Suppression Of Immune System Research Articles

Detoxification Impacts of Dietary Probiotic and Prebiotic Supplements Against Aflatoxins: An Updated Knowledge – A Review

Abstract The widespread prevalence of food pollutants seriously threatens human and animal health. Mycotoxins are secondary metabolites primarily formed by toxigenic fungal genera, including Aspergillus, Penicillium, Fusarium, and Alternaria, demonstrating one of the principal pollutants in diets or feed products. Mycotoxin contamination in food can harm health, including stunted development, immune system suppression, infertility, vomiting, and gastrointestinal and cancerous conditions. These effects can occur both acutely and chronically. The complex food chain can be contaminated with mycotoxins at any point, including during harvest, industrial processing, shipping, or storage, putting the food sector under societal pressure owing to the waste generated by infected goods. One of the biological controls of mycotoxin is provided by probiotics and prebiotics, controlled as foods and dietary supplements made of bacteria or yeast. Aflatoxin’s bioavailability and gastrointestinal absorption can be reduced using various probiotics and prebiotics.

Minimal invasive extracorporeal circulation in comorbid patients

Background: As the severity of comorbid diseases increases, risks of cardiopulmonary bypass (CPB) complications significantly increase. A complex of the procedure’s damaging factors provokes a systemic inflammatory response that in some cases is accompanied by the damage to target organs, transitioning from chronic organ dysfunctions into acute ones. Some studies on the use of minimal invasive extracorporeal circulation (MiECC) systems show their advantage over conventional extracorporeal circulation (CECC); however, the diversity of MiECC systems, patients, and outcomes precludes us from confidently extrapolating these data to older comorbid patients.Objective: To compare the severity of systemic inflammation and treatment outcomes in comorbid patients who underwent cardiac surgery with CECC and MiECC.Methods: We conducted a retrospective cohort study of 760 patients who consecutively underwent elective cardiac operations in 2019-2022. Inclusion criteria: comorbid status (age-adjusted Charlson Comorbidity Index score of ≥6); CPB time ≥90 min. Exclusion criteria: emergency surgery, refusal to participate in the study. A total of 68 patients met the inclusion criteria. We formed 2 study groups based on the extracorporeal circulation method: CECC group (n = 51) and MiECC group (n = 17). Control points: before CPB and 24 hours after the surgery (lactate; creatinine; oxygenation index, hemolysis level). For systemic inflammatory response markers: 1 hour after the CPB start and 24 hours after the CPB end (interleukin 6; interleukin 10; procalcitonin; C-reactive protein; soluble Triggering Receptor Expressed on Myeloid Cells-1 [sTREM-1]). We evaluated respiratory and renal complications, drainage-related hemorrhages, hemostatic disorders, the need for sympathomimetic drugs, and the length of stay in an intensive care unit and inpatient hospital.Results: Between the groups there were no statistically significant differences in gender and anthropometric characteristics, surgery types, and main perfusion parameters. In the CECC group, we observed significantly higher doses of vasoconstrictors (norepinephrine) as well as a decrease in urine output and lung injury and an increase in lactate and hemolysis. The systemic inflammatory response markers were also significantly higher.Conclusion: Compared with CECC, MiECC does not significantly affect the frequency of organ dysfunctions; however, it reduces the severity of the systemic inflammatory response and immune suppression that are trigger mechanisms for multiple organ dysfunction syndrome. It is particularly important for patients with chronic organ dysfunctions. A range of indications for MiECC systems should be defined given its high cost and off-target effect on pleiotropic factors of systemic inflammatory response development. Received 6 April 2023. Revised 17 August 2023. Accepted 18 August 2023. Funding: The study was conducted within the framework of the research project "Development of minimally invasive and hybrid technologies for surgical treatment of heart diseases". Conflict of interest: The authors declare no conflict of interest. Contribution of the authorsConception and study design: A.Sh. Revishvili, G.P. Plotnikov, V.A. PopovData collection and analysis: R.A. Kornelyuk, L.B. Berikashvili, I.P. Komkov, E.S. Malyshenko, V.M. ZemskovStatistical analysis: L.B. BerikashviliDrafting the article: R.A. Kornelyuk, G.P. Plotnikov, L.B. Berikashvili Critical revision of the article: G.P. PlotnikovFinal approval of the version to be published: A.Sh. Revishvili, R.A. Kornelyuk, G.P. Plotnikov, L.B. Berikashvili, I.P. Komkov, E.S. Malyshenko, V.M. Zemskov, V.A. Popov

Immune Evasion of G-CSF and GM-CSF in Lung Cancer.

Tumor immune evasion is a complex process that involves various mechanisms, such as antigen recognition restriction, immune system suppression, and T cell exhaustion. The tumor microenvironment contains various immune cells involved in immune evasion. Recent studies have demonstrated that granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) induce immune evasion in lung cancer by modulating neutrophils and myeloid-derived suppressor cells. Here we describe the origin and function of G-CSF and GM-CSF, particularly their role in immune evasion in lung cancer. In addition, their effects on programmed death-ligand 1 expression and clinical implications are discussed.

Short-term function and immune-protection of microencapsulated adult porcine islets with alginate incorporating CXCL12 in healthy and diabetic non-human primates without systemic immune suppression: A pilot study.

Replacement of insulin-producing pancreatic beta-cells by islet transplantation offers a functional cure for type-1 diabetes (T1D). We recently demonstrated that a clinical grade alginate micro-encapsulant incorporating the immune-repellent chemokine and pro-survival factor CXCL12 could protect and sustain the integrity and function of autologous islets in healthy non-human primates (NHPs) without systemic immune suppression. In this pilot study, we examined the impact of the CXCL12 micro encapsulant on the function and inflammatory and immune responses of xenogeneic islets transplanted into the omental tissue bilayer sac (OB; n = 4) and diabetic (n = 1) NHPs. Changes in the expression of cytokines after implantation were limited to 2-6-fold changes in blood, most of which did not persist over the first 4 weeks after implantation. Flow cytometry of PBMCs following transplantation showed minimal changes in IFNγ or TNFα expression on xenoantigen-specific CD4+ or CD8+ T cells compared to unstimulated cells, and these occurred mainly in the first 4 weeks. Microbeads were readily retrievable for assessment at day 90 and day 180 and at retrieval were without microscopic signs of degradation or foreign body responses (FBR). In vitro and immunohistochemistry studies of explanted microbeads indicated the presence of functional xenogeneic islets at day 30 post transplantation in all biopsied NHPs. These results from a small pilot study revealed that CXCL12-microencapsulated xenogeneic islets abrogate inflammatory and adaptive immune responses to the xenograft. This work paves the way toward future larger scale studies of the transplantation of alginate microbeads with CXCL12 and porcine or human stem cell-derived beta cells or allogeneic islets into diabetic NHPs without systemic immunosuppression.

Searching for Natural Plants with Antimelanogenesis and Antityrosinase Properties for Cosmeceutical or Nutricosmetics Applications: A Systematic Review.

Excessive UV radiation (UVR) exposure has been shown in studies to be a major risk factor for most melanomas, causing premature skin aging as well as immune system suppression due to the increased production of hydrogen peroxide (H2O2) and other reactive oxygen species (ROS) during the melanogenesis process. Although several compounds with antioxidant and antityrosinase activities are widely used in the cosmetic industry, like kojic acid, hydroquinone, ascorbic acid, and arbutin, their use has been limited due to their adverse effects on the skin and cytotoxic issues. Recently, attempts have been made to develop new natural skin-lightening products by using plant extracts that are less toxic and exhibit numerous biological properties with great market demand. In this study, information on the depigmentation effects of various natural plant species was gathered from the SCOPUS database according to the PRISMA guidelines. A total of 414 records were retrieved, and finally, 76 articles were included in the qualitative synthesis by fulfilling all the inclusion criteria. In this review, we discuss the extraction methods and biological assays of 75 highly potential plant species, including the olive, yuzu, longan, and lotus. We concluded that the use of natural plants as skin-whitening agents is highly effective as there is a significant correlation between the content of polyphenolic compounds, antimelanogenesis, antityrosinase, and antioxidant activities. However, it is worth noting that the use of extraction methods or types of solvents is very important in determining the biological activities of plants.

Blood Plasma Concentration of Polycyclic Aromatic Hydrocarbons in Under Five Children in Niger Delta, Nigeria

PAHs are known carcinogens associated with immune system suppression, skin irritation, allergic reactions, respiratory problems, mutagenic issues and are generally toxic to humans. In this study, we assessed the presence and proportions of PAHs in the blood plasma of under-five children living in crude oil-polluted environment in Ogoniland, Niger Delta region of Nigeria. Communities resident in close proximity to crude oil exploration sites are constantly faced with environmental, socio-economic and health consequences of crude oil pollution. People can be exposed to PAHs through multiple routes including inhalation, ingestion and dermal contact. Ethical clearance for this study was obtained from the Ethics Committee, University of Port Harcourt. A total of 78 children were recruited from Gokana (male =17, female= 22) and Ideato (Male=15, female=24) using multi-clustered sampling method. Standard procedures were observed in this study. Results obtained were compared with under five children living in non-oil polluted environments within the Niger Delta province. The overall average PAHs was 0.331±0.383 mg/kg for Gokana males and 0.058±0.057mg/kg for Ideato males; overall average PAHs was 0.514±0.373 mg/kg for Gokana females and 0.100±0.049 mg/kg for Ideato female; overall average PAHs was 0.423±0.383 mg/kg Gokana and 0.081±0.057 mg/kg for Ideato. Under-five children in Ogoniland showed positive blood plasma PAHs higher than the comparison group in Ideato. However, carcinogenic PAHs were below levels of concern in the study population. The male gender showed higher positive PAHs than the female gender. Further studies on inflammation, stress factors and overall health status are recommended considering the vulnerability of the study population.

Magnitude and predisposing factors of intestinal parasitosis and tuberculosis coinfection at five health institutions in Southern Ethiopia: A cross-sectional study.

Intestinal parasites affect the tuberculosis disease outcome by shifting the cell-mediated to humoral immune response and host immune system suppression. However, Mycobacterium tuberculosis (MTB) infection favors the immune escape of parasites. Hence, exploring the rate of intestinal parasitic coinfection with pulmonary tuberculosis (PTB) and its predisposing factors to take better preventive, control, and management measures. A facility-based cross-sectional study was conducted from September to December 2020 at five health institutions in Hawassa city. A total of 214 PTB patients were diagnosed using the GeneXpert assay and enrolled in this study. Demographic, clinical, and risk factors data were collected using a structured questionnaire. Stool samples were collected using a clean, labeled, and leak-proof stool cup. Stool samples were examined using direct saline microscopy and the formal-ether concentration technique. The data were entered and coded in SPSS software for analysis. Bivariate and multivariate logistic regression were employed to identify the associated risk factors. A p-value less than 0.05 was considered statistically significant. The overall rate of intestinal parasitic-MTB coinfection was 36.9%. The most dominant intestinal parasite was Gardia lamblia (17.8%, 38), followed by Entamoeba histolytica/dispar (9.3%, 20). Intestinal parasitosis coinfection of PTB was associated with being rural resident (adjusted odds ratio [AOR] = 2.42; 95% confidence interval [CI]: 1.23-4.8), not washing of fruits and vegetables before eating [AOR = 4.14; 95% CI: 1.92-9], being at the early stage of anti-TB treatment [AOR = 3; 95% CI: 1.5-6.3] and presence of chronic diseases [AOR = 7; 95% CI: 3.4-14]. The burden of intestinal parasites-MTB coinfection was high. Those who wash fruits and vegetables before eating should be encouraged, early treatment of PTB patients and avoiding the practice of open-field defecation, especially in rural communities, is necessary. The dual effect of coinfection on disease severity and treatment success needs further cohort study.

Prediction of the Peptide-TIM3 Binding Site in Inhibiting TIM3-Galectin 9 Binding Pathways.

T-cell immunoglobulin and mucin domain-containing protein-3 (TIM3) is an important receptor protein that modulates the immune system. The binding of TIM3 with Galectin 9 (GAL9) triggers immune system suppression, but the TIM3-GAL9 binding can be inhibited by binding of the peptide P26 to TIM3. A fast and accurate prediction of the P26-TIM3 binding site is crucial and a prerequisite for the investigation of P26-TIM3 interactions and TIM3-GAL9 binding pathways. Here, we present a machine learning approach, which considers protein conformational changes, to quickly identify the ligand-binding site on TIM3. Our results show that the P26 binding site is located near the C″-D loop of TIM3. Further simulations show that the binding pose is stabilized by a variety of electrostatic and hydrophobic interactions. Binding of P26 can alter the conformations of nearby glycan side chains on TIM3, providing possible mechanisms of how P26 inhibits TIM3-GAL9 binding pathways. The insights from this work will facilitate the identification of other peptides or antibodies that may also inhibit the TIM3-GAL9 pathways and eventually lead to improved attempts in the modulation of the TIM3-GAL9 immunosuppression pathways. The strategies and machine learning method can be generalized to study ligand-receptor binding when the conformational changes during the binding are important.

Counteractive effects of extracts of Mangifera indica on testes of Wistar Rat exposed to cyclophosphamide

IntroductionInfertility may have a variety of causes that can affect both the male and female reproductive systems. Cyclophosphamide is a drug used in chemotherapy and immune system suppression. Leaf extracts of Mangifera indica exhibit a wide spectrum of pharmacological properties which have been shown in studies, including antioxidant and protective advantages. This study evaluate the antagonistic implications of leaf extracts of Mangifera indica on the testis following the exposure to cyclophosphamide. Methods25 male Wistar rats were assigned to five groups with five rats in each. Group A (Control), Group B (administered 150 mg of cyclophosphamide only), Group C (administered 50 mg of extracts of leaf extracts of Mangifera indica only), Group D (administered 150 mg of cyclophosphamide and 50 mg of leaf extracts of Mangifera indica) and Group E (administered 150 mg of cyclophosphamide and 100 mg of leaf extracts of Mangifera indica) for two weeks. The rats were euthanized under the anesthetic of ketamine (30 mg/kg IP). Blood was taken by cardiac puncture for biochemical examination. Testes were excised, preserved in 10% Neutral Buffered Formalin for histological investigation. One-way analysis of variance was used to examine the data, and then the Student Newman-Keul post-hoc analysis was performed. The significance of the result was assessed using p < 0.05. ResultsThe study showed statistically significant differences (p < 0.05) in the hormonal assay, including LH, FSH, and testosterone across all test groups, with group B (cyclophosphamide only) having significantly lower levels. Cyclophosphamide administration was observed to have a negative effect on the testicular histology and immunohistochemical results and leaf extracts of Mangifera indica attenuated the damage induced by cyclophosphamide in groups D and E. ConclusionLeaf Extracts of Mangifera indica considerably reduced the effects of cyclophosphamide-induced changes in testis.

The relationship of lifetime history of depression on the ovarian tumor immune microenvironment

BackgroundDepression is associated with a higher ovarian cancer risk. Prior work suggests that depression can lead to systemic immune suppression, which could potentially alter the anti-tumor immune response. MethodsWe evaluated the association of pre-diagnosis depression with features of the anti-tumor immune response, including T and B cells and immunoglobulins, among women with ovarian tumor tissue collected in three studies, the Nurses’ Health Study (NHS; n = 237), NHSII (n = 137) and New England Case-Control Study (NECC; n = 215). Women reporting depressive symptoms above a clinically relevant cut-point, antidepressant use, or physician diagnosis of depression at any time prior to diagnosis of ovarian cancer were considered to have pre-diagnosis depression. Multiplex immunofluorescence was performed on tumor tissue microarrays to measure immune cell infiltration. In pooled analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the positivity of tumor immune cells using a beta-binomial model comparing those with and without depression. We used Bonferroni corrections to adjust for multiple comparisons. ResultsWe observed no statistically significant association between depression status and any immune markers at the Bonferroni corrected p-value of 0.0045; however, several immune markers were significant at a nominal p-value of 0.05. Specifically, there were increased odds of having recently activated cytotoxic (CD3+CD8+CD69+) and exhausted-like T cells (CD3+Lag3+) in tumors of women with vs. without depression (OR = 1.36, 95 %CI = 1.09–1.69 and OR = 1.24, 95 %CI = 1.01–1.53, respectively). Associations were comparable when considering high grade serous tumors only (comparable ORs = 1.33, 95 %CI = 1.05–1.69 and OR = 1.25, 95 %CI = 0.99–1.58, respectively). There were decreased odds of having tumor infiltrating plasma cells (CD138+) in women with vs. without depression (OR = 0.54, 95 %CI = 0.33–0.90), which was similar among high grade serous carcinomas, although not statistically significant. Depression was also related to decreased odds of having naïve and memory B cells (CD20+: OR = 0.54, 95 %CI = 0.30–0.98) and increased odds of IgG (OR = 1.22, 95 %CI = 0.97–1.53) in high grade serous carcinomas. ConclusionOur results provide suggestive evidence that depression may influence ovarian cancer outcomes through changes in the tumor immune microenvironment, including increasing T cell activation and exhaustion and reducing antibody-producing B cells. Further studies with clinical measures of depression and larger samples are needed to confirm these results.

Production, bioprocessing and antiproliferative activity of camptothecin from Aspergillus terreus, endophyte of Cinnamomum camphora: restoring their biosynthesis by indigenous microbiome of C. camphora

Fungal producing potency of camptothecin (CPT) raise the hope for their usage to be a platform for industrial production of CPT, nevertheless, attenuation of their productivity of CPT with the subculturing and preservation is the challenge. So, screening for novel endophytic fungal isolates with a reliable CPT-biosynthetic stability was the objective. Among the isolated endophytic fungi from the tested medicinal plants, Aspergillus terreus OQ642314.1, endophyte of Cinnamomum camphora, exhibits the highest yield of CPT (89.4 μg/l). From the NMR, FT-IR and LC–MS/MS analyses, the extracted CPT from A. terreus gave the same structure and molecular mass fragmentation pattern of authentic CPT (349 m/z). The putative CPT had a significant activity against MCF7 (0.27 µM) and HEPG-2 (0.8 µM), with a strong affinity to inhibits the human Topoisomerase 1 activity (IC50 0.362 μg/ml) as revealed from the Gel-based DNA relaxation assay. The purified CPT displayed a strong antimicrobial activity for various bacterial (E. coli and B. cereus) and fungal (A. flavus and A. parasiticus) isolates, ensuring the unique tertiary, and stereo-structure of A. terreus for penetrating the microbial cell walls and targeting the topoisomerase I. The higher dual activity of the purified CPT as antimicrobial and antitumor, emphasize their therapeutic efficiency, especially with growth of the opportunistic microorganisms due to the suppression of human immune system with the CPT uses in vivo. The putative CPT had an obvious activity against the tumor cell (MCF7) metastasis, and migration as revealed from the wound healing assay. The overall yield of A. terreus CPT was maximized with the Blackett-Burman design by twofolds increment (164.8 μg/l). The CPT yield by A. terreus was successively diminished with the multiple fungal subculturing, otherwise, the CPT productivity of A. terreus was restored, and increased over the zero culture upon coculturing with C. camphora microbiome (1.5% w/v), ensuring the restoring of CPT biosynthetic potency of A. terreus by the plant microbiome-derived chemical signals “microbial communication”. This is the first report exploring the feasibility of A. terreus “endophyte of C. camphora” to be a preliminary platform for commercial production of CPT with a reliable sustainability upon uses of indigenous C. camphora microbiome.

Circulating extracellular vesicles derived from tumor endothelial cells hijack the local and systemic anti-tumor immune response: Role of mTOR/G-CSF pathway

Circulating tumour-derived extracellular vesicles are supposed to contribute to the spreading of distant metastasis. In this study, we investigated the impact of circulating extracellular vesicles derived from tumour-endothelial cells (TEVs) in the expansion of the metastatic bulk. We focus on the role of immune cells in controlling this process using the 4T1 triple negative breast cancer (TNBC) syngeneic model.4T1 cells were intravenously injected and exposed to circulating TEVs from day 7. The lung, spleen, and bone marrow (BM) were recovered and analysed. We demonstrated that circulating TEVs boost lung metastasis and angiogenesis. FACS and immunohistochemically analyses revealed a significant enrichment of Ly6G+/F4/80+/CD11b+ cells and Ly6G+/F4/80-/CD11b+ in the lung and in the spleen, while Ly6G+/F4/80-/CD11b+ in the BM, indicating the occurrence of a systemic and local immune suppression. TEV immune suppressive properties were further supported by the increased expression of PD-L1, PD-1, and iNOS in the tumour mass. In addition, in vitro experiments demonstrated an increase of CD11+ cells, PD-L1+ myeloid and cancer cells, upregulation of LAG3, CTLA4 and PD-1 in T-cells, release of ROS and NOS, and impaired T-cell-mediated cytotoxic effect in co-culture of TEVs-preconditioned PBMCs and cancer cells. Granulocyte-colony stimulating factor (G-CSF) level was increased in vivo, and was involved in reshaping the immune response. Mechanistically, we also found that mTOR enriched TEVs support G-CSF release and trigger the phosphorylation of the S6 (Ser235/236) mTOR downstream target. Overall, we provided evidence that circulating TEVs enriched in mTOR supported G-CSF release thereby granting tumour immune suppression and metastasis outgrowth.

Evaluation of the Effect of Surgical Access on the Innate Immune Response During Liver Resections of Various Volume, Experimental Study

Introduction. The major components of the immune system are affected in almost all surgical operations, including those related to the tumor removal. The volume of the operation correlates with the level of the immune system suppression and frequency of complications. The issue of the effect of surgical access for liver resection with different volumes on surgical trauma and severity of the innate immune response are still challenging nowadays. The aim of the study is to evaluate the effect of open and laparoscopic surgical approaches on the severity of the innate immune response in small and large liver resections in laboratory animals.Methods. The study included 4 groups of rabbits, 10 animals each, formed depending on the surgical approach and the volume of liver resection: laparoscopic small and large liver resections, open small and large liver resections. The following parameters of the innate immune response were studied: phagocytic, cytotoxic and proliferative activity in dynamics. The experimental data were processed using the STATISTICA 6.0 software package (StatSoft, 2001). The results were considered statistically significant at p0.05.Results. Open extensive liver resections are characterized by a more significantly decreased phagocytic activity of neutrophils - from 95.7% to 32.05% - than similar interventions using laparoscopic access - from 96.4% to 52.4%, respectively. Cytotoxic activity in the group of animals exposed to surgery with laparotomy access decreased by 40% compared to 23% in animals exposed to laparoscopy surgery. There was registered a more than twice increased spontaneous and decreased induced proliferation in the postoperative period. Conclusion. The study results allow concluding on a positive effect manifested as a reduced surgical injury for liver resections of various volumes due to laparoscopic access; this is evidenced by the parameters of immune reactivity.

Maize and groundnut crop production among rural households in Zambia: Implications in the management of aflatoxins

Maize and groundnut are important crops for both commercial and smallholder farming in Zambia, whose production is being threatened by their susceptibility to aflatoxin contamination. Despite this threat, there is limited knowledge of household growers' behaviour and applications related to suitable agricultural management practices, as well as growers’ perception and knowledge of aflatoxins and their effects. This limited knowledge has major implications for acute human health effects such as liver cirrhosis and death, cancer, stunting in children, immune system suppression, impaired food conversion, and reduced livestock productivity and/or increased livestock mortality.This cross-sectional survey of smallholder household growers in Zambia was conducted to identify the gaps in the knowledge and application of aflatoxin-associated agricultural management practices. A sample of 3865 maize- and groundnut-producing smallholder farm households were selected in 27 priority districts implementing the Scaling Up Nutrition (SUN)/First 1000 Most Critical Days Programme (MCDP) Phase II. Among the five pre-harvest management practices for maize and groundnuts – namely, controlling weeds, timely planting, controlling pests, and applying basal and top-dressing fertilisers – few households (8%) reported practising all of them. Among the recommended techniques for harvesting and handling maize and groundnuts, the most common harvest-management practices under maize production were drying (95.2% of households) and sorting at harvest (72%). In contrast, very few households (2%) practised at least three of four maize harvest management practices. Similarly, very few households (10%) practised at least 4 of the 6 groundnut harvest-management measures. Comparatively, post-harvest and storage management practices were more commonly practised, although most households did not practise all six post-harvest and storage management measures.Overall, very few households (1% for maize and 4% for groundnuts) were observed to be practising at least 12 of the 14 recommended management practices, implying that there are considerable gaps in the implementation of aflatoxin-related management practices along all stages of maize and groundnut production, consequently posing a significant threat to health and contributing to malnutrition levels in Zambia.As such, there is a need to develop tailored interventions and trainings for farming households, extension officers, and frontline health workers to prevent and manage aflatoxin contamination at different stages of crop production. Furthermore, the elimination of policy constraints, practical barriers of affordability and consumer awareness, and the value attached to the commercial product of Aflasafe, noted to reduce aflatoxin contamination by 80–100%, are of utmost urgency.

Influence of microbiota inoculum as a substitute for antibiotic growth promoter during the initial laying phase on productivity performance, egg quality, and the morphology of reproductive organs in laying hens.

Antibiotics that increase growth have long been employed as a component of chicken growth. Long-term, unchecked usage may lead to microbial imbalance, resistance, and immune system suppression. Probiotics are a suitable and secure feed additive that may be provided as a solution. The objective of this research was to ascertain the effects of dietary multistrain probiotics (Lactobacillus acidophilus, Bifidobacterium spp., and Lactobacillus plantarum) on the morphology (length and weight) of reproductive organs and productivity performance of laying hens during the early stage of laying. One hundred ISA Brown commercial layer chicks of the same body weight (BW) that were 5 days old were divided into five treatments, each with four replicates and four chicks in each duplicate. There were five different dietary interventions: (T1) 100% base feed; (T2) base feed with 2.5 g of antibiotic growth promoter/kg feed; (T3) base feed plus probiotics; (T4) base feed at 1 mL/kg with probiotics; and (T5) base feed with probiotics, 3 mL/kg feed, 5 mL/kg of feed. The parameters observed were performance, internal and exterior egg quality, and the morphology (length and weight) of laying hens' reproductive organs. Probiotic supplementation (L. acidophilus, Bifidobacterium, and L. plantarum) significantly affected the BW, feed intake, egg weight, yolk index, albumin index, Haugh unit, egg height, egg width, and morphology (length and weight) of laying hens' reproductive organs compared to the control group (basic feed). In addition, there was no discernible difference between treatment groups in theeggshell weight and thickness variables across all treatment groups. When laying hens were between 17 and 21 weeks old, during the early laying period, microbiota inoculum supplements (L. acidophilus, Bifidobacterium, and L. plantarum) increased growth, the quality of the internal and external layers' eggs, and the morphology of the laying hens' reproductive organs.

89-OR: Immunoprivileged Hydrogels Extend Functionality of Islets in Immunocompetent Animals

Background: Despite the promise of current islet cell transplantation, the need for systemic immune suppression significantly limits its utility for patients with diabetes. Until safe and immune-evasive cells are realized, physical immuno-protection offers an alternate route to allogeneic islet implants. Our proprietary synthetic hydrogels provide shape-agnostic, robust and retrievable Islet environments with anti-fouling and non-fibrotic properties. Methods: Rat and human donor islets were encapsulated and implanted in the peritoneal space of streptozotocin (STZ)-induced diabetic immunocompetent mice and pigs to assess islet functionality over time through measurement of blood glucose, C-peptide, and HbA1c. Next generation shape-agnostic hydrogels were also tested for in-vitro and in-vivo function. Results: Our hydrogels enabled rapid and persistent blood glucose control for 140+ days in immunocompetent mice with marginal loads of 1000 rat IEQ/mouse. Human donor islet function in mice was extended to day 45 (~8x longer than free human islets), with C-peptide detected at day 50, and corresponding HbA1c decreases. Our hydrogels showed minimal fibrosis when explanted after 45 days and showed robustness and integrity at day 340 post-implant in immunocompetent mice. Next-gen shape-agnostic hydrogels successfully excluded immune components including IgG and maintained good islet function in vitro. Our data also demonstrate function of human donor islets in immunocompetent pigs, based on C-peptide and cell viability data. Conclusion: Our proprietary synthetic and retrievable hydrogels show strong immune protection in xenogenic transplants of donor islets into immune-competent animals. We are currently scaling to therapeutic doses in large animals, in pursuit of a curative therapy based on an optimal balance of Islet protection and functionality, without immunosuppression. Disclosure H.Stover: Employee; Allarta Life Science Inc.

Combinatorial islet protective therapeutic approaches in β-cell transplantation: Rationally designed solutions using a target product profile.

While progress has been made in the development of islet cell transplantation (ICT) as a viable alternative to the use of exogenous insulin therapy in the treatment of type 1 diabetes, it has not yet achieved its full potential in clinical studies. Ideally, ICT would enable lifelong maintenance of euglycemia without the need for exogenous insulin, blood glucose monitoring or systemic immune suppression. To achieve such an optimal result, therapeutic approaches should simultaneously promote long-term islet viability, functionality, and localized immune protection. In practice, however, these factors are typically tackled individually. Furthermore, while the requirements of optimal ICT are implicitly acknowledged across numerous publications, the literature contains few comprehensive articulations of the target product profile (TPP) for an optimal ICT product, including key characteristics of safety and efficacy. This review aims to provide a novel TPP for ICT and presents promising tried and untried combinatorial approaches that could be used to achieve the target product profile. We also highlight regulatory barriers to the development and adoption of ICT, particularly in the United States, where ICT is only approved for use in academic clinical trials and is not reimbursed by insurance carriers. Overall, this review argues that the clear definition of a TPP in addition to the use of combinatorial approaches could help to overcome the clinical barriers to the widespread adoption of ICT for the treatment of type 1 diabetes.

G-CSF rescue of FOLFIRINOX-induced neutropenia leads to systemic immune suppression in mice and humans

BackgroundRecombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes...

Paradoxically Increased Inflammation in Immunosuppressed Individuals with COVID-19

Abstract Dysregulated inflammation is central to the morbidity and mortality associated with COVID-19. Treatment with dexamethasone and IL-6 blockade can be life-saving in patients stratified for moderate - severe disease. Patients with suppressed immunity are often excluded from immune blockade therapy due to the assumption that additional suppression of an impaired immune system will be detrimental to viral clearance. We hypothesised that patients with suppressed immune systems would be slower to clear viral infection, leading to increased damage and therefore, paradoxically, a more intense acute phase response to SARS-CoV-2 infection. This was tested by a sub-group analysis of the Coronavirus Immune Response and Clinical Outcomes (CIRCO) cohort, an observational study of acute COVID-19 in Greater Manchester, UK. Patients were included if they were treated with dexamethasone and had a research blood sample retrieved within 48 hours of admission, and excluded if they were treated with IL-6 blockade or antiviral therapy prior to research sampling. Acute phase serum cytokine levels were compared between eight immunosuppressed and 12 immunocompetent patients positive for SARS-CoV-2. In support of our hypothesis, we found that immunosuppressed individuals had higher levels of the inflammatory cytokines IP-10 (p=0.03) and MCP-1 (p=0.01) compared to immunocompetent patients matched for COVID-19 severity. This suggests that immunosuppressed patients may benefit as much as immunocompetent individuals from systemic treatments to dampen inflammation in COVID-19, and current recommendations of excluding these patients from treatment solely on the basis of immune competence may need to be re-evaluated.

Tapinarof ameliorates rejection in a human skin grafted model of face transplantation

Abstract T cell mediated immune rejection is the primary barrier to broader implementation of face transplants (vascularized composite allografts, VCA). Our bulk and single cell transcriptional profiling of human face transplant rejection demonstrated that VCA rejection is an INFγ driven cytotoxic process with unique induction of skin specific immunoregulatory pathways including SOCS1, KIR3DL2, and LY9. Tapinarof is a novel small-molecule topical aryl hydrocarbon receptor agonist and antioxidant that is effective in treating psoriasis and atopic dermatitis. Patients who cleared on once a day topical tapinarof remained clear for an average of four months after discontinuation, suggesting it has durable immunoregulatory effects in skin. We modeled VCA by grafting NSG mice with freshly excised, living, immunologically intact adult human skin. Once healed, 5×10 6allogeneic PBMCs from a second unrelated human donor were infused via tail vein. The inflamed skin mimicked VCA rejection after 21 days, with grafts showing epidermal injury, T cell infiltration, dyskeratosis, and genetic signatures of cytotoxicity, antigen presentation, and INFγ signaling. Topical tapinarof ameliorated this inflammation, with fewer T cells and reduced antigen-specific T cell activation. Induction of immunoregulatory pathways was also noted, including upregulation of SOCS1 signaling, TREX1 mediated reductions in cytosolic nucleotide sensing, and IL1RN inhibition of IL-1 mediated inflammation. Tapinarof could be a novel therapy for VCA rejection that does not require systemic immune suppression. Our results suggest that strengthening immunoregulatory networks in skin is a viable approach to combat inflammation and promote tolerance in VCA rejection. NIH T32 Training Grant 2T32AR007098-47 Dept. of Dermatology, Harvard Medical School RT170025 (P.I. Rachael A. Clark) Department of Defense - congressionally Directed Medical Research Programs; "T cells and Rejection in Vascularized Composite Allografts).