Immunomodulatory Potential Research Articles

Assessing Novel Antibody-Based Therapies in Reconstructive 3D Cell Models of the Tumor Microenvironment.

Targeted, combinatorial, and immunomodulatory therapies, such as antibody-drug conjugates (ADCs) and immunomodulatory antibodies (Abs), are powerful weapons against tumor cells and immune cells within the tumor microenvironment (TME). Therefore, the evaluation of such therapies should be conducted in pre-clinical models able to recapitulate the complex cellular and molecular crosstalk of the TME. To build-in critical hallmarks of the TME, a breast cancer heterotypic 3D cell model (3D-3) is devised using a microencapsulation strategy with an inert biomaterial (alginate) and agitation-based cultures. Both stromal and immune components are added to multicellular tumor spheroids, therefore fostering cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) immunomodulatory interactions. The potential of the methodology to assess Ab-based therapies is then addressed by employing a series of anti-HER2-based ADCs. ADCs induced tumor-cell specific cytotoxicity toward HER2+ breast cancer spheroids while sparing HER2-negative CAFs. In addition, an immunomodulatory blocking Ab against colony-stimulating factor 1 receptor (CSF1R) decreases the expression of immunosuppressive and anti-inflammatory markers in TAMs, like what is previously observed upon in vivo α-CSF1R administration. Collectively, the human TME-based 3D-3 cell model is a suitable tool to evaluate the anti-tumor and immunomodulatory potential of novel antibody-based therapies directed against TME targets, such as cancer cells and macrophages.

Initial Evaluation of Safety and Immunomodulatory Potential of Dietary Supplementation with Mangosteen Pericarp Extract for Sustainable Meat Production in Native Crossbred Chickens.

The utilization of mangosteen biomass not only solves environmental problems but also raises the value of agricultural waste. The current study aimed to evaluate the potential of mangosteen pericarp extract (MPE) for enhancing the immunity and productivity of Thai native crossbred chickens on-farm. A total of 180 three-week-old chickens were divided into negative control and supplemented groups, with 1000 mg MPE/kg of diet. The safety of MPE was further confirmed by the absence of noticeable differences in mortality and biochemical parameters during the entire study period. The MPE-supplemented group displayed significant differences in the relative transcription levels of IL-10 compared to the basal diet group (p ≤ 0.01). Preslaughter body weight, average daily gain, and carcass weight in the MPE-supplemented group were higher than those in the basal diet group (p ≤ 0.05). Furthermore, MPE supplementation improved meat quality by enhancing the nutritional composition of protein and fat (p ≤ 0.05), as well as improving water-holding capacity, lowering boiling, and lowering grilling losses (p ≤ 0.01). These findings indicate that MPE can be an effective supplement for enhancing flock immunity, growth performance, and meat quality in poultry. This contributes to more sustainable agriculture and food security within agroecosystems.

Unlocking the Immunomodulatory Potential of Rosmarinic Acid Isolated from Punica granatum L. using Bioactivity-Guided Approach: In Silico, In Vitro, and In Vivo Approaches.

Punica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.

Freund’s adjuvant is a classic of vaccine adjuvants and the basis of experimental immunology

Background. The invention of vaccines is rightfully considered one of the triumphs of medical research and one of the most remarkable achievements in public health in the history of humanity. According to the World Health Organization, vaccination saves 5 lives every minute and has saved over 25 million lives from 2011 to 2020. The effectiveness of a vaccine depends not only on the components of the antigen but also on the adjuvants, which are often used for more effective stimulation of the immune system. Purpose – to characterize the modern understanding of vaccine adjuvants, particularly Freund’s adjuvant, as a foundation of experimental immunology based on open source information. Materials and Methods. The selection of publications was conducted using databases such as PubMed, Clinical Key Elsevier, Cochrane Library, eBook Business Collection, and others, which provided information on vaccine adjuvants, particularly Freund’s adjuvant. In the first stage, a search for literature sources was performed using keywords: vaccine adjuvants, complete Freund’s adjuvant, alum, adjuvant arthritis, experimental immunology. In the second stage, the abstracts of the articles were reviewed, and publications that did not meet the research criteria were excluded. In the third stage, the full texts of the selected articles were examined for compliance with the inclusion criteria and relevance of the studies. Results. In 1924, G. Ramon demonstrated that the co-administration of the diphtheria anatoxin he had recently developed with other compounds such as tapioca, lecithin, agar, starch oil, saponin, and others enhances antitoxin reactions to diphtheria. In 1942, J. Freund developed a potent adjuvant in the form of a water-in-oil emulsion using mineral oil that contained heat-killed mycobacteria (Mycobacterium tuberculosis), which was named complete Freund’s adjuvant. However, over time, Freund’s adjuvant was banned for use in vaccines for humans due to its toxicity. Despite numerous studies, until 2009, aluminum salts dominated the use of adjuvants in licensed vaccines. Beginning in 2010, the demand for the development of new adjuvants noticeably increased, especially following several pandemics such as Ebola, Zika, and COVID-19. It is known that adjuvants enhance the adaptive immunity of vaccines by activating innate immune cells. The main concept of their effect is that adjuvants promote the production of antigen presentation signals and costimulatory signals by activating antigen-presenting cells. The model of adjuvant arthritis induced by complete Freund’s adjuvant was created to study the pathogenesis of arthritis, including rheumatoid arthritis, gout, and osteoarthritis, as well as to evaluate the effectiveness of certain anti-arthritis and anti-inflammatory drugs. Conclusions. Vaccine adjuvants encompass a wide range of chemical compounds and substances that enhance immune responses through physical or chemical binding with antigens. The most significant influences on the formation of the modern understanding of vaccine antigens and immunology in the 20th century were Gaston Ramon (1886–1963), Alexander Glenny (1882–1965), and Jules Freund (1890–1960). Complete Freund’s adjuvant has historically been and remains one of the most useful tools for immunologists. The use of antigenic mixtures from biological tissue extracts along with complete Freund’s adjuvant allows for the reproduction of various organ-specific autoimmune diseases in laboratory animals (such as autoimmune arthritis, myocarditis, hepatitis, thyroiditis, encephalomyelitis, etc.), facilitating preclinical studies on the effectiveness of potential immunomodulating and symptomatic therapeutic agents.

Immunomodulatory potential of dietary soybean-derived saponins.

Soybeans are widely recognized as a valuable crop, often included as a high-quality protein source in production animal diets. In addition to contributing to the macronutrient composition of the diet, soybeans also contain many minor bioactive components which can influence the health and growth of animals. This review examined the immunomodulatory potential of soy saponins and their specific effects on the inflammatory response, oxidative stress, and intestinal barrier function. Saponins are amphiphilic molecules, a property imparted by their polar carbohydrate chains that attach to a nonpolar aglycone backbone. This structure also complicates their isolation, thus most research investigating soy saponins has been performed in models that only require small amounts of isolated material. Many experiments conducted in vitro or in rodents reported that saponins can reduce damage, particularly in conditions where a challenge was first introduced to stimulate inflammation or oxidative stress. It appears that saponins can exert their anti-inflammatory effects through modulation of the NF-κB pathway, reducing its activation and the release of pro-inflammatory molecules later in the cascade. Furthermore, soy saponins can influence levels of important antioxidative enzymes and reduce the generation of reactive oxygen species, thus attenuating levels of oxidative stress in the model. As these results were obtained from experiments done in vitro or in rodents, they neglect to provide a good representation of how soy saponins may affect some of the greatest consumers of soy-based products, with those being production animals. The work that has been done seems to indicate that soy saponins may exert similar anti-inflammatory and anti-oxidative effects in production animals as those observed in other research models along with immunostimulatory activity that may help boost host defense systems. Overall, there is a dearth of research regarding the effects of soy saponins on species that commonly consume soy products, which begins by developing more effective methods of saponin extraction.

Can letrozole be repurposed for the treatment of visceral leishmaniasis?

Visceral leishmaniasis, caused by Leishmania infantum in New World countries, is the most serious and potentially fatal form of leishmaniasis, if left untreated. There are currently no effective prophylactic measures, and therapeutic options are limited. Therefore, we investigated whether the aromatase inhibitor letrozole (LET), which is already used to treat breast cancer, has an antileishmanial activity and/or immunomodulatory potential and therefore may be used to treat L. infantum infection. LET was active against L. infantum promastigote and amastigote life cycle stages in an in vitro infection model using human THP-1 cell-derived macrophages. In human peripheral blood leukocytes ex vivo, LET reduced the internalized forms of L. infantum by classical monocytes and activated neutrophils. Concomitantly, LET stimulated the production of IL-12/TNF-α and decreased the production of IL-10/TGF-β by peripheral blood phagocytes, while in T and B cells, it promoted the production of TNF-α/IFN-γ and decreased that of IL-10. In a murine infection model, LET significantly reduced the parasite load in the liver after just 5 days and in the spleen after 15 days. During in vivo treatment with LET, the production of TNF-α/IFN-γ also increased. In addition, the proportion of developing granulomas decreased and that of mature granulomas increased in the liver, while there was no significant change in organ architecture in the spleen. Based on these data, repositioning of LET may be promising for the treatment of visceral leishmaniasis in humans.

Benzoic Acid potentiates intestinal IgA response in broiler chickens against Salmonella enterica Serovar Typhimurium infection

As a feed additive, Benzoic Acid (BA) has been demonstrated to significantly enhance feed conversion efficiency, regulate gastrointestinal pH, and improve overall animal health. Young animals, highly susceptible to S. Typhimurium infection, suffer from high mortality rates and substantial economic losses due to this pathogen. Despite promising indications of BA's immunomodulatory potential in boosting intestinal immunity, its underlying mechanisms remain insufficiently understood. This study investigates how BA strengthens intestinal anti-infection defenses in young animals via immunomodulatory pathways, focusing on its impact on macrophage polarization and IgA-mediated immune responses. Employing in vitro cell experiments and animal models, we examined the macrophage phenotypic alterations following BA treatment. We assessed the expression of immune-related genes in the intestine through immunofluorescence staining, Western blotting, and quantitative real-time PCR. The results demonstrate that BA promotes M2 macrophage polarization by activating the mTOR/PPAR-γ/STAT3 signaling pathways. Furthermore, BA enhances the intestinal expression of the polymeric immunoglobulin receptor (PIgR), B-cell activating factor (BAFF) from the TNF family, and activation-induced cytidine deaminase (AID), thereby enhancing IgA production by B-cells. These results underscore the potential of BA to bolster innate immune functions in young chickens, mitigate intestinal damage caused by S. Typhimurium infection, and ultimately promote both animal health and food safety.

Decellularized Extracellular Matrix Scaffolds: Recent Advances and Emerging Strategies in Bone Tissue Engineering.

Bone tissue engineering (BTE) is a complex biological process involving the repair of bone tissue with proper neuronal network and vasculature as well as bone surrounding soft tissue. Synthetic biomaterials used for BTE should be biocompatible, support bone tissue regeneration, and eventually be degraded in situ and replaced with the newly generated bone tissue. Recently, various forms of bone graft materials such as hydrogel, nanofiber scaffolds, and 3D printed composite scaffolds have been developed for BTE application. Decellularized extracellular matrix (DECM), a kind of natural biological material obtained from specific tissues and organs, has certain advantages over synthetic and exogenous biomaterial-derived bone grafts. Moreover, DECM can be developed from a wide range of biological sources and possesses strong molding abilities, natural 3D structures, and bioactive factors. Although DECM has shown robust osteogenic, proangiogenic, immunomodulatory, and bone defect healing potential, the rapid degradation and limited mechanical properties should be improved for bench-to-bed translation in BTE. This review summarizes the recent advances in DECM-based BTE and discusses emerging strategies of DECM-based BTE.

New insights into the immunomodulatory potential of sialic acid on monocyte-derived dendritic cells

Sialic acids at the cell surface of dendritic cells (DCs) play an important immunomodulatory role, and their manipulation enhances DC maturation, leading to heightened T cell activation. Particularly, at the molecular level, the increased stability of surface MHC-I molecules in monocyte-derived DCs (MoDCs) underpins an improved DC: T cell interaction. In this study, we focused on the impact of sialic acid remodelling by treatment with Clostridium perfringens sialidase on MoDCs' phenotypic and functional characteristics. Our investigation juxtaposes this novel approach with the conventional cytokine-based maturation regimen commonly employed in clinical settings.Notably, C. perfringens sialidase remarkably increased MHC-I levels compared to other sialidases having different specificities, supporting the idea that higher MHC-I is due to the cleavage of specific sialoglycans on cell surface proteins. Sialidase treatment induced rapid elevated surface expression of MHC-I, MHC-II and CD40 within an hour, a response not fully replicated by 48 h cytokine cocktail treatment. These increases were also observable 48 h post sialidase treatment. While CD86 and PD-L1 showed significant increases after 48 h of cytokine maturation, 48 h post sialidase treatment showed a higher increase in CD86 and shorter increase in PD-L1. CCR-7 expression was significantly increased 48 h after sialidase treatment but not significantly affected by cytokine maturation. Both treatments promoted higher secretion of the IL-12 cytokine. However, the cytokine cocktail induced a more pronounced IL-12 production. SNA lectin staining analysis demonstrated that the sialic acid profile is significantly altered by sialidase treatment, but not by the cytokine cocktail, which causes only slight sialic acid upregulation. Notably, the lipid-presenting molecules CD1a, CD1b and CD1c remained unaffected by sialidase treatment in MoDCs, a finding also further supported by experiments performed on C1R cells. Inhibition of endogenous sialidases Neu1 and Neu3 during MoDC differentiation did not affect surface MHC-I expression and cytokine secretion. Yet, sialidase activity in MoDCs was minimal, suggesting that sialidase inhibition does not significantly alter MHC-I-related functions. Our study highlights the unique maturation profile induced by sialic acid manipulation in MoDCs. These findings provide insights into the potential of sialic acid manipulation as a rapid immunomodulatory strategy, offering promising avenues for targeted interventions in inflammatory contexts.

Urolithin A attenuates bupivacaine-induced neurotoxicity in SH-SY5Y cells by regulating the SIRT1-activated PI3K/AKT pathway.

Urolithin A (UroA) is well-recognized for its anti-oxidative, anti-inflammatory, and immunomodulatory potentials and has been proven to have neuroprotective effects. Nevertheless, the potential of UroA on bupivacaine (BUP)-induced neurotoxicity has never been reported. Using SH-SY5Y cells to establish a cell model, it was revealed that BUP stimulated cell viability reduction, LDH release increase, and suppression of SIRT1-activated PI3K/AKT signaling in SH-SY5Y cells, whereas UroA treatment caused an effective abrogation of the effects of BUP. Besides, SIRT1 overexpression caused an enhancement in the activity of PI3K/AKT signaling in BUP and UroA co-treated cells, indicating that SIRT1 mediated the activity of PI3K/AKT signaling. Moreover, UroA inhibited BUP-induced apoptosis, oxidative stress, and inflammatory responses in SH-SY5Y cells. However, the effects of UroA on BUP-induced neurotoxicity were all abated by inhibiting SIRT1 or PI3K/AKT signaling through EX527 or LY294002. In conclusion, UroA protected SH-SY5Y cells against BUP-induced injuries through PI3K/AKT signaling in a SIRT1-dependent manner.

Culture Expansion Alters Human Bone Marrow Derived Mesenchymal Stem Cell Production of Osteoarthritis-relevant Cytokines and Growth Factors

PurposeThe purposes of this study were to characterize the human bone marrow derived mesenchymal stem cells (BM-MSCs) production of osteoarthritis-relevant cytokines and growth factors as they are purified and multiplied, a process termed culture expansion, and to compare the immunomodulatory potential of BM-MSCs based on source and medium used for culture expansion. MethodsBM-MSCs were obtained from iliac crest bone marrow aspirates of four healthy donors. These four BM-MSC cell lines underwent four rounds, or “passages,” of the institutional culture expansion protocol, using institutional culture media. The secretory molecules known to play a role in OA-related inflammatory immune response, cartilage degradation and patient symptoms, together called the BM-MSC “secretome,” were measured at each passage. Three lines of commercially available BM-MSCs from healthy donors underwent culture expansion by the same protocol, using commercial culture media. The commercial BM-MSCs secretome and the institutional BM-MSCs secretome were compared at each passage. Significance was set at p<0.05. ResultsInstitutional BM-MSCs produced less IL-6 at passages 3 (237±113 pg/mL) and 4 (237±113 pg/mL) compared to passages 1 (884±97 pg/mL) and 2 (1071±129 pg/mL; p<0.01). Institutional BM-MSCs produced more MIP-3α at passage 4 than at passage 1 (106±41 vs 32±7 pg/mL; p<0.01). Across passages of culture expansion, institutional BM-MSCs grown on institutional medium expressed more IL-6 (P<0.001), IL-10 (P<0.001), IL-1β (P<0.001), TNFα (P=0.004), and VEGF-C (P=0.003) than commercially available BM-MSCs grown on commercial medium. ConclusionCulture expansion alters key molecules within the BM-MSC secretome. Additionally, differences in BM-MSC source and culture medium alter the BM-MSC secretome and its immunomodulatory potential.

Afatinib boosts CAR-T cell antitumor therapeutic efficacy via metabolism and fate reprogramming

BackgroundChimeric antigen receptor T (CAR-T) cell therapy has been shown remarkable efficacy in the treatment of hematological malignancies in recent years. However, a considerable proportion of patients would experience tumor...

Dexamethasone and IFN-γ primed mesenchymal stem cells conditioned media immunomodulates aberrant NETosis in SLE via PGE2 and IDO.

Systemic Lupus Erythematosus (SLE) is characterized by dysregulated immune responses, with neutrophil extracellular traps (NETs) playing a significant role. NETs are recognized by autoantibodies in SLE patients, exacerbating pathology. Both excessive NET formation and impaired degradation contribute to SLE pathophysiology. To investigate the immunomodulatory effects of Dexamethasone-primed Wharton's jelly (WJ) derived MSCs CM (DW) and IFN-γ-primed WJ-MSCs-CM (IW) on NETosis and associated protein markers in SLE patients' LPS or ribonucleoprotein immune complexes (RNP ICs) induced neutrophils and in pristane induced lupus (PIL) model. And to elucidate the mechanism involved therein. We investigated the immunomodulatory effects of DW and IW on NETosis in SLE. Utilizing ex vivo and in vivo models, we assessed the impact of preconditioned media on NET formation and associated protein markers neutrophil elastase (NE), citrullinated histone (citH3), myeloperoxidase (MPO), cytoplasmic and mitochondrial ROS production. We also examined the involvement of key immunomodulatory factors present in DW and IW, including prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor-beta (TGF-β). Preconditioned media effectively suppressed NETosis and reduced ROS generation in SLE neutrophils, indicating their immunomodulatory potential. Inhibition studies implicated IDO and PGE2 in mediating this effect. Combined treatment with DW or IW together with hydroxychloroquine (HCQ) demonstrated superior efficacy over HCQ alone, a standard SLE medication. In PIL mouse model, DW and IW treatments reduced NETosis, ROS generation, as evidenced by decreased NET-associated protein expression in vital organs. Our study highlights the multifaceted impact of IW and DW on NETosis, ROS dynamics, and lupus severity in SLE. These findings underscore the potential of preconditioned media for the development of targeted, personalized approaches for SLE treatment.

Chemical Characterization and In Vitro Evaluation of Glucans from Fermentation-Produced Nutraceutical Bionutri-AR1®: Antioxidant and Immunomodulatory Properties.

Background: The consumption of nutraceuticals or food supplements has increased crucially, aiming to address nutrient deficits and enhance immune system function. To develop safe food products with unique nutritional and functional benefits, new production methods of these nutraceuticals such as the fermentative process have been gaining prominence for industrial applications. Bionutri-AR1® is a nutraceutical produced via this bioprocess, featuring a complex composition, that has been used to improve the immune systems of debilitated people. Objectives: Considering the various biological properties attributed to glucans, one of its main components, this study aims to structurally characterize and evaluate, in vitro, the antioxidant and immunomodulatory potential of the polymers from this nutraceutical to assess whether these polymers contribute to the product's reported biological effects. Methods/Results: Unlike previous reports, this study characterized by NMR, GC-MS, and Congo Red assay techniques two main glucans: a water-insoluble linear α-D-glucan with glycosidic bonds (1→4) and a soluble branched (1→3)- and (1→6)-linked β-glucan with a triple helix. Both glucans showed significant antioxidant activity, measured by their capacity to scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. They were also capable of inducing the secretion of cytokines such as tumoral necrosis factor-alpha (TNF-α), interleukin 10 (IL-10), and interleukin 6 (IL-6), determined through capture enzyme-linked immunosorbent assay (ELISA), especially when co-stimulated with lipopolysaccharide (LPS). Conclusions: This suggests a dual action of these glucans in both proinflammatory and regulatory pathways. Future studies will describe the mechanisms by which these glucans, especially the insoluble ones, enhance immune system function, highlighting their potential use in immunotherapy.

Macrophage Immunomodulation and Suppression of Bacterial Growth by Polydimethylsiloxane Surface-Interrupted Microlines' Topography Targeting Breast Implant Applications.

Since breast cancer is one of the most common forms of cancer in women, silicone mammary implants have been extensively employed in numerous breast reconstruction procedures. However, despite the crucial role they play, their interaction with the host's immune system and microbiome is poorly understood. Considering this, the present work investigates the immunomodulatory and bacterial mitigation potential of six textured surfaces, based on linear step-like features with various regular and irregular multiscaled arrangements, in comparison to a flat PDMS surface. We hypothesise that the chosen surface geometries are capable of modulating the cellular response through mechanical interdigitation within the multiscaled surface morphology, independent of the surface chemical properties. Each type of sample was characterised from a physico-chemical and biological points of view and by comparison to the flat PDMS surface. The overall results proved that the presence of linear multiscaled step-like features on the PDMS surface influenced both the surface's characteristics (e.g., surface energy, wettability, and roughness parameters), as well as the cellular response. Thus, the biological evaluation revealed that, to different degrees, biomaterial-induced macrophage activation can be mitigated by the newly designed microtextured surfaces. Moreover, the reduction in bacteria adherence up to 90%, suggested that the topographical altered surfaces are capable of suppressing bacterial colonisation, therefore demonstrating that in a surgical environment at risk of bacterial contamination, they can be better tolerated.

Body Composition and Senescence: Impact of Polyphenols on Aging-Associated Events.

Aging is a dynamic and progressive process characterized by the gradual accumulation of cellular damage. The continuous functional decline in the intrinsic capacity of living organisms to precisely regulate homeostasis leads to an increased susceptibility and vulnerability to diseases. Among the factors contributing to these changes, body composition-comprised of fat mass and lean mass deposits-plays a crucial role in the trajectory of a disability. Particularly, visceral and intermuscular fat deposits increase with aging and are associated with adverse health outcomes, having been linked to the pathogenesis of sarcopenia. Adipose tissue is involved in the secretion of bioactive factors that can ultimately mediate inter-organ pathology, including skeletal muscle pathology, through the induction of a pro-inflammatory profile such as a SASP, cellular senescence, and immunosenescence, among other events. Extensive research has shown that natural compounds have the ability to modulate the mechanisms associated with cellular senescence, in addition to exhibiting anti-inflammatory, antioxidant, and immunomodulatory potential, making them interesting strategies for promoting healthy aging. In this review, we will discuss how factors such as cellular senescence and the presence of a pro-inflammatory phenotype can negatively impact body composition and lead to the development of age-related diseases, as well as how the use of polyphenols can be a functional measure for restoring balance, maintaining tissue quality and composition, and promoting health.

Human gut commensal Alistipes timonensis modulates the host lipidome and delivers anti-inflammatory outer membrane vesicles to suppress colitis in an Il10 -deficient mouse model.

Correlative studies have linked human gut microbes to specific health conditions. Alistipes is one such microbial genus negatively linked to inflammatory bowel disease (IBD). However, the protective role of Alistipes in IBD has not been studied and the underlying molecular mechanisms also remain unknown. In this study, colonization of Il10 -deficient mice with Alistipes timonensis DSM 27924 delays the development of colitis. Colonization with Alistipes does not significantly alter the gut microbiome composition during colitis development, but instead shifts the host plasma lipidome, increasing phosphatidic acids while decreasing triglycerides. Outer membrane vesicles (OMVs) derived from Alistipes are also detected in the plasma of colonized mice, which carry metabolites with immunomodulatory potential into the host circulatory system. We further demonstrate that fractions of A. timonensis OMVs suppress LPS-induced Il6 , Il1b , and Tnfa expression in vitro in murine macrophages. We detect immunomodulatory sulfonolipids (SoLs) in the active fraction, which are also increased in the blood of A. timonensis -colonized mice; and we identify other putative bioactive lipids in the A. timonensis OMVs. Thus, A. timonensis OMVs represent a potential mechanism for Alistipes -mediated delay of colitis progression in Il10 -deficient mice through the delivery of immunomodulatory lipids, including SoLs, and modulation of the host plasma lipidome.

Evaluation of Anti-Inflammatory and Immunosuppressant Potential of Isotelekin in Lipopolysaccharide (LPS) Stimulated Macrophage (RAW 264.7) and Sheep Red Blood Cells (SRBC) Sensitized Murine Models.

The present study explored the natural compound Isotelekin isolated from Inula racemose against anti-inflammatory and immunomodulatory potential in LPS-induced RAW264.7 cell lines and immune-elevated SRBC-sensitized animal models. Isotelekin in in vitro studies, inhibited the production of Th-1 cytokines Interleukin-6 (IL-6), Tumour necrosis factor (TNF-α), and Interferon-gamma (INF-γ),and increased Th-2 cytokines Interleukin-10 (IL-10). Whereas it inhibited the nitrites and reactive oxygen species (ROS) production by mitigating the effect of LPS significantly. In vivo immunomodulatory activity in Delayed-type hypersensitivity (DTH) and Hemagglutinating antibody (HA), Isotelekin suppressed the cellular as well as humoral immunity in immune-affected and SRBC-sensitized mice. Isotelekin decreased the phagocytic responses against carbon particles and plaque-forming mainly IgG (Immunoglobulin G) production. Additionally, Isotelekin showed immunosuppressive potential through the evaluation of splenocytes, allograft acceptance, and haematological parameters. Molecular studies, including western blot analysis and immunocytochemistry, revealed that Isotelekin reduced the expression of iNOS (Inducible nitric oxide synthase), COX-2 (Cyclo-Oxygenase 2), and p-IkBα (Phospho I-kappa-B-alpha), and significantly inhibited the nuclear translocation of NF-κB/p65. Based on these results, Isotelekin at 10 µm in in vitro and at 30mgkg-1 in in vivo demonstrated strong anti-inflammatory and immunosuppressive therapeutic potential.

Unveiling the Immunomodulatory and regenerative potential of iPSC-derived mesenchymal stromal cells and their extracellular vesicles

Induced pluripotent stem cell (iPSC)-derived mesenchymal stromal cells (iMSCs) offer a promising alternative to primary mesenchymal stromal cells (MSCs) and their derivatives, particularly extracellular vesicles (EVs), for use in advanced therapy medicinal products. In this study we evaluated the immunomodulatory and regenerative potential of iMSCs as well as iMSC-EVs, alongside primary human umbilical cord-derived mesenchymal stromal cells (hUCMSCs). Our findings demonstrate that iMSCs exhibit comparable abilities to hUCMSCs in regulating lymphocyte proliferation and inducing an anti-inflammatory phenotype in monocytes. We also observed decreased TNFα levels and increased IL-10 induction, indicating a potential mechanism for their immunomodulatory effects. Furthermore, iMSC-EVs also showed effective immunomodulation by inhibiting T cell proliferation and inducing macrophage polarization similar to their parental cells. Additionally, iMSC-EVs exhibited pro-regenerative potential akin to hUCMSC-EVs in in vitro scratch assays. Notably, priming iMSCs with pro-inflammatory cytokines significantly enhanced the immunomodulatory potential of iMSC-EVs. These results underscore the considerable promise of iMSCs and iMSCs-EVs as an alternate source for MSC-derived therapeutics, given their potent immunomodulatory and regenerative properties.

Synergistic role of Mycobacterium indicus pranii and human beta Defensin-2 as adjunctive therapy against Mycobacterium tuberculosis

Host-directed therapies (HDT) via modulation of specific host responses like inflammation can limit mycobacterial infection. HDTs could be included in current TB therapy as an adjunct to increase bacterial clearance and limit tissue damage to control spread. Individually, Mycobacterium indicus pranii (MIP) and human beta defensin-2 (hBD-2) are promising therapies for tuberculosis (TB). They can directly target the TB bacilli and enhance cell-mediated immune responses, which is limiting with conventional drugs. Therefore, our study investigated the combined application of MIP and hBD-2 to evaluate their efficacy in clearing infections caused by Mycobacterium smegmatis (M.smeg) and Mycobacterium tuberculosis (M.tb) (both avirulent; H37Ra and virulent strain; H37Rv) in THP-1 cells and human monocyte-derived macrophages (MDMs). A strong pro-inflammatory response was observed against the combination of MIP and hBD-2 which also correlated with a significant reduction in the bacterial load. This combination further showed protection against M.tb by enhancing pyroptosis in the infected cells. The study suggests the combined use of these potent immunomodulators, which could be employed as an effective mode of therapy as adjuvants against mycobacterial infections after validation in a suitable animal model.