Impaired Immune Response Research Articles

Humoral and cellular response to the third COVID-19 vaccination in patients with inborn errors of immunity or mannose-binding lectin deficiency : Aprospective controlled open-label trial.

Impaired immune response to COVID-19 (coronavirus disease 2019) vaccination has been reported in patients with inborn errors of immunity (IEI). Repetitive vaccinations are recommended for this vulnerable group. Due to the high diversity within IEI patients, additional safety and immunogenicity data are needed to better understand these aspects especially in less common immunodeficiency syndromes. In this prospective open-label clinical trial, we assessed the humoral immune response and the T‑cell response in patients with IEI or severe MBL (mannose-binding lectin) deficiency (IEI/MBLdef) after three vaccinations. A total of 16 patients and 16 matched healthy controls (HC) with suboptimal humoral response defined by anti-SARS-CoV‑2 RBD (severe acute respiratory syndrome coronavirus type 2 receptor binding domain) antibodies below 1500 BAU/ml (binding antibody units per ml) after the second COVID-19 vaccination were enrolled in this study and qualified for athird mRNA vaccine dose. After 4 weeks following vaccination, 100% of HC and 75% of IEI/MBLdef patients exhibited anti-SARS-CoV‑2 RBD antibodies > 1500 BAU/ml, although the difference was not statistically significant (75% vs. 100%; p = 0.109). Although post-vaccination IEI/MBLdef patients demonstrated significantly increased anti-SARS-CoV‑2 RBD antibodies and neutralizing antibodies compared to baseline, these responses were significantly lower in IEI/MBLdef patients compared to HCs. Notably, the third vaccination augmented the cellular immune response to both wild-type and omicron peptide stimulation. No serious adverse events were reported within the 4‑week follow-up period and, importantly, vaccination had little to no effect on the long-term disease activity and fatigue. This trial strongly supports the recommendation of repeated COVID-19vaccinations for patients suffering from immunodeficiencies, especially when they exhibit an initially limited response to the vaccine.

Metapopulation model of phage therapy of an acute Pseudomonas aeruginosa lung infection.

Phage therapy is increasingly employed as a compassionate treatment for severe infections caused by multidrug-resistant (MDR) bacteria. However, the mixed outcomes observed in larger clinical studies highlight a gap in understanding when phage therapy succeeds or fails. Previous research from our team, using in vivo experiments and single-compartment mathematical models, demonstrated the synergistic clearance of acute P. aeruginosa pneumonia by phage and neutrophils despite the emergence of phage-resistant bacteria. In fact, the lung environment is highly structured, prompting the question of whether immunophage synergy explains the curative treatment of P. aeruginosa when incorporating realistic physical connectivity. To address this, we developed a metapopulation network model mimicking the lung branching structure to assess phage therapy efficacy for MDR P. aeruginosa pneumonia. The model predicts the synergistic elimination of P. aeruginosa by phage and neutrophils but emphasizes potential challenges in spatially structured environments, suggesting that higher innate immune levels may be required for successful bacterial clearance. Model simulations reveal a spatial pattern in pathogen clearance where P. aeruginosa are cleared faster at distal nodes of the bronchial tree than in primary nodes. Interestingly, image analysis of infected mice reveals a concordant and statistically significant pattern: infection intensity clears in the bottom before the top of the lungs. The combined use of modeling and image analysis supports the application of phage therapy for acute P. aeruginosa pneumonia while emphasizing potential challenges to curative success in spatially structured in vivo environments, including impaired innate immune responses and reduced phage efficacy.

Research Progress of Immune Mechanisms Related to Persistent HPV Infection in CIN after Cervical Conization

Persistent human papillomavirus (HPV) infection is associated with the grading of cervicalintraepithelial neoplasia (CIN), high-risk HPV infection, multiple HPV infections, high HPV load,HPV infection of surgical margin, and age in CIN after conization. The immune mechanism iscomplex and is primarily related to vaginal microecology disorders, immune escape, immuneresponse impairment, and the release of regulatory cytokines. Currently, the treatment methods forpostoperative persistent HPV infection include surgical treatment, antiviral treatment, vaccination,and other approaches.

Understanding host's response to staphylococcal scalded skinsyndrome.

The aim of this review was to summarise the current knowledge on host-related factors that contribute to the development and severity of staphylococcal scalded skin syndrome (SSSS) in children. A comprehensive assessment and analysis of the existing literature on SSSS clinical features, pathogenesis and susceptibility factors. SSSS is a blistering skin disease caused by circulating exfoliative toxins (ETs) of Staphylococcus aureus (S. aureus), almost exclusively affecting infants, young children and immunocompromised individuals. ETs possess serine protease activity and target desmoglein-1 (Dsg-1) in the superficial epidermis. While the role of S. aureus ETs and site of action are well-described, other host factors such as impaired immune responses to ETs, poor renal clearance and genetic factors are crucial for the onset of and/or the severity of SSSS in children. The fate of desmosomal fractions after cleavage by ETs, as well as the role of dermal inflammatory cell infiltrates remain to be elucidated.

Evaluating the Therapeutic Efficacy of Lactobacillus Strains in the Management of Ulcerative Colitis: An Overview of Recent Advances.

Ulcerative Colitis (UC) known as a sub-category of Inflammatory Bowel Diseases (IBD) is a longterm condition that causes inflammation, irritation, and ulcers in the colon and rectum. Though the precise pathogenesis of UC is not fully understood yet, impaired immune responses and imbalanced intestinal microbiome composition have been regarded as two main key players in colitis pathobiology. As conventional treatments are challenged with limitations and side effects, finding a new therapeutic approach has gained increasing attention. Probiotic bacteria with multifunctional health-promoting properties have been considered novel therapeutic options. There is strong evidence indicating that probiotics exert their therapeutic effects mostly by regulating immune system responses and restoring gut microbiome homeostasis. These results validate the rationale behind the clinical application of probiotics in UC management whether prescribed alone or in combination with conventional therapy. This article explores the pathogenesis of UC, concentrating on the influence of immune dysregulation and intestinal microbiome imbalances. Also, it reviews recent in vitro, in vivo, and clinical studies that have demonstrated the efficacy of Lactobacillus species in decreasing UC symptoms by modifying immune responses, restoring gut microbiota balance, and promoting intestinal barrier function.

The Modulation of Septic Shock: A Proteomic Approach.

Sepsis poses a significant challenge due its lethality, involving multiple organ dysfunction and impaired immune responses. Among several factors affecting sepsis, monocytes play a crucial role; however, their phenotype, proteomic profile, and function in septic shock remain unclear. Our aim was to fully characterize the subpopulations and proteomic profiles of monocytes seen in septic shock cases and discuss their possible impact on the disease. Peripheral blood monocyte subpopulations were phenotype based on CD14/CD16 expression by flow cytometry, and proteins were extracted from the monocytes of individuals with septic shock and healthy controls to identify changes in the global protein expression in these cells. Analysis using 2D-nanoUPLC-UDMSE identified 67 differentially expressed proteins in shock patients compared to controls, in which 44 were upregulated and 23 downregulated. These proteins are involved in monocyte reprogramming, immune dysfunction, severe hypotension, hypo-responsiveness to vasoconstrictors, vasodilation, endothelial dysfunction, vascular injury, and blood clotting, elucidating the disease severity and therapeutic challenges of septic shock. This study identified critical biological targets in monocytes that could serve as potential biomarkers for the diagnosis, prognosis, and treatment of septic shock, providing new insights into the pathophysiology of the disease.

Endogenous glucocorticoids are required for normal macrophage activation and gastric Helicobacter pylori immunity.

Glucocorticoids are steroid hormones well known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using the LysM-Cre driver (myGRKO). We examined the impact on macrophage activation and gastric immune responses to Helicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that, compared with wild type (WT), glucocorticoid receptor knockout (GRKO) macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization with H. pylori revealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric H. pylori immunity.NEW & NOTEWORTHY Signaling by endogenous glucocorticoids primes macrophages toward more robust responses to pathogens. Disruption of glucocorticoid signaling caused dysregulation of the chromatin landscape, blunted proinflammatory gene activation upon bacterial challenge, and impaired the gastric inflammatory response to Helicobacter pylori infection.

Immune response and cognitive impairment in Post-COVID Syndrome: A systematic review

BackgroundAltered immune response and cognitive difficulties have been demonstrated in studies of post-COVID syndrome, including differences in immune status and cognitive functioning in the months following infection. This review aimed to examine immune status and cognitive differences in post-COVID Syndrome twelve or more weeks after COVID-19 infection. A further aim of this review was to explore a link between immune response and the cognitive deficits observed in this group. MethodsA systematic review was carried out of PubMed, PsychInfo, EMBASE and Web of Science electronic databases of observational studies 12+ weeks after COVID-19 infection, with assessment of immune status and cognitive function in post-COVID Syndrome samples. This review protocol was recorded on PROSPERO with registration number CRD42022366920. ResultsFollowing eligibility screening, eleven studies met inclusion criteria and were selected for our review. Six of eight studies which examined between group differences in specific domains suggested impaired cognition in the Post COVID Syndrome population, with the domains of executive function particularly affected. Of the eleven studies with immune data, nine studies reported increased markers of inflammation in the Post COVID Syndrome group, when compared to an age and gender matched “healthy control” sample, or population norms. Finally, when immune function and cognition are examined together, six studies presented results indicating a significant association between elevated immune response and cognitive function. ConclusionThis review highlights the frequency of cognitive difficulties months after COVID-19 infection and explores heighted immune response as a predictor of this change. Six studies suggest that immune status is a predictor of cognitive function, examining a marker of immune function and objective cognitive performance at 12 or more weeks following infection. Future studies of cognitive function in Post COVID Syndrome are needed to explore this relationship, and underlying mechanisms leading to changes in cognitive performance.

Method to Assess Immunosenescent CD8+ T Cells in Respiratory Viral Infections.

Immunosenescence is a well-characterized phenomenon that occurs with increasing age in all immune and somatic cells. In order to best study immunosenescence, it is imperative to develop methods to accurately identify immunosenescent cells. Elderly patients are known to have impaired immune responses to respiratory viruses, and it is hypothesized that this is due, in part, to immunosenescent, terminally exhausted CD8+ T cells. To test this hypothesis, we developed an aged mouse model and a flow cytometry protocol using the Cytek® Aurora to assess the CD8+ T-cell response during respiratory viral infection and identify immunosenescent CD8+ T cells. This protocol and our aged mouse model have great potential to be incredibly valuable for future studies elucidating how to rejuvenate and possibly reverse immunosenescent CD8+ T cells, which could improve the immune response to respiratory viruses in this at-risk population.

Detection of Adenovirus Among a Sample of Hemodialysis Patients in Baghdad city

Background: Adenovirus is a DNA virus that was identified in the 1950s from cases of atypical pneumonia in military recruits. Most of the elevated serotype group has been isolated from People who are immunocompromised. While most viral infections are self-limiting, those that affect people with impaired immune systems can be significantly more hazardous and occasionally fatal. Due to increased rates of viral infection, individuals whose renal function has reached its end are suffering from impaired immune responses. The instant study was designed to detect the infection with adenovirus among HD patients in Baghdad city. Objective: To detect of adenovirus in hemodialysis (HD) patients. Methods: In this cross-sectional study, a total of ninety samples patients on maintenance HD attending the Dialysis centers of Al-Kadhimiya Educational Hospital and Al-Yarmouk Teaching Hospital and Al-Shu’ala General Hospital in the period from November 2023 to March 2024. Using enzyme linked immunosorbent assay (ELISA) kit, serum samples were examined for the existence of adenovirus-specific immunoglobulin (IgG) and conformation by using molecular polymerase chain reaction (PCR). Results: Out of 90 hemodialysis patients, the seropositive result for adenovirus-IgG was 41 (68.33). While 16 (26.67) patients were positive by PCR with significant difference (p≤0.01). In addition, 22 (36.67%) patients were males and 19 (31.67%) were females. Conclusions: Patients undergoing HD are susceptible to adenovirus infection, the sero-prevalence of adenovirus in patients considered as risk factor.

Tim-3 Is Required for Regulatory T Cell-Mediated Promotion of T Cell Exhaustion and Viral Persistence during Chronic Lymphocytic Choriomeningitis Virus Infection.

Expression of T cell Ig and mucin domain-containing protein 3 (Tim-3) is upregulated on regulatory T cells (Tregs) during chronic viral infections. In several murine and human chronic infections, the expression of Tim-3 is associated with poor control of viral burden and impaired antiviral immune responses. However, the role of Tim-3+ Tregs during persistent viral infections has not been fully defined. We employed an inducible Treg-specific Tim-3 loss-of-function (Tim-3 Treg knockout) murine model to dissect the role of Tim-3 on Tregs during chronic lymphocytic choriomeningitis virus infection. Tim-3 Treg knockout mice exhibited a decrease in morbidity, a more potent virus-specific T cell response, and a significant decrease in viral burden. These mice also had a reduction in the frequency of PD-1+Tim-3+ and PD-1+Tox+ gp33-specific exhausted CD8+ T cells. Our findings demonstrate that modulation of a single surface protein on Tregs can lead to a reduction in viral burden, limit T cell exhaustion, and enhance gp33-specific T cell response. These studies may help to identify Tim-3-directed therapies for the management of persistent infections and cancer.

Damping excessive viral-induced IFN-γ rescues the impaired anti-Aspergillus host immune response in influenza-associated pulmonary aspergillosis

Influenza-associated pulmonary aspergillosis (IAPA) is a severe fungal superinfection in critically ill influenza patients that is of incompletely understood pathogenesis. Despite the use of contemporary therapies with antifungal and antivirals, mortality rates remain unacceptably high. We aimed to unravel the IAPA immunopathogenesis as a means to develop adjunctive immunomodulatory therapies. We used a murine model of IAPA to investigate how influenza predisposes to the development of invasive pulmonary aspergillosis. Immunocompetent mice were challenged with an intranasal instillation of influenza on day 0 followed by an orotracheal inoculation with Aspergillus 4 days later. Mice were monitored daily for overall health status, lung pathology with micro-computed tomography (μCT) and fungal burden with bioluminescence imaging (BLI). At endpoint, high parameter immunophenotyping, spatial transcriptomics, histopathology, dynamic phagosome biogenesis assays with live imaging, immunofluorescence staining, specialized functional phagocytosis and killing assays were performed. We uncovered an early exuberant influenza-induced interferon-gamma (IFN-γ) production as the major driver of immunopathology in IAPA and delineated the molecular mechanisms. Specifically, excessive IFN-γ production resulted in a defective Th17-immune response, depletion of macrophages, and impaired killing of Aspergillus conidia by macrophages due to the inhibition of NADPH oxidase-dependent activation of LC3-associated phagocytosis (LAP). Markedly, mice with partial or complete genetic ablation of IFN-γ had a restored Th17-immune response, LAP-dependent mechanism of killing and were fully protected from invasive fungal infection. Together, these results identify exuberant viral induced IFN-γ production as a major driver of immune dysfunction in IAPA, paving the way to explore the use of excessive viral-induced IFN-γ as a biomarker and new immunotherapeutic target in IAPA. This research was funded by the Research Foundation Flanders (FWO), project funding under Grant G053121N to JW, SHB and GVV; G057721N, G0G4820N to GVV; 1506114N to KL and GVV; KU Leuven internal funds (C24/17/061) to GVV, clinical research funding to JW, Research Foundation Flanders (FWO) aspirant mandate under Grant 1186121N/1186123N to LS, 11B5520N to FS, 1SF2222N to EV and 11M6922N/11M6924N to SF, travel grants V428023N, K103723N, K217722N to LS. FLvdV was supported by a Vidi grant of the Netherlands Association for Scientific Research. FLvdV, JW, AC and GC were supported by the Europeans Union's Horizon 2020 research and innovation program under grant agreement no 847507 HDM-FUN. AC was also supported by the Fundação para a Ciência e a Tecnologia (FCT), with the references UIDB/50026/2020, UIDP/50026/2020, PTDC/MED-OUT/1112/2021 (https://doi.org/10.54499/PTDC/MED-OUT/1112/2021), and 2022.06674.PTDC (http://doi.org/10.54499/2022.06674.PTDC); and the "la Caixa" Foundation under the agreement LCF/PR/HR22/52420003 (MICROFUN).

TH1 Cell Frequency and Neutrophil-to-Lymphocyte Ratio in Hemodialysis: Potential Contributions to Patient Monitoring.

Introduction: Patients undergoing hemodialysis (HD) often exhibit an impaired cellular immune response, which may contribute to an increased susceptibility to infections and other complications. Th1 cells, a subset of T-helper cells, play a crucial role in cellular immunity. However, the modulation of Th1 cells by HD treatment remains unclear. Objective: This study aims to investigate the levels of circulating T cells, especially Th1 cells, and the neutrophil-to-lymphocyte ratio (NLR) in HD patients. Methods: We recruited 26 HD patients and 10 healthy volunteers. Demographical data were collected, and peripheral blood samples were analyzed. Absolute blood cell counts were determined, and T-cell populations were identified using flow cytometry. Th1 cells were defined as IFN-γ-producing CD4+ T cells after in vitro activation, and NLR was calculated through the ratio between the neutrophil and lymphocyte counts measured in peripheral blood. Results: We have observed a significant decrease in Th1 subpopulation frequency in HD patients, as well as significant correlations between immunological and demographic parameters, among which are the NLR values and the absolute values of T-cell subsets. Conclusions: These results seem to clarify the role of Th1 cells in modulating the immune responses of hemodialysis-treated patients, potentially considering its frequency as an indicator for CKD development.

‘Ritlecitinib: unveiling hair regrowth for alopecia areata’

Alopecia Areata (AA) is an autoimmune disorder characterized by non-scarring hair loss on the scalp and other parts of the body. It is a complex medical condition associated with an impaired immune response in hair follicles. Various therapies are available for AA, including topical, systemic, and injectable treatments. However, their effectiveness varies, and no treatment consistently achieves and maintains remission. Therefore, this review aims to highlight the breakthrough advancement in treatment of AA i.e., the United State Food and Drug Administration (FDA) approved Ritlecitinib, the first and only oral treatment for moderate to severe alopecia areata in patients aged 12 and older. This approval represents a significant achievement in AA management, offering a targeted and effective treatment for those with more extensive hair loss.

Opioid-free anesthesia attenuates perioperative immunosuppression by regulating macrophages polarization in gastric cancer patients treated with neoadjuvant PD-1 inhibitor.

Opioid anesthesia can modulate the impaired immune response and opioid-sparing anesthesia may preserve immune functions. This study was performed to assess the effects of opioid-free anesthesia (OFA) and opioid-based anesthesia (OA) on perioperative macrophages differentiation, cytokine changes, and perioperative complications in locally advanced GC (LAGC) patients. We used quality of recovery-15 (QoR-15) questionnaire scores and visual analog scale (VAS) scores to compare postoperative quality of recovery and pain level. In addition, the adverse reactions of patients in the two groups were compared. The perioperative serum level of inflammatory cytokines and the ratio of macrophage subtypes were detected. The OFA group had significantly longer extubation time and PACU stay, whereas the OA group had significantly higher rate of hypotension, higher doses of norepinephrine, higher PONV and dizziness rate, and delayed flatus passage time. The QoR-15 score on postoperative 24 h was significantly higher in OFA group than in OA group. At the end of or after the surgery, the OFA group had higher levels of interleukin (IL)-12, IL-1β, tumor necrosis factor (TNF)-α, CD68+CD163- macrophage rate, but lower levels of IL-10, transforming growth factor (TGF)-β, and CD68+CD163+ macrophage rate, indicating OFA attenuated perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization. And the reversal tendency is more obvious in LAGC patients with neoadjuvant PD-1 inhibitor. The OFA may attenuate perioperative immunosuppression by diminishing M2 and promoting M1 macrophage polarization in LAGC patients with neoadjuvant PD-1 inhibitor. http://gcpgl.sysucc.org.cn, identifier 2022-FXY-001.

Impact of diabetes mellitus on endodontic treatment outcomes

Diabetes mellitus (DM) is a chronic metabolic disorder that affects various systemic functions, including oral health. Its impact on endodontic treatment outcomes has become a significant concern for dental practitioners. The relationship between DM and endodontic outcomes is complex, involving several pathophysiological mechanisms. Hyperglycemia leads to the formation of advanced glycation end-products, causing vascular dysfunction and impaired blood supply to the pulp, which exacerbates pulpal inflammation and increases the risk of necrosis. Additionally, chronic low-grade inflammation and an impaired immune response in diabetic patients contribute to a higher susceptibility to infections, delayed healing, and compromised tissue repair after endodontic procedures. Diabetic patients often experience lower success rates and prolonged recovery following endodontic treatment due to these systemic challenges. Reduced bone healing, persistent periapical lesions, and altered microbial flora are common complications that can hinder treatment success. Effective management of endodontic treatment in diabetic patients requires a multifaceted approach that includes strict glycemic control, the use of enhanced antimicrobial strategies, and the adoption of minimally invasive techniques to reduce tissue trauma. Additionally, patient education and close monitoring of the healing process are essential for minimizing complications. Understanding the pathophysiological interactions between diabetes and pulpal inflammation, as well as the factors that influence healing and success rates, is crucial for optimizing endodontic care in diabetic patients. By addressing both systemic and local factors, dental practitioners can improve the prognosis of endodontic treatment and ensure better outcomes for patients with diabetes. Ongoing research into the mechanisms underlying these complications will further enhance the ability of clinicians to manage endodontic cases effectively in this growing patient population.

Abstract B074: Aberrant pericytes in PDAC: effects on endothelial-pericyte adhesion, vascular integrity, and tumor microenvironment

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in men and women in the U.S., with a 5-year survival rate of 13%. Within the PDAC tumor microenvironment (TME), morphologically aberrant leaky vessels are responsible for hypoxia and impaired immune response, which likely reduces the efficacy of cancer therapies. We and others showed that pericyte (PC) coverage significantly correlates with vascular integrity, function, and intratumor hypoxia. Therefore, understanding the contribution of abnormal PC to the TME evolution is a critical step toward PDAC treatment options. Consequently, we hypothesize that correcting such undesirable phenotype via vascular normalization will enhance treatment efficacy. Our study revealed that tumor-associated pericytes across all PDAC tumor tissues exhibited ectopic alpha-smooth muscle actin (αSMA) cytoskeletal protein expression up to 10 times higher than normal pericytes, which was significantly correlated with vascular leakiness and hypoxia. Our previous publication showed that PDAC-derived extracellular vesicles are potent inducers of αSMA expression in pericytes characterized by biomechanical abnormalities. To evaluate the vascular functional defect, we performed a tube formation assay showing abnormal pericytes contribute to abnormal vasculatures in vitro. Our investigation aims to uncover the cause of the abnormal pericyte phenotype that disrupts the physical adhesion between pericytes and endothelial cells (EC), resulting in compromised vasculature. Our findings reveal consistently upregulated monocarboxylate transporters in vascular cells. To enhance EC-pericyte adhesion, we investigated lactate metabolic communication, which is tightly linked due to the proximity of ECs and pericytes. We have shown that in PDAC, MCT1 lactate exporters are upregulated in EC. Conversely, MCT12 lactate importers are highly expressed in pericytes. The high amount of lactate produced by ECs decreases the pH in the basement membrane. So, we knocked down MCT1 transporters in ECs to increase basement pH, leading to improved PC-EC attachment and pericyte homeostasis. Finally, we performed single-cell RNA sequencing to determine the pathological signature of tumor pericytes and identify potential target molecules for vascular normalization. In conclusion, our study indicates that tumor-associated pericytes undergo phenotype switching and disturbed metabolic communication under the influence of pancreatic cancer cells. These aberrant pericytes might contribute to non-optimal vascular integrity and function. Single-cell RNA sequencing helped understand the molecular signature of the PDAC pericyte, providing a powerful tool to develop novel targeting strategies for vascular normalization. Future work includes exploring the vascular normalization approach by suppressing pericyte phenotype switching to enhance vascular function and chemo- and immunotherapeutic efficacy. Citation Format: Vikneshwari Natarajan, Sangdeuk Ha, Jiha Kim. Aberrant pericytes in PDAC: effects on endothelial-pericyte adhesion, vascular integrity, and tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B074.

Expression of antigen-presenting cells in lung of postmortem SARS-CoV-2 cases.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a deadly pulmonary disease with impaired immunological response that causes significant tissue damage and organ failure. Postmortem examination of the lung is a useful tool for understanding the immunopathogenesis of this virus. Lung autopsy samples from seven dead SARS-CoV-2 patients were obtained and evaluated using hematoxylin and eosin stain to analyze the histopathological changes in those samples, on the other hand, Immunohistochemical (IHC) staining was used for detection of CD21, CD1a, CR1 (CD35), CD68, Myeloperoxidase (MPO), CD15, CD56, CD3, CD20, CD4, and CD8 cells markers. Histopathological examination revealed diffuse alveolar damage with extensive parenchymal architecture distortion, intravascular fibrin clot, deposition of collagen fibers, vascular congestions and blood vessels containing thrombi, pneumocyte type II with inflammatory cell infiltration. The IHC staining for the innate immune cells such as antigen-presenting cells (APCs) including dendritic cells, Macrophages, and neutrophils showed a strong positive staining, while CD56 Natural killer (NK) cells showed negative staining. On the other hand, the specific immune cells including; CD20 B cells, CD3 T cells, and CD4 helper T cells, showed positive staining while CD8 Cytotoxic T cells showed negative staining. The lung autopsy samples from patients with COVID-19 confirmed the presence of APCs through the positive staining of CD21, CD1a, CD35, CD68, MPO, and CD15 expressed the virus recognition, proinflammatory cytokine production, and adaptive immune cells activation through CD3, CD4, and CD20 positive staining and the role of APCs in the severity of pulmonary infection and pathogenesis of SARS-CoV-2 infection however the absence of the CD56 NK and CD8 cytotoxic T explains the worse infection status for the patients.

Humoral immune response as an indicator for protection against Covid-19 after anti-SARS-COV2-booster vaccination in hematological and oncological patients.

Cancer patients are at a higher risk to develop severe COVID-19 symptoms after SARS-CoV-2 infection compared to the general population and regularly show an impaired immune response to SARS-CoV-2 vaccination. In our oncological center, 357 patients with hematological and oncological diseases were monitored for neutralizing antibodies from October 2021 over 12 months. All patients had received three anti-SARS-CoV-2 vaccinations with an mRNA-(Comirnaty/BionTech or Spikevax/Moderna) or a vector vaccine (Vakzevria/AstraZeneca or JCOVDEN/Johnson&Johnson). Neutralizing anti-SARS-CoV-2 IgG antibodies in the patients' sera were detected within 3 months before, 3-10 weeks and 5-7 months after the booster vaccination (third vaccination). 112 patients developed a breakthrough SARS-CoV-2 infection during the observation period. High anti-SARS-Cov-2 antibody levels before infection significantly protected against symptomatic Covid-19 disease (p = .003). The median antibody titer in patients with asymptomatic Covid-19 disease was 2080 BAU/ml (binding antibody units per Milliliter) and 765 BAU/ml in symptomatic patients. 98% of the solid tumor patients reached seroconversion after the booster vaccination in comparison to 79% of the hematological patients. High antibody titers of >2080 BAU/ml after the booster vaccination were detected in 61% of the oncological and 34.8% of the hematological patients. 7-10 months after the booster vaccination, the anti-SARS-CoV-2 antibody titer declined to an average of 849 BAU/ml. Considering the heterogenous humoral immune response of cancer patients observed in this study, an individual vaccination strategy based on regular measurement of anti-SARS-CoV-2 antibody levels should be considered in contrast to fixed vaccination intervals.

Thromboembolic Disease and COVID-19: Experience of a University and Emergency Hospital During the Pandemic.

COVID-19 leads to vasculopathy, which is linked to both a prothrombotic state and an impaired immune response. A notable increase in pulmonary embolism (PE) and deep venous thrombosis (DVT) has been documented. We conducted a retrospective analysis of all patients who were admitted with venous thromboembolic disease (VTD) in the largest university and emergency hospital in Romania, between May 1, 2020, and April 30, 2021. Patients were categorized into two groups based on the presence (Group 1) or absence (Group 2) of COVID-19 virus infection at the time of admission. The aim of this study was to assess the characteristics of VTD in COVID-19 patients and to compare the clinical and paraclinical parameters of the Group 1 and Group 2 patients admitted for VTD in an emergency hospital during the first two waves of the pandemic (12 months). We compared clinical, biological, and imaging parameters and applied binary logistic analysis for the predictive models. A total of 198 patients were diagnosed with VTD (at admission or during the hospitalization); out of 33,373 patients hospitalized, 43 (21.7%) were diagnosed with COVID-19 (12.2% with mild COVID-19, 61.0% moderate, and 26.8% severe). Group 1 showed higher heart rates and leukocytes, more severe pulmonary changes (p<0.05), higher N-terminal-pro-B-type natriuretic peptide (NTproBNP), and high sensitivity troponin I (hs-cTnI) (p>0.05). Not reaching statistical significance, the mortality tended to be higher in Group 1. These patients were admitted to the intensive care units for longer (3.5 vs. 1.5 days, p > 0.05). The minimum value of thrombocytes during hospitalization was inversely correlated with the risk of death. Interestingly, the Pulmonary Embolism Severity Index (PESI) score was not predictive for in-hospital death in Group 1, but only in Group 2 (area under the curve (AUC) = 0.821, CI 0.689-0.952). Individuals with severe manifestations of COVID-19 remain vulnerable to developing VTD and are prone to adverse outcomes. The efficacy of PESI as a predictive tool for in-hospital death is non-significant. Further refinement of specific predictive scores tailored to VTD associated with COVID-19 is needed.