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PubMed2004

Cloning and characterisation of natural resistance associated macrophage protein (Nramp) cDNA from red sea bream (Pagrus major).

Nramp (natural resistance associated macrophage protein) controls aspects of innate resistance to intracellular parasites. Its function is to enhance the ability of macrophages to kill pathogens. However, little is known about the structure and function of Nramp in lower vertebrates such as teleosts. We have recently isolated a cDNA encoding Nramp from spleen of red sea bream (Pagrus major). The full-length cDNA of the Nramp is 4709 bp in length, including 197 bp 5'-terminal untranslated region (UTR), 1662 bp encoding region and 2850 bp 3'-terminal UTR. The 1662 nt open reading frame was found to code for a protein with 554 amino acid residues. Comparison of the amino acid sequence indicated that red sea bream Nramp consists of 12 transmembrane region (TM) domains. A consensus transport motif (CTM) containing 20 residues was observed between transmembrane domains 8 and 9. The deduced amino acid sequence of red sea bream Nramp had 77.8%, 83.0%, 82.3%, 80.0%, 81.1%, 60.4%, 70.3%, 58.5% and 69.5% identity with that of rainbow trout Nramp alpha and beta, channel catfish Nramp, fathead minnow Nramp, common carp Nramp, mouse Nramp 1 and 2, and human Nramp1 and 2, respectively. Reverse transcription-polymerase chain reaction indicated that levels of Nramp expression were similar among head kidney, spleen, intestine and liver in non-challenged red sea bream, and that challenge of red sea bream with the pathogenic bacterium, Vibrio anguillarum, significantly elevated Nramp mRNA levels in liver and spleen in a time-dependent fashion.

Amino Acid Motifs↗

PubMed2005

Inflammatory response and re-stenosis after percutaneous coronary intervention in heart transplant recipients and patients with native atherosclerosis.

BACKGROUND: The clinical benefit of percutaneous coronary intervention (PCI) in heart transplant recipients (HTRs) with coronary allograft vasculopathy (CAV) has been questioned. We investigated the degree of inflammatory reaction during PCI in CAV compared to patients with native atherosclerosis, and the possible relationship between PCI-induced inflammation and the degree of re-stenosis in these 2 patient groups. METHODS: In 11 CAV patients and 10 patients with native atherosclerosis, blood samples were drawn before and 24 hours and 6 months after PCI, and analyzed with regard to hsCRP, MCP-1, components of complement activation, von Willebrand factor (vWf), soluble L-selectin and ICAM-1. Quantitative angiography was performed before and after PCI, and at 6-month follow-up. RESULTS: Baseline levels of hsCRP, vWf and MCP-1 were significantly elevated and levels of L-selectin and ICAM-1 and activation products of the alternative pathway of the complement system were decreased in CAV patients compared to those with native atherosclerosis. PCI induced significant increases of hsCRP in both groups as well as an increase in vWf in native atherosclerosis, whereas a decrease in L-selectin was observed in native atherosclerosis. Plasma levels of MCP-1 correlated with percent stenosis at follow-up in both groups, whereas a correlation between hsCRP and percent stenosis was evident only in patients with native atherosclerosis. There were no differences in rates of re-stenosis between the 2 groups. CONCLUSIONS: HTRs with CAV and patients with native atherosclerosis are characterized by different profiles of immune activation and respond differently to PCI. Nevertheless, an inappropriate inflammatory reactivity may predispose to re-stenosis after PCI in both groups of patients, with pre-procedural inflammation being of particular importance in CAV.

Aged↗

PubMed2005

LASSBio-468: a new achiral thalidomide analogue which modulates TNF-alpha and NO production and inhibits endotoxic shock and arthritis in an animal model.

As part of a program researching the synthesis and immunopharmacological evaluation of novel synthetic compounds, we have described the immune modulatory profile of the new achiral thalidomide analogue LASSBio-468 in the present work. This compound was planned as an N-substituted phthalimide derivate, structurally designed as a hybrid of thalidomide and aryl sulfonamides, which were previously described as tumor necrosis factor-alpha (TNF-alpha) and PDE4 inhibitors. LASSBio-468 was recently demonstrated to inhibit the TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Here, we investigated whether this compound would affect chronic inflammation processes associated with the production of this pro-inflammatory cytokine. Treatment with LASSBio-468 before a lethal dose injection of LPS in animals greatly inhibited endotoxic shock. This effect seems to be mediated by a specific down regulation of TNF-alpha and nitric oxide production, regulated mainly at the RNA level. In another model, histopathological analysis indicated that this compound also inhibited adjuvant-induced arthritis in rats. Taken together, our data demonstrated a potent anti-inflammatory effect of LASSBio-468, suggesting its use as a potential drug against chronic inflammatory diseases.

Animals↗

PubMed2026

A versatile reversed-phase liquid chromatography charged aerosol detection method for streamlined monitoring of QS-21 content and stability in liposomal adjuvant formulations.

Identifying and quantifying an active adjuvant along with its degradants in drug formulations is essential for ensuring the safety and efficacy of the drug product. QS-21 is a potent adjuvant that is being evaluated in several clinical trials and is currently formulated in licensed vaccines that protect against shingles, malaria, and RSV. In aqueous environments, QS-21 is subject to hydrolytic degradation that is influenced by pH and temperature, resulting in the formation of a degradant known as QS-21 Hydrolyzed Product, QS-21 HP, which can occur during manufacturing and/or prolonged storage. The intact QS-21 and QS-21 HP induce distinct immune response profiles, making it critical to monitor the degradation of QS-21 in vaccine adjuvant formulations. To date, there has been a paucity of reliable assays for QS-21, its isomers, and degradant QS-21 HP in liposomal adjuvant formulations available that can be transferred seamlessly in quality control (QC) environments. Herein, we introduce a simple and QC-friendly liquid chromatography coupled to a charged aerosol detector (LC-CAD) enabled by stationary phase screening combined with in silico method development optimization. The method exploits 2.7 μm fused-core phenyl hexyl particles, ensuring its versatility in standard and ultra-high pressure LC systems. This approach demonstrates a high correlation between predicted retention time (RT) and experimental outcomes with overall ∆RT < 4%. In addition, this assay shows great linearity, precision, specificity, and accuracy to advance process development characterization of new vaccine formulations.

Liposomes↗

PubMed2026

Single-nucleus profiling reveals hepatocyte identity and immune features associated with corticosteroid response in severe alcohol-related hepatitis.

BACKGROUND & AIMS: Severe alcohol-related hepatitis (sAH) is associated with high short-term mortality. However, 30-40% of patients fail to respond to corticosteroids, the only proven pharmacological treatment. The pathophysiological mechanisms underlying sAH and the marked heterogeneity in treatment response remain incompletely understood. We aimed to define cellular changes associated with corticosteroid response in sAH and to identify baseline markers predictive of treatment outcome. METHODS: Single-nucleus RNA sequencing was performed on liver biopsies from patients with biopsy-proven sAH (n = 17), including paired baseline and day 8 biopsies in a subset of patients (n = 8). Patients were classified as corticosteroid responders (sAH-R; Lille score <0.45) or non-responders (sAH-NR; Lille score ≥0.45). Liver biopsies from patients with acute decompensation of alcohol-related cirrhosis (AD; n = 5) and healthy controls (n = 4) were included for comparison. Findings were validated using immunohistochemistry and spatial proteomics in a large multicenter validation cohort (n = 172). RESULTS: At baseline, sAH-R exhibited a significantly higher proportion of liver-infiltrating S100A8+ monocytes compared to sAH-NR, a difference that persisted at day 8. sAH livers showed a marked reduction in mature hepatocytes and an expansion of stressed and intermediate hepatocyte populations, indicating progressive loss of mature hepatocyte identity. This loss was more pronounced in sAH-NR, who also exhibited fewer cycling hepatocytes at day 8, consistent with impaired regenerative capacity. Expression of SULT2A1, a marker of mature hepatocyte identity, was significantly reduced in sAH-NR at baseline. Finally, liver biopsies with ≥50% SULT2A1-positive hepatocytes at baseline were strongly predictive of corticosteroid response. CONCLUSIONS: This study delineates distinct immune and hepatocyte changes associated with corticosteroid response in sAH. Baseline SULT2A1 expression may facilitate stratified treatment approaches in sAH. IMPACT AND IMPLICATIONS: Severe alcohol-related hepatitis (sAH) represents one of the most devastating manifestations of alcohol-related disorders. sAH is characterized by acute hepatic inflammation and high short-term mortality. Clinical management remains challenging, as corticosteroids - the only pharmacological therapy currently applied - are ineffective in a substantial proportion of patients and are associated with significant adverse effects. These limitations highlight the need for a more detailed understanding of sAH pathophysiology and for approaches that enable improved patient stratification and therapeutic decision-making. In this study, we identify distinct pre-treatment differences between corticosteroid responders and non-responders at the level of both hepatocytes and myeloid cells, providing new insight into the cellular mechanisms underlying treatment heterogeneity in sAH. Furthermore, leveraging these findings, we developed a histology-based SULT2A1 scoring system using a commercially available antibody, which predicts corticosteroid response at baseline and may support stratified treatment approaches in clinical practice.

Humans↗

PubMed2026

Tumor-Infiltrating Basophils Are Associated With Improved Prognosis in Colorectal Cancer.

PURPOSE: Basophils are rare granulocytic cells known for their role in allergic reactions, but they may also be involved in other diseases such as cancer. However, the role of tumor-infiltrating basophils in colorectal cancer (CRC) remains unexplored. Here, we aimed to clarify the significance of basophils in CRC by analyzing tumor tissue from 2 CRC cohorts (n = 1830) and blood samples from 730 patients. MATERIALS AND METHODS: Tumor-infiltrating basophils were identified and quantified using double immunohistochemistry (proMBP1 for basophils and cytokeratin for tumor cells) combined with digital image analysis, and blood basophil counts were measured. The associations between basophils (in tumor tissue and blood) and clinicopathological features, prognosis, immune cell profiles, and systemic inflammation markers were examined. RESULTS: Higher densities of tumor-infiltrating basophils showed an inverse association with cancer-specific mortality, with stronger evidence in cohort 2 than in cohort 1. After adjusting for key prognostic factors (including disease stage and mismatch repair status), the hazard ratios for cancer-specific mortality comparing high versus low basophil density were 0.67 (95% CI, 0.43-1.03; Ptrend = .051) in cohort 1 (n = 749) and 0.54 (95% CI, 0.40-0.74; Ptrend < .001) in cohort 2 (n = 1039). Higher basophil densities were also associated with lower disease stage and less frequent lymphovascular invasion but not with mismatch repair deficiency. Blood basophil count correlated with tumor-infiltrating basophil density (r = 0.113; P = .003) but not with prognosis. CONCLUSIONS: Tumor-infiltrating basophils seem to be associated with favorable clinicopathological features and potentially improved CRC outcomes, suggesting that basophils may contribute to the tumor microenvironment.

Humans↗

PubMed2006

Human cytomegalovirus infection and T cell immunosenescence: a mini review.

The mammalian immune system defends the organism against pathogens, and possibly cancer, but is known to become dysregulated with increasing age. This results in greater morbidity and mortality due to infectious disease in old people. The most important changes occur in T cell immunity, manifested sometimes dramatically as altered clonal expansions of cells of limited antigen specificity and a marked shrinkage of the T cell antigen receptor repertoire. At the same time, it was independently reported that CMV seropositivity was associated with many of the same T cell changes that were being identified as biomarkers of immune ageing. It has now become clear that CMV is commonly the driving force behind the oligoclonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. These changes are much less obvious in centenarians and most extreme in people whom longitudinal studies have shown to possess an "immune risk profile". This is a cluster of immunological parameters of which CMV seropositivity is one component and which predicts incipient mortality in an elderly population. Taken together, these findings suggest the hypothesis that persistence of CMV as a chronic antigenic stressor is a major contributor to immunosenescence and associated mortality.

Aged↗

PubMed2004

Chronic fentanyl or buprenorphine infusion in the mouse: similar analgesic profile but different effects on immune responses.

It is known that morphine has a negative impact on the immune responses. The potent opioids fentanyl and buprenorphine have recently become available as transdermal preparation for the treatment of chronic pain. We analyze the effect of fentanyl and buprenorphine on splenic cellular immune responses in the mouse. The parameters evaluated were lymphoproliferation, natural killer cell activity and interleukin-2 and interferon-gamma production. Drugs were administered acutely at the equianalgesic doses of 0.25 mg/kg for fentanyl and 5 mg/kg for buprenorphine, or delivered continuously with osmotic pumps for 24 h, 3 and 7 days at the rate of 7.5 microg/h per mouse (fentanyl) and 12.5 microg/h per mouse (buprenorphine). After acute administration, a significant decrease of lymphoproliferation is observed in fentanyl-treated animals only. After 24 h of fentanyl administration all the parameters were significantly reduced. After 3 days of fentanyl infusion NK activity had returned to normal values, while all the other parameters were still significantly reduced. In 7 day fentanyl-treated animals immunological tolerance had developed, since no differences with controls were present. In contrast no immune alterations were ever present in buprenorphine-treated animals. No tolerance to the antinociceptive effect of drugs had yet developed. After 1 week of infusion with fentanyl and buprenorphine, new pumps were implanted releasing double amounts of drugs. Neither fentanyl nor buprenorphine-treated animals showed altered immune responses at any time considered. These results indicate that fentanyl and buprenorphine exert different immune effects. Opioid-induced immunosuppression is less relevant in chronic administration than in acute or short-time administration.

Administration, Cutaneous↗

PubMed2007

Toxicogenomics in the assessment of immunotoxicity.

Microarray analysis is used for simultaneous measurement of expression of thousands of genes in a given sample and as such extends and deepens our understanding of biological processes. Application of the technique in toxicology is referred to as toxicogenomics. The examples of assessment of immunotoxicity by gene expression profiling presented and discussed here, show that microarray analysis is able to detect known and novel effects of a wide range of immunomodulating agents. Besides the elucidation of mechanisms of action, toxicogenomics is also applied to predict consequences of exposing biological systems to toxic agents. Successful attempts to classify compounds using signature gene expression profiles have been reported. These did, however, not specifically focus on immunotoxicity. Databases containing expression profiles can facilitate the applications of toxicogenomics. Platforms and methodologies for gene expression profiling may vary, however, hampering data compiling across different laboratories. Therefore, attention is paid to standardization of the generation, reporting, and management of microarray data. Obtained gene expression profiles should be anchored to pathological and functional endpoints for correct interpretation of results. These issues are also important when using toxicogenomics in risk assessment. The application of toxicogenomics in evaluation of immunotoxicity is thus not yet without challenges. It already contributes to the understanding of immunotoxic processes and the development of in vitro screening assays, though, and is therefore expected to be of value for mechanistic insight into immunotoxicity and hazard identification of existing and novel compounds.

Animals↗

PubMed2002

Pro-inflammatory effects of aluminum in human glioblastoma cells.

Inflammatory events have been associated with senile plaques, one of the pathological hallmarks of Alzheimer's disease (AD). It is believed that aggregated beta-amyloid (betaA) proteins, which form the core of these plaques, may be responsible for triggering the inflammatory reaction. In the present study, the ability of aluminum (Al) to initiate similar inflammatory events was investigated in a human glioblastoma cell line. A 6-day exposure to either lipopolysaccharide (LPS) or aluminum sulfate caused a significant increase in the rate of proliferation of the glioblastoma cells. Both treatments also caused activation of the immune-responsive transcription factor NF-kappaB although there were time-related differences. The levels of secreted cytokines, interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were both increased by the LPS treatment although exposure to Al decreased the secretion of the former while elevating the levels of the latter. These events may be due to the activation of glial cells and subsequent stress response to either Al complexes or LPS. Although exposure to either stress factor caused a stimulation of inflammatory markers, there were time-dependent differences in the response. This may reflect the ability of the cells to discern different stress factors and thus orchestrate an innate immune response profile distinct to each immunogen.

Alum Compounds↗

PubMed2003

Morbidity does not influence the T-cell immune risk phenotype in the elderly: findings in the Swedish NONA Immune Study using sample selection protocols.

A critical issue in our understanding of ageing and the immune system refers to the health status of the population from which inferences are drawn. The commonly used SENIEUR protocol, selecting individuals representing 'normal ageing' has recently been under debate because a substantial amount of individuals with various health problems are excluded. The aim of the present study was to investigate the influence of morbidity on immune parameters and to evaluate the associations with the T-cell immune risk phenotype (IRP), related to cytomegalovirus (CMV) seropositivity by applying the SENIEUR protocol and the OCTO-Immune protocol in the unselected population based sample (n=138) of oldest-olds, participating in the Swedish NONA Immune Study. The SENIEUR protocol excluded over 90% of the sample whereas the OCTO-Immune protocol excluded almost 65% of the sample. Three independent groups, very healthy (SENIEUR), moderately healthy (OCTO-Immune) and frail (non-SENIEUR/non-OCTO-Immune) were created. Flow cytometry studies on lymphocyte sub-populations revealed no significant difference in CD4/CD8 ratio, CD3+CD4-CD8+, CD3+CD4+CD8-, CD8+CD57+CD28-, CD8+CD56+CD57- or CD8+CD56+CD57+ between the very healthy, moderately healthy and the frail subsamples. Our findings indicate that morbidity does not significantly influence the T-cell immune risk profile in the elderly, and we suggest the inclusion of broader samples in future immunogerontological studies.

Aged↗

PubMed2000

Exclusive expression of transketolase in the vanadocytes of the vanadium-rich ascidian, Ascidia sydneiensis samea.

Ascidians, especially those belonging to the Ascidiidae, are known to accumulate extremely high levels of vanadium in vanadocytes, one type of blood (coelomic) cell. Vanadium, which exists in the +5 oxidation state in seawater, is accumulated in the vanadocytes and reduced to the +3 oxidation state. We have been trying to characterize all of the polypeptides specific to vanadocytes and to specify the proteins that participate in the accumulation and reduction of vanadium. To date, we have localized three enzymes in vanadocytes: 6-phosphogluconate dehydrogenase (6-PGDH: EC 1.1.1.44), glucose-6-phosphate dehydrogenase (G6PDH: EC 1.1.1.49), and glycogen phosphorylase (GP: EC 2.4.1.1), all of which are involved in the pentose phosphate pathway. In the current study, we cloned a cDNA for transketolase, an essential and rate-limiting enzyme in the non-oxidative part of the pentose phosphate pathway, from vanadocytes. The cDNA encoded a protein of 624 amino acids, which showed 61.8% identity to the human adult-type transketolase gene product. By immunocytochemistry and immunoblot analyses, the transketolase was revealed to be a protein that was expressed only in vanadocytes and not in any of the more than ten other types of blood cell. This finding, taken together with the localized expression of the other three enzymes, strongly supports the hypothesis that the pentose phosphate pathway functions exclusively in vanadocytes.

Amino Acid Sequence↗

PubMed2002

Adjuvant regulation of cytokine profile and antibody isotype of immune responses to Mycoplasma agalactiae in mice.

Traditionally, adjuvants have been administered with antigens to enhance immunity. We studied the effect of several adjuvants such as Freund's complete adjuvant (FCA), Freund's incomplete adjuvant (FIA), lipopolysaccharide (LPS), homopolymers of polyinosinic-polycytidylic acid (poly I:C) and polyadenylic-polyuridylic acid (poly A:U), lithium chloride (LiCl), saponin Quil A and calcium phosphate gel (CaHPO(4)) on the immune response of mice to formalin-inactivated Mycoplasma agalactiae. The specific antibody or cytokine producing splenocytes were detected by ELISAspot and immunocytochemistry, respectively. Depending on the adjuvant given, the number of M. agalactiae-specific antibody producing cells was increased 2.5-6-fold. IgG was the major class of M. agalactiae-specific antibodies followed by IgM, IgA and IgE. Among IgG isotypes, FCA, FIA, Quil A and CaHPO(4) induced an IgG1 response with substantial increase of the IgG2a, IgG2b and IgG3 isotypes while poly I:C shifted the response toward an IgG2a/IgG3 production. Finally, poly A:U induced an IgG2b response while LPS and LiCl augmented the IgG3/IgG1/IgG2a secretion. FCA augmented IL-4, IL-5 and IL-10 production suggesting a strong Th2 response, while IFN-gamma and IL-12 remained low; poly I:C enhanced IFN-gamma, IL-12 and TNF-alpha eliciting a Th1 response; poly A:U resulted in a IL-10, IL-5, IL-6 and IL-12 secretion; and LPS enhanced the IL-10, IL-6 and TNF-alpha production. Our data show that adjuvants augment M. agalactiae-specific antibody production and lead to B cell isotype-switching via the appropriate cytokine milieu. Certain adjuvants, such as poly I:C, therefore, appear as promising immune enhancers for vaccination against M. agalactiae infections.

Adjuvants, Immunologic↗

PubMed2002

Bag-1 up-regulation in anti-CD4 mAb-treated allo-activated T cell confers resistance to activation-induced cell death (AICD).

The non-depleting anti-CD4 monoclonal antibody (mAb) RIB5/2 is a powerful inducer of tolerance to major histocompatibility complex (MHC)-incompatible allografts in rat recipients. The unresponsiveness induced is characterized by the persistence (over 300 days) of donor-reactive regulatory T cells within the graft. We applied differential-display reverse-transcription polymerase chain reaction (RT-PCR) to identify differences at the mRNA level between graft-infiltrating cells of anti-CD4 mAb-treated and non-treated control rats at day 5 after kidney transplantation. A 550-bp DNA fragment appearing only in anti-CD4 mAb-treated rats is identical with the anti-apoptotic protein Bag-1. A further investigation of Bag-1 expression during mixed lymphocyte reactions (MLR) revealed a three-four-fold up-regulation of Bag-1 mRNA expression in anti-CD4 mAb-treated allogeneic cultures. Bag-1 up-regulation is associated with higher protection against apoptosis of anti-CD4 mAb-treated cultures. Application of antisense oligonucleotides specific for Bag-1 leads to both a reduction in Bag-1 expression and sensibility against apoptosis. Thus, the expression of Bag-1 in anti-CD4 mAb-treated alloreactive T cells conferred resistance against apoptosis, which may contribute to the long-term survival of tolerance-mediating T cells in vivo.

Animals↗

PubMed2005

DNA-based immunotherapy to treat atopic disease.

OBJECTIVE: To review the current literature regarding DNA-based immunotherapy with respect to signaling mechanisms, cytokine profiles, and the applicability and success of this strategy to treat allergic disease. DATA SOURCES: English-language articles were identified from the PubMed database using both standard and clinical queries. Search terms included CpG, allergy, atopic disease, immunotherapy, DNA vaccination, immunomodulation, and immunostimulatory DNA. Other sources included bibliographies from relevant articles. STUDY SELECTION: Recent studies that provide information about the mechanisms or applications of DNA-based immunotherapy with respect to atopic disease are included in this review. RESULTS: DNA-based immunotherapy composed of unmethylated CpG repeats is capable of inducing a shift in the cytokine profile and immune response that favors the T(H)1 arm. This observation makes DNA-based immunotherapy a promising candidate for the treatment of atopic diseases, which are known to be mediated by T(H)2-based responses. Early animal and human trials of DNA-based immunotherapy have shown the strategy to be both safe and effective. CONCLUSIONS: DNA-based immunotherapy, although still in the early stages of development, has thus far been shown to be both safe and effective for a variety of atopic diseases and offers the potential for significant improvements over current immunotherapy protocols.

Animals↗

PubMed1997

[Screening and confirmation of anti-HCV antibodies in Tunisian blood donors].

Antibodies to Hepatitis C virus (HCV) were tested in 43000 Tunisian blood donors by using enzyme immuno-assay. Our results show that 0.7% (304/43000) were anti-HVC positive. Of these 304.78 were confirmed anti-HCV positive (0.18%) by immuno-blot, and 99 displayed an indeterminate profile. Different immune responses were observed: In donors with positive serologic pattern (78/304), 25.6% response towards whole antigens (C + NS3 + NS4 + NS5) was frequently observed (44/78) 56.4%. Reactivity to 2 antigens was observed in 28.2% (22/78) and with 3 antigens in only 15.4% (12/78), with systematic reactivity to core. In donors with indeterminate serologic pattern (99/304) 32.5%, reactivity to non-structural antigen NS5 was the most frequently observed (54/99) 54.5%, reactivity to non-structural NS3 antigen was noted in 27.3% (27/99) and to core antigen in 18.2% (18/99). No donors with isolated reactivity to NS4 were observed in our series.

Adolescent↗

PubMed2003

Helper-free HSV-1 amplicons elicit a markedly less robust innate immune response in the CNS.

The development and implementation of direct gene transfer technologies for the study and treatment of chronic CNS disorders inherently requires consideration of vector safety. Virus-based vectors represent the most efficient modalities but harbor the potential to induce vigorous innate and adaptive immune responses when administered in vivo. These responses can arise because of virus particle components, resultant viral gene expression, and/or transgene expression. In the current study, we describe the innate responses elicited upon stereotactic delivery of herpes simplex virus type 1-based amplicon vectors. C57BL/6 mice were injected with sterile saline, beta-galactosidase-expressing amplicon (HSVlac) packaged by a conventional helper virus-based technique, or helper virus-free HSVlac. After killing the mice at either 1 or 5 days after transduction, we analyzed them by immunocytochemistry and quantitative RT-PCR for various chemokine, cytokine, and adhesion molecule gene transcripts. All injections induced inflammation, with blood/brain barrier opening on day 1 that was enhanced with both amplicon preparations as compared with saline controls. By day 5, mRNA levels for the pro-inflammatory cytokines (IL-1beta, TNF-alpha, IFN-gamma), chemokines (MCP-1, IP-10), and an adhesion molecule (ICAM-1) had returned to baseline in saline-injected mice and to near-baseline levels in helper virus-free amplicon groups. In contrast, mice injected with helper virus-packaged amplicon stocks elicited elevated inflammatory molecule expression and immune cell infiltration even at day 5. In aggregate, we demonstrate that helper virus-free amplicon preparations exhibit a safer innate immune response profile, presumably as a result of the absence of helper virus gene expression, and provide support for future amplicon-based CNS gene transfer strategies.

3T3 Cells↗

PubMed2026

Serum Proteomic Profiling Reveals Renin-Associated Immune and Cytoskeletal Dysregulation in Post-COVID-19 Condition Patients with Secondary Adrenal Insufficiency.

Post-COVID-19 condition (PCC) with secondary adrenal insufficiency (SAI) involves multiorgan dysfunction, potentially linked to renin-angiotensin-aldosterone system dysregulation. The molecular basis of renin-associated pathology remains unclear. Here, PCC+SAI patients were stratified by upright renin into low- (<38.8 pg/mL) and high-renin (≥38.8 pg/mL) groups. Clinical, endocrine, and proteomic analyses were performed. We found that high-renin patients showed increased BMI, lipids, renin, and aldosterone, but reduced aldosterone-to-renin ratio. Proteomic annalysis identified 20 differentially expressed proteins (DEPs), including 17 upregulated and 3 downregulated proteins in Ren-H patients. Functional annotation revealed that 15 DEPs were immune-related (e.g., APOC4, APOE, C4BPA, CFAH, CFHR3, PF4V, PLF4), while FLNA and COF1 represented cytoskeletal proteins. These DEPs were primarily involved in immune response, complement and coagulation cascades, and MAPK signaling pathways. Correlation analyses indicated that upright renin was positively correlated with complement-related proteins and platelet-derived immune factors, while cytoskeletal proteins (FLNA, COF1) showed positive associations with serum Na+ levels. Additionally, white blood cell and platelet counts were positively correlated with the majority of DEPs. In conclusion, exploratory proteomic analyses suggest that elevated upright renin in PCC+SAI may be associated with immune dysregulation, complement activation, and cytoskeletal remodeling, offering novel insights into the endocrine-immune interactions driving postviral sequelae.

Humans↗