis and its impact on immune response in HIV positive patients. A total of 200 HIV positive patients receiving ART at the centre of SGH Pune were randomly selected for this study. Blood sample which is routinely collected for CD4 count was taken for our study. No extra sample was taken. This group comprised of 102 male 97 female and one transgender. The age group included in the study was 3years to 76years. A total of 25.5% (51/200) of the patients were tested positive for co-infections. 60.78% (31/51) were positive for Hepatitis B, 3.92% (2/51) for Hepatitis C, 35.29% (18/51) for Syphilis. To study the effect of co-infection on immune response, patient's periodic CD4 count data was analyzed. CD4 count ranged from 15 to 4329 with mean of 392 while in the 51 co-infected patients CD4 count ranged from 3 to 1044 mean 354). A signicant difference in CD4 count was observed between the non-co-infected and co-infected groups. A constantly decrementing trend of CD4 count was the cardinal nding in patients with underlying co-infection.

Immune drivers of HBsAg loss in HBeAg-negative CHB patients after stopping nucleotide analog and administration of Peg-IFN.

The stoppage of nucleoside analog (NA) can lead to immune flare and loss of HBsAg in a proportion of HBeAg-negative chronic hepatitis B (CHB) patients. HBsAg loss could be improved by instituting Peg-Interferon therapy in those who show an immune flare after the stoppage of NA. We investigated the immune drivers of HBsAg loss in NA-treated HBeAg-negative CHB patients after stopping NAs and administration of Peg-IFN-α2b therapy. Fifty-five NA-treated eAg-ve, HBV DNA not detected CHB patients were subjected to stopping NA therapy. Twenty-two (40%) patients relapsed (REL-CHBV) within 6 months (HBV DNA ≥2000IU/mL, ALT ≥2XULN) and were started on Peg-IFN-α2b (1.5mcg/kg) for 48 weeks (PEG-CHBV). Cytokine levels, immune responses, and T-cell functionality were assessed. Only 22 (40%) of 55 patients clinically relapsed, of which 6 (27%) cleared HBsAg. None of the 33 (60%) nonrelapsers cleared HBsAg. REL-CHBV patients had significantly increased IL-6 (p=0.035), IFN-γ (p=0.049), Th1/17 (p=0.005), CD4 effector memory (EM) (p=0.01), Tfh1/17 (p=0.005), and mature B cells (p=0.04) compared with CHBV. Six months after Peg-IFN therapy, immune resetting with a significant increase in CXCL10 (p=0.042), CD8 (p=0.01), CD19 (p=0.001), and mature B cells (p=0.001) was observed. HBV-specific T-cell functionality showed increased Tfh-secreting IFN-γ (p=0.001), IL-21 (p=0.001), and TNF-α (p=0.005) in relapsers and IFN-γ-secreting CD4 T cell (p=0.03) in PEG-CHBV. Stopping NA therapy induces flare in about 40% of HBeAg-negative patients. Peg-IFN therapy given to such patients causes immune restoration with HBsAg loss in one fourth of them.

Four-level regulation of lifespan through the biopsychological clock

A model of life expectancy regulation through biopsychological clocks of four levels is considered. The first level is represented by the intracellular molecular genetic clock, which is responsible for maximum life expectancy. At the second level, the regulation of activity time occurs (time management), this level is associated with the psychological clock, there is also a connection with the activity of annual and monthly biorhythms. This level is associated with the organization of life path, regulation of lifestyle, and professional longevity of a person. At the third level, wakefulness and sleep are regulated through circadian biorhythms with a period of 20-28 hours. Here the regulation of health and restoration of immunity occurs. The fourth level is associated with the regulation of the rhythms of the respiratory and cardiac systems, the phenomenon of premature death is associated with it, and it is responsible for the cessation of life. We consider regulation from top to bottom, with each level responsible for its own aspect of life expectancy. There is interaction between the levels, but its mechanisms have been little studied. In addition, there are also mechanisms that ensure the autonomous functioning of metabolism at each level. Conclusion: to restore health, prevent sudden death, and potentially increase life expectancy, it is necessary to develop comprehensive strategies that combine all levels of the biopsychological clock.

How Can We Predict Disease Severity in Viral Infections?

How Can We Predict Disease Severity in Viral Infections?

Changes in Population Immunity Against Infection and Severe Disease From Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variants in the United States Between December 2021 and November 2022.

Although a substantial fraction of the US population was infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during December 2021-February 2022, the subsequent evolution of population immunity reflects the competing influences of waning protection over time and acquisition or restoration of immunity through additional infections and vaccinations. Using a Bayesian evidence synthesis model of reported coronavirus disease 2019 (COVID-19) data (diagnoses, hospitalizations), vaccinations, and waning patterns for vaccine- and infection-acquired immunity, we estimate population immunity against infection and severe disease from SARS-CoV-2 Omicron variants in the United States, by location (national, state, county) and week. By 9 November 2022, 97% (95%-99%) of the US population were estimated to have prior immunological exposure to SARS-CoV-2. Between 1 December 2021 and 9 November 2022, protection against a new Omicron infection rose from 22% (21%-23%) to 63% (51%-75%) nationally, and protection against an Omicron infection leading to severe disease increased from 61% (59%-64%) to 89% (83%-92%). Increasing first booster uptake to 55% in all states (current US coverage: 34%) and second booster uptake to 22% (current US coverage: 11%) would increase protection against infection by 4.5 percentage points (2.4-7.2) and protection against severe disease by 1.1 percentage points (1.0-1.5). Effective protection against SARS-CoV-2 infection and severe disease in November 2022 was substantially higher than in December 2021. Despite this high level of protection, a more transmissible or immune evading (sub)variant, changes in behavior, or ongoing waning of immunity could lead to a new SARS-CoV-2 wave.

The problem of recurrent bacterial vaginosis: modern strategies

Objective: to evaluate the clinical tolerability, effectiveness and stability of the therapeutic result when using different regimens for the treatment of recurrent bacterial vaginosis (BV) in women of reproductive age.Materials and methods. 105 women of reproductive age with diagnosed recurrent symptomatic BV participated in the study. The participants were randomized into three comparable groups of 35 women each. A ten-day primary decontamination of the vaginal tract was carried out in all groups: intravaginal administration of the drug Tergynan for group 1 and Femiril suppositories in groups 2 and 3. After the initial treatment patients of group 3 received the vaginal probiotic suppositories Alactel Femi for 15 days, after that they used it twice a week No. 10.The effectiveness of BV therapy was evaluated immediately after the antibacterial course and after a 6-month follow-up period based on the results of clinical examination and determination of vaginal pH.Results. Subjective and objective signs of bacterial infection were not detected in all participants after the course of vaginal decontamination. The pH of vaginal secretion was within the normal range and did not differ statistically between the groups. After 6 month, according to the results of a gynecological examination and pH test, one recurrence of BV was confirmed in group 1 and 2. The patients of group 3 had no complaints about manifestations of reinfection, which, in combination with the data of pH-metry, allowed confirming the absence of BV recurrences in them. Additional use of a probiotic in a complex with lactic acid in group 3 was associated with a stable normalization of the acid-alkaline balance of the vaginal secretion: 4.43 ± 0.12 and 4.39 ± 0.14 in groups 1 and 2, respectively, against 4.02 ± 0 ,12 in the 3rd group (p &lt; 0.05).Conclusions. Obtained results indicate a more stable anti-relapse effectiveness and safety of the local use of Femiril, followed by the restoration of the physiological parameters of the vaginal biotope with a complex of probiotics and lactic acid in the Alactel femi. The effectiveness of this approach consists in combining the antibacterial effect of phytoextracts with the successive restoration of vaginal immunity and metabolism through persistent colonization of the mucous membrane with living lactobacilli of eubiotic origin.

Reinforcement of cell-mediated immunity driven by tumor-associated Epstein-Barr virus (EBV)-specific T cells during targeted B-cell therapy with rituximab.

In immunocompromised patients, Epstein-Barr virus (EBV) infection or reactivation is associated with increased morbidity and mortality, including the development of B-cell lymphomas. The first-line treatment consists of reduction of immunosuppression and administration of rituximab (anti-CD20 antibody). Furthermore, the presence of EBV-specific T cells against latent EBV proteins is crucial for the control of EBV-associated diseases. Therefore, in addition to effective treatment strategies, appropriate monitoring of T cells of high-risk patients is of great importance for improving clinical outcome. In this study, we hypothesized that rituximab-mediated lysis of malignant EBV-infected B cells leads to the release and presentation of EBV-associated antigens and results in an augmentation of EBV-specific effector memory T-cell responses. EBV-infected B lymphoblastoid cell lines (B-LCLs) were used as a model for EBV-associated lymphomas, which are capable of expressing latency stage II and III EBV proteins present in all known EBV-positive malignant cells. Rituximab was administered to obtain cell lysates containing EBV antigens (ACEBV). Efficiency of cross-presentation of EBV-antigen by B-LCLs compared to cross-presentation by professional antigen presenting cells (APCs) such as dendritic cells (DCs) and B cells was investigated by in vitro T-cell immunoassays. Deep T-cell profiling of the tumor-reactive EBV-specific T cells in terms of activation, exhaustion, target cell killing, and cytokine profile was performed, assessing the expression of T-cell differentiation and activation markers as well as regulatory and cytotoxic molecules by interferon-γ (IFN-γ) EliSpot assay, multicolor flow cytometry, and multiplex analyses. By inhibiting parts of the cross-presentation pathway, B-LCLs were shown to cross-present obtained exogenous ACEBV-derived antigens mainly through major histocompatibility complex (MHC) class I molecules. This mechanism is comparable to that for DCs and B cells and resulted in a strong EBV-specific CD8+ cytotoxic T-cell response. Stimulation with ACEBV-loaded APCs also led to the activation of CD4+ T helper cells, suggesting that longer peptide fragments are processed via the classical MHC class II pathway. In addition, B-LCLs were also found to be able to take up exogenous antigens from surrounding cells by endocytosis leading to induction of EBV-specific T-cell responses although to a much lesser extent than cross-presentation of ACEBV-derived antigens. Increased expression of activation markers CD25, CD71 and CD137 were detected on EBV-specific T cells stimulated with ACEBV-loaded APCs, which showed high proliferative and cytotoxic capacity as indicated by enhanced EBV-specific frequencies and increased secretion levels of cytotoxic effector molecules (e.g. IFN-γ, granzyme B, perforin, and granulysin). Expression of the regulatory proteins PD-1 and Tim-3 was induced but had no negative impact on effector T-cell functions. In this study, we showed for the first time that rituximab-mediated lysis of EBV-infected tumor cells can efficiently boost EBV-specific endogenous effector memory T-cell responses through cross-presentation of EBV-derived antigens. This promotes the restoration of antiviral cellular immunity and presents an efficient mechanism to improve the treatment of CD20+ EBV-associated malignancies. This effect is also conceivable for other therapeutic antibodies or even for therapeutically applied unmodified or genetically modified T cells, which lead to the release of tumor antigens after specific cell lysis.

Response to intranasal Lactococcus lactis W136 probiotic supplementation in refractory CRS is associated with modulation of non-type 2 inflammation and epithelial regeneration.

We have previously documented that in individuals with chronic rhinosinusitis (CRS) refractory to surgery, intranasal application of live Lactococcus lactis W136, a probiotic bacterium, improves sinus-specific symptoms, SNOT-22, and mucosal aspect on endoscopy, accompanied by a reduction in sinus pathogens and an increase in protective bacteria. The present work explores the molecular mechanisms underpinning these observations using transcriptomics of the sinus mucosa. Epithelial brushings collected prospectively as a sub-study of the L. lactis W136 clinical trial were used to probe epithelial responses to microbiome supplementation using a hypothesis-free bioinformatic analysis of gene expression analysis. Samples from twenty-four patients with CRS refractory to medical and surgical management were prospectively collected during a clinical trial assessing the effect of 14 days of BID nasal irrigation with 1.2 billion CFU of live L. lactis W136 probiotic bacteria (CRSwNP = 17, CRSsNP = 7). Endoscopically guided sinus brushings were collected as part of the initial study, with brushings performed immediately before and after treatment. Following RNA extraction, samples were assessed using the Illumina HumanHT-12 V4 BeadChip. Differential gene expression was calculated, and pathway enrichment analysis was performed to identify potentially implicated processes. Differentially identified transcripts and pathways were assessed for the overall population and the clinical phenotypes of CRSwNP and CRSsNP. Patterns of response to treatment were similar across all groups, implicating pathways for the regulation of immunity and epithelial cell regulation. These resemble the patterns of improvement observed following successful treatment with endoscopic sinus surgery or azithromycin. Gene expression profiling following the application of live bacteria to the diseased sinus epithelium highlights the implication of multiple components of the inflammation-microbiome-epithelial barrier axis implicated in CRS. These effects appear to involve both epithelial restoration and modulation of innate and adaptive immunity, supporting the potential interest of targeting the sinus epithelium and the microbiome as potential CRS therapies.

Utility of novel viral and immune markers in predicting HBV treatment endpoints: A systematic review of treatment discontinuation studies

Antivirals represent the mainstay of chronic hepatitis B treatment given their efficacy and tolerability, but rates of functional cure remain low during long-term therapy. Treatment discontinuation has emerged as a strategy to maintain partial cure and achieve functional cure in select patient groups. We aimed to evaluate how data from treatment discontinuation studies exploring novel viral and/or immune markers could be applied to the functional cure program. Treatment discontinuation studies evaluating novel viral and/or immune markers were identified by a systematic search of the PubMed database through to October 30, 2022. Data extraction focused on information regarding novel markers, including identified cut-off levels, timing of measurement, and associated effect on study outcomes of virological relapse, clinical relapse, and HBsAg seroclearance. From a search of 4,492 citations, 33 studies comprising a minimum of 2,986 unique patients met the inclusion criteria. Novel viral markers, HBcrAg and HBV RNA, were demonstrated across most studies to be helpful in predicting off-therapy partial cure, with emerging evidence to support a link with functional cure. From novel immune marker studies, we observed that treatment discontinuation has the potential to trigger immune restoration, which may be associated with a transient virological relapse. To this end, these studies support the combination of virus-directing agents with immunomodulator therapies to induce two key steps underlying functional cure: viral antigen load reduction and restoration of the host immune response. Patients with a favourable profile of novel viral and immune markers stand to benefit from a trial of antiviral treatment discontinuation alongside novel virus-directing agents with the aim of achieving functional cure without excessive risk of severe clinical relapse. Select patients with chronic hepatitis B undergoing nucleoside analogue therapy may benefit from a trial of treatment discontinuation, aiming to maintain partial cure and/or achieve functional cure. We propose a profile of novel viral and immune markers to identify patients who are likely to achieve these goals without excessive risk of hepatic decompensation. Furthermore, treatment discontinuation may also be considered as a therapeutic strategy to trigger immune restoration, which may increase the chance of functional cure when used in conjunction with novel virus-directing agents.

Successful restoration of protective immunity against measles, mumps, and rubella following MMR vaccination in adult hematopoietic cell transplant recipients.

The optimal number of doses as well as the role for measurement of postvaccination titers after measles, mumps, rubella (MMR) vaccination in adult hematopoietic cell transplantation (HCT) recipients remains unknown. In the present study, we assessed humoral immunity against measles, mumps and rubella before and after MMR vaccination in 187 adults who received at least one dose of the MMR vaccine after HCT. Among those with baseline titers, posttransplant prevaccination seroprotection rates were 56%, 30%, and 54% for measles, mumps, and rubella, respectively; and significantly lower in allogeneic versus autologous HCT recipients for measles (39%vs. 80%, p = .0001), mumps (22%vs. 41%; p = .02) and rubella (48%vs. 62%, p = .12). Among those who were seronegative at baseline, seroconversion rates after one dose of MMR were 69%, 56%, and 97% for measles, mumps, and rubella, respectively. Seronegative patients after one dose of MMR (i.e., nonresponders) seroconverted for measles and mumps after a second MMR vaccine dose. Our findings demonstrate successful restoration of protective immunity against measles, mumps, and rubella after vaccination in adult HCT recipients; one dose of MMR elicited protective titers in the majority of patients, and a second vaccine dose was immunogenic in nonresponders.

Solubilized curcuminoid complex prevents extensive immunosuppression through immune restoration and antioxidant activity: Therapeutic potential against SARS-CoV-2 (COVID-19).

The therapeutic benefits of curcuminoids in various diseases have been extensively reported. However, little is known regarding their preventive effects on extensive immunosuppression. We investigated the immunoregulatory effects of a curcuminoid complex (CS/M), solubilized with stevioside, using a microwave-assisted method in a cyclophosphamide (CTX)-induced immunosuppressive mouse model and identified its new pharmacological benefits. CTX-treated mice showed a decreased number of innate cells, such as dendritic cells (DCs), neutrophils, and natural killer (NK) cells, and adaptive immune cells (CD4 and CD8 T cells) in the spleen. In addition, CTX administration decreased T cell activation, especially that of Th1 and CD8 T cells, whereas it increased Th2 and regulatory T (Treg) cell activations. Pre-exposure of CS/M to CTX-induced immunosuppressed mice restored the number of innate cells (DCs, neutrophils, and NK cells) and increased their activity (including the activity of macrophages). Exposure to CS/M also led to the superior restoration of T cell numbers, including Th1, activated CD8 T cells, and multifunctional T cells, suppressed by CTX, along with a decrease in Th2 and Treg cells. Furthermore,CTX-injected mice pre-exposed to CS/M were accompanied by an increase in the levels of antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase), which play an essential role against oxidative stress. Importantly, CS/M treatment significantly reduced viral loads in severe acute respiratory syndrome coronavirus2-infected hamsters and attenuated the gross pathology in the lungs. These results provide new insights into the immunological properties of CS/M in preventing extensive immunosuppression and offer new therapeutic opportunities against various cancers and infectious diseases caused by viruses and intracellular bacteria.