Immunomodulatory Molecules Research Articles

Engineered Immunomodulatory Extracellular Vesicles from Epithelial Cells with the Capacity for Stimulation of Innate and Adaptive Immunity in Cancer and Autoimmunity.

Extracellular vesicles (EVs) are generated in all cells. Systemic administration of allogenic EVs derived from epithelial and mesenchymal cells has been shown to be safe, despite carrying an array of functional molecules, including thousands of proteins. To address whether epithelial cell-derived EVs can be modified to acquire the capacity to induce an immune response, we engineered 293T EVs to harbor the immunomodulatory molecules CD80, OX40L, and PD-L1. We demonstrated abundant levels of these proteins in the engineered cells and EVs. Functionally, the engineered EVs efficiently elicited positive and negative costimulation of human and murine T cells. In the setting of cancer and autoimmune hepatitis, the engineered EVs modulated T cell functions and altered disease progression. OX40L EVs also provided enhanced antitumor activity in combination with anti-CTLA-4 in melanoma-bearing mice. In addition, we added multiple immunomodulatory proteins in EVs (EVmIM), attempting to elicit an immune response in both lymphoid and myeloid compartments. The EVmIM containing CD80, 4-1BBL, CD40L, CD2, and CD32 engaged both T cells and antigen presenting cells (APCs) in melanoma tumors, demonstrating the capacity for EVmIM to elicit antitumor activity. Our work provides evidence that EVs can be engineered to induce specific immune responses with translational potential to modulate immune cell functions in pathological settings.

Identification of GBN5 as a molecular biomarker of pan-cancer species by integrated multi-omics analysis

IntroductionWe conducted a panoramic analysis of GBN5 expression and prognosis in 33 cancers, aiming to deepen the systematic understanding of GBN5 in cancer.Materials and methodsWe employed a multi-omics approach, including transcriptomic, genomic, proteomic, single-cell cytomic, spatial transcriptomic, and genomic data, to explore the prognostic value and potential oncogenic mechanisms of GBN5 across pan-cancers from multiple perspectives.ResultsWe found that GBN5 was differentially expressed in multiple tumors and showed early diagnostic value. Mutations, somatic copy number alterations, and DNA methylation lead to its aberrant expression. GBN5 expression is associated with many clinical features. GBN5 expression has been validated to be associated with many metabolic, metastatic, and immune-related pathways. We also demonstrated that GBN5 expression was significantly associated with immunomodulatory molecules and biomarkers of lymphocyte subpopulation infiltration. Methylation levels of GBN5 expression were significantly negatively correlated in a variety of tumors, and GBN5 missense mutations were the predominant SNP type in pan-cancer. In addition, GBN5 was positively correlated with multiple genomic scores, implying that higher GBN5 expression tends to imply that patients have higher chromosomal instability. More importantly, GBN5 has an important role in predicting drug sensitivity. We have also developed effective targeted drugs against GBN5.ConclusionGBN5 plays an important role in the genesis and progression of various tumors and is a potential tumor diagnostic and prognostic biomarker as well as an anti-cancer therapeutic target.

Characterization and Proteomic Profiling of Hepatocyte-Like Cells Derived from Human Wharton’s Jelly Mesenchymal Stromal Cells: De Novo Expression of Liver-Specific Enzymes

End-stage liver disease (ESLD), affecting millions worldwide, represents a challenging issue for clinical research and global public health. Liver transplantation is the gold standard therapeutic approach but shows some drawbacks. Hepatocyte transplantation could be a reliable alternative for patient treatment. Mesenchymal stromal cells derived from Wharton’s jelly of the umbilical cord (WJ-MSCs) can differentiate into hepatocyte-like cells (HLCs) and show immunomodulatory functions. Due to the increasing demand for fully characterized cell therapy vehicles warranting both the safety and efficacy of treatments, in this work, we extensively characterized WJ-MSCs before and after the application of a hepatocyte-directed differentiation protocol. HLCs exhibited a morphology resembling that of hepatocytes, expressed early and late hepatic markers (α-fetoprotein, albumin, CK18, HNF4-α), and acquired hepatic functions (glycogen synthesis, xenobiotics detoxification), as also revealed by the shotgun proteomics approach. HLCs maintained the same pattern of immunomodulatory molecule expression and mesenchymal markers, other than displaying specific enzymes, suggesting these cells as promising candidates for cellular therapy of ESLD. Our work shed new light on the basic biology of HLCs, suggesting new therapeutic approaches to treat ESLD.

The role of immunity in insulin resistance in patients with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a prevalent disorder of the endocrine system with significant clinical implications, often leading to health complications related to adipose tissue accumulation, including obesity, insulin resistance (IR), metabolic syndrome, and type 2 diabetes mellitus. While the precise pathogenesis of PCOS remains unclear, it is now recognized that genetic, endocrine, and metabolic dysregulations all contribute significantly to its onset. The immunopathogenesis of PCOS has not been extensively explored, but there is growing speculation that immune system abnormalities may play a pivotal role. This chronic inflammatory state is exacerbated by factors such as obesity and hyperinsulinemia. Therefore, this review aims to elucidate the interplay between IR in PCOS patients, the controlled immune response orchestrated by immune cells and immunomodulatory molecules, and their interactions with adipocytes, hyperandrogenemia, chronic inflammation, and metabolic homeostasis.

Analysis of IL10 gene promoter haplotypes and changes in mRNA expression and soluble levels in patients with basal cell carcinoma.

Interleukin-10 (IL-10) is an immunomodulatory molecule that may play an immunosuppressive role in nonmelanoma skin cancer (NMSC), specifically basal cell carcinoma (BCC). We analyzed the role of IL10 promoter variants in genetic determinants of BCC susceptibility and their association with IL10 mRNA and IL-10 serum levels. Three promoter variants (-1082 A > G, -819T > C, and -592 A > C) were examined in 250 BCC patients and 250 reference group (RG) individuals. IL10 relative gene expression was evaluated in total leucocytes in peripheral blood, and IL-10 levels were quantified in serum. The allelic and genotypic frequencies did not show significant differences between the groups. However, haplotype analysis revealed that the ATA haplotype was associated with a decreased risk of BCC (OR: 0.73, 95% CI 0.56-0.95, p = 0.02), whereas the ATC and ACA haplotypes were associated with an increased risk for the neoplasia (OR: 4.15, 95% CI 1.56-11.04, p < 0.01, and OR: 3.51, 95% CI 1.33-9.29, p < 0.01, respectively). BCC patients showed a 0.09-fold reduction in IL10 mRNA expression compared to the RG. Significant differences were in IL-10 median serum levels between the RG and BCC patients (0.4 vs 0.64pg/mL, p = 0.02). Significant median serum differences were also observed between low- and high-grade histopathological BCC (0.34 vs 1.35pg/mL, p = 0.02). The ATA, ATC, and ACA haplotypes, and serum IL-10 levels, could be markers of susceptibility to BCC in Western Mexican individuals. BCC patients had higher serum IL-10 levels than the RG, with levels increasing with the severity of lesions, confirming the role of IL-10 in immunosuppression in neoplasia.

The impact of COVID-19 infection on thyroid function.

Extensive research on COVID-19 has revealed a notable link between the disease and thyroid disorders, highlighting complex interactions between thyroid hormones, immunomodulatory signaling molecules within the thyroid gland, and viral infections. This study evaluated the relationship between thyroid function and COVID-19 in Iraqi patients at Adiwaniyah Teaching Hospital. The cohort for this investigation comprised all patients who were admitted to the isolation center at the Teaching Hospital during the timeframe extending from January 2024 to June 2024. Each participant included in this research underwent comprehensive evaluations of their thyroid function, which is composed of the measurement of thyroid-stimulating hormone (TSH), total triiodothyronine (T3), and serum total thyroxine (T4) levels. Results showed that the serum T4 levels in all participants included in the study were observed to range from 20 to 182 (ng/dl), with the average concentration recorded at 87.26 ± 38.29 (ng/dl); no statistically significant disparity was noted in the mean serum T4 levels relative to the severity of the disease (p = 0.291). The serum TSH levels across all enrolled individuals spanned from 0.03 to 82 (mU/L), with a mean concentration of 5.55 ± 12.36 (mU/L); similarly, there was no statistically significant difference in the mean serum TSH levels when assessed against the disease severity (p = 0.926). According to the serum thyroid hormone concentrations, the cohort was stratified into 17 (24.6%) individuals classified as hypothyroid, 34 (49.3%) categorized as euthyroid, and 18 (26.1%) identified as hyperthyroid. Furthermore, no significant correlation was identified between the disease's severity and the participants' thyroid status (p = 0.556). In conclusion, patients with COVID-19 are liable to develop thyroid function abnormalities that may explain several of the long-term symptoms associated with the disease.

GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer.

Pancreatic cancer is one of the most aggressive cancers and poses significant challenges to current therapies because of its complex immunosuppressive tumor microenvironment (TME). Oncolytic viruses armed with immunoregulatory molecules are promising strategies to overcome limited efficacy and target inaccessible and metastatic tumors. In this study, we constructed a tumor-selective vaccinia virus (VV) with deletions of the TK and A49 genes (VVLΔTKΔA49, VVL-DD) using CRISPR-Cas9-based homologous recombination. VVL-DD exhibited significant tumor selectivity in vitro and anti-tumor potency in vivo in a murine pancreatic cancer model. Then, VVL-DD was armed with an optimal combination of immunomodulatory molecules, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-21 (IL-21), to produce VVL-GL21. VVL-GL21 induced significant tumor regression after intratumoral and systemic administration. Moreover, VVL-GL21 increased the infiltration of dendritic cells (DCs), macrophages, and T cells; induced DC maturation; increased the transition from M2 to M1 macrophages; improved the formation of immune memory; prevented tumor recurrence; and effectively bolstered the immune response against tumors in multiple key immune compartments. Interestingly, mice bearing-pancreatic cancer tumors treated with VVL-GL21 showed anti-tumor immunity against lung and colon cancer tumors. Importantly, treatment with VVL-GL21 enhanced the responsiveness of tumors to the immune checkpoint inhibitor anti-PD1. Taken together, VVL-GL21 remodels the suppressive TME and has powerful anti-tumor activities as monotherapy or in combination with anti-PD1 by intratumoral or systemic delivery for the treatment of pancreatic cancer. VVL-GL21 could be used as a therapeutic cancer vaccine.

Molecular and biological characterization of transforming growth factor-β homolog derived from Trichinella spiralis

The cytokine homologs, particularly transforming growth factor (TGF)-β, is a crucial immunomodulatory molecule and involved in growth and developmental processes in several helminths. In this study, the basic properties and functions of T. spiralis TGF-β homolog 2 (TsTGH2) were characterized using bioinformatics and molecular biology approaches. Bioinformatics analyses indicated that TsTGH2 belongs to the TGF-β subfamily. Recombinant TsTGH2 (rTsTGH2) expressed in Escherichia coli was used to produce a polyclonal antibody (pAb) in mice. Western blot and immunolocalization using pAb detected native TsTGH2 in crude worm antigens from muscle larvae and adults, showing it was mainly localized in the body wall muscles and the epithelia of the ovary and uterus. To assess the interplay between TsTGH2 and the human TGF-β signaling pathway, rTsTGH2 produced in a HEK293T cell was incubated with the SBE luciferase-HEK293 cell. The result indicated a significant increase in luciferase activity after treatment with rTsTGH2 compared to untreated control (p < 0.05). In conclusion, these findings are the first to characterize the basic properties and functions of TGF-β homologs in T. spiralis, demonstrating their interaction with the human TGF-β receptor. Further investigation is required to identify and optimize an appropriate expression system or conditions for TsTGH2. Additionally, studies are needed to clarify the specific role of native TsTGH2 in parasite development and host immunomodulation.

Cathelicidin antimicrobial peptide expression in neutrophils and neurons antagonistically modulates neuroinflammation.

Multiple sclerosis (MS) is an autoimmune disease that affects the central nervous system (CNS), the pathophysiology of which remains unclear and for which there is no definitive cure. Antimicrobial peptides (AMPs) are immunomodulatory molecules expressed in various tissues, including the CNS. Here, we investigated whether the cathelicidin-related AMP (CRAMP) modulated the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We showed that, at early stage, CNS-recruited neutrophils produced neutrophil extracellular traps (NETs) rich in CRAMP that was required for EAE initiation. NET-associated CRAMP stimulated IL-6 production by dendritic cells via the cGAS/STING pathway, thereby promoting encephalitogenic Th17 response. However, at a later disease stage, neurons also expressed CRAMP that reduced EAE severity. Camp knockdown in neurons led to disease exacerbation, while local injection of CRAMP1-39 at the peak of EAE promoted disease remission. In vitro, CRAMP1-39 regulated the activation of microglia and astrocytes through the formyl peptide receptor (FPR)2. Finally, administration of butyrate, a gut microbiota-derived metabolite, stimulated the expression of neural CRAMP via the free fatty acids receptors (FFAR)2/3, and prevented EAE. This study shows that CRAMP produced by different cell types have opposing effects on neuroinflammation, offering therapeutic opportunities for MS and other neuroinflammatory disorders.

Advancing osteosarcoma 3D modeling in vitro for novel tumor microenvironment-targeted therapies development

Osteosarcoma (OS) represents one of the most common primary bone cancers affecting children and young adults. The available treatments have remained unimproved for the past decades, hampered by the poor knowledge of OS etiology/pathophysiology and the lack of innovative, predictive and biologically relevant in vitro models, that can recapitulate the 3D OS tumor microenvironment (TME). Here, we report the development and characterization of an innovative 3D model of OS, composed of OS tumor cells, immune cells (macrophages) and mesenchymal stem cells (MSCs), that formed a multicellular tissue spheroid (MCTS). This fully humanized 3D model was shown to accurately mimic the native histological features of OS, while innately leading to the polarization of macrophages towards an M2-like phenotype, highly aggressive and pro-tumor profile. Upon the exposure to immunomodulatory molecules, the MCTS were shown to be responsive by shifting macrophages polarization, and dramatically altering the TME secretome. In agreement, when treated with immunomodulatory/stimulatory nanoparticles (NPSs), we were able to revert the TME secretome towards an anti-inflammatory profile. This study establishes an advanced 3D OS model capable of shedding light on macrophages and MSCs contributions to disease progression, paving the way for the development of innovative therapeutic approaches targeting the OS TME, while providing a biologically relevant in vitro tool for the efficacy screening of novel OS therapeutic approaches.

Multi-modal analysis reveals tumor and immune features distinguishing EBV-positive and EBV-negative post-transplant lymphoproliferative disorders.

The oncogenic Epstein-Barr virus (EBV) can drive tumorigenesis with disrupted host immunity, causing malignancies including post-transplant lymphoproliferative disorders (PTLDs). PTLD can also arise in the absence of EBV, but the biological differences underlying EBV(+) and EBV(-) B cell PTLD and the associated host-EBV-tumor interactions remain poorly understood. Here, we reveal the core differences between EBV(+) and EBV(-) PTLD, characterized by increased expression of genes related to immune processes or DNA interactions, respectively, and the augmented ability of EBV(+) PTLD B cells to modulate the tumor microenvironment through elaboration of monocyte-attracting cytokines/chemokines. We create a reference resource of proteins distinguishing EBV(+) B lymphoma cells from EBV(-) B lymphoma including the immunomodulatory molecules CD300a and CD24, respectively. Moreover, we show that CD300a is essential for maximal survival of EBV(+) PTLD B lymphoma cells. Our comprehensive multi-modal analyses uncover the biological underpinnings of PTLD and offer opportunities for precision therapies.

Immunological mechanisms involved in the protection against development of pulmonary tuberculosis in naturally infected goats

Tuberculosis (TB) is a notifiable zoonotic disease caused by bacteria of the Mycobacterium tuberculosis complex (MTBC) that affects a multitude of domestic and wild species. The main lesions caused by these mycobacteria are tuberculous granulomas, which determine the organism's immune response to the disease. Although TB pathogenesis in cattle has been extensively studied, information regarding its progression in other species of interest for the maintenance and transmission of TB such as goats remains limited. This study aimed to characterise the immune response developed in the lungs of goats naturally infected with mycobacteria of MTBC by assessing key cell populations and immunomodulatory molecules involved in defending against TB. Hence, twelve 6–12-month-old Guadarrama kid goats, initially TB-free, were selected and exposed to M. bovis through close contact with other infected goats. Only animals that tested positive by any of the TB diagnostic methods at the end of the experiment were included in the final analysis (n = 9). Gross and microscopic lesions compatible with TB (TBL) in different organs, as well as local response to TB in lungs were evaluated. Our results revealed that after five months of exposure, 44.4 % (4/9) of the M. bovis-infected animals exhibited TBL in the lungs (TBLL+), characterized by a predominance of non-cavitary necrotic granulomas. TBLL+ animals showed significantly higher presence of neutrophils, macrophages (MΦs) and lymphocytes along with greater expression of interferon (IFN)-γ. Conversely, the remaining animals did not present macroscopic or microscopic TBL in the lungs (TBLL-) (5/9). However, these goats displayed elevated expression of toll-like receptors (TLR)2 and TLR4 alongside heightened expression of pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and interleukin (IL)-10. These results suggest the potential development of an effective immune response that may suppress or delay of TBL in infected animals. Further research is needed to elucidate how these molecules, which are involved in the defence against MTBC, confer protection and modulate their expression during infection for TB control.

The danger theory of immunity revisited.

The danger theory of immunity, introduced by Polly Matzinger in 1994, posits that tissue stress, damage or infection has a decisive role in determining immune responses. Since then, a growing body of evidence has supported the idea that the capacity to elicit cognate immune responses (immunogenicity) relies on the combination of antigenicity (the ability to be recognized by T cell receptors or antibodies) and adjuvanticity (additional signals arising owing to tissue damage). Here, we discuss the molecular foundations of the danger theory while focusing on immunologically relevant damage-associated molecular patterns, microorganism-associated molecular patterns, andneuroendocrine stress-associated immunomodulatory molecules, as well as on their receptors. We critically evaluate patient-relevant evidence, examining how cancer cells and pathogenic viruses suppress damage-associated molecular patterns to evade immune recognition, how intestinal dysbiosis can reduce immunostimulatory microorganism-associated molecular patterns and compromise immune responses, and which hereditary immune defects support the validity of the danger theory. Furthermore, we incorporate the danger hypothesis into a close-to-fail-safe hierarchy of immunological tolerance mechanisms that also involve the clonal deletion and inactivation of immune cells.

Molecular mechanisms of obesity predisposes to atopic dermatitis.

Obesity is a prevalent metabolic disease that reduces bacterial diversity, colonizes the epidermis with lipophilic bacteria, and increases intestinal pro-inflammatory species, all of which lead to impaired epithelial barriers. Adipose tissue secretes immunomodulatory molecules, such as adipokines, leptin, and adiponectin, which alters the morphology of adipocytes and macrophages as well as modulates T cell differentiation and peripheral Th2-dominated immune responses. Atopic dermatitis (AD) and obesity have similar pathological manifestations, including inflammation as well as insulin and leptin resistance. This review examines the major mechanisms between obesity and AD, which focus on the effect on skin and gut microbiota, immune responses mediated by the toll like receptor (TLR) signaling pathway, and changes in cytokine levels (TNF-a, IL-6, IL-4, and IL13). Moreover, we describe the potential effects of adipokines on AD and finally mechanisms by which PPAR-γ suppresses and regulates type 2 immunity.

Pathophysiology of Medical Parasites: Mechanisms of Disease and Immune Evasion

Medical parasites are diverse organisms that can cause significant morbidity and mortality worldwide. Understanding the pathophysiology of these parasites is crucial for developing effective treatment and prevention strategies. This review explores the mechanisms through which medical parasites induce disease and evade host immune responses. Key parasitic pathogens, including protozoa, helminths, and ectoparasites, employ various strategies to establish infection and promote survival within the host. Mechanisms of tissue invasion, such as the secretion of proteolytic enzymes and the alteration of host cell signaling pathways, are critical for establishing parasitic niches. Additionally, many parasites possess sophisticated immune evasion tactics, such as antigenic variation, secretion of immunomodulatory molecules, and the ability to mimic host antigens. These adaptations allow parasites to persist in hostile environments and evade detection by the host immune system. The interplay between the parasite's pathogenic mechanisms and the host's immune response is complex, leading to a range of clinical manifestations, from mild to severe disease. Understanding these interactions not only sheds light on the biology of these organisms but also highlights potential targets for therapeutic intervention. This review aims to provide a comprehensive overview of the pathophysiological processes underlying parasitic infections and their implications for public health.

Interleukin-12 decorated nanosized semiflexible Immunofilaments enable directed targeting and augmented IFNγ responses of natural killer cells

Immunotherapies are a powerful strategy to treat cancer by modulating the immune system to raise an anti-tumor immune response. A prime example of immunotherapies are cytokines - small immunomodulatory molecules that are widely used to stimulate immune cells. Undirected administration of cytokines, however, can cause severe side effects, preventing the use of potent cytokines, such as Interleukin (IL)-12, which induces IFNγ responses by cytotoxic effector lymphocytes, including NK cells. Biomaterials, like nanoparticles, can encapsulate IL-12 and accumulate at the tumor site to alleviate side effects. Yet, the released IL-12 might not be directly targeted to extracellular IL-12 receptors on the specific effector cells, thereby potentially compromising the cytokine's therapeutic efficacy. Here, we develop a polymer-based platform to target NK cells, which we call immunofilaments. Immunofilaments are nanosized linear polymers that present an anti-CD16 antibody and IL-12 effectively to NK cells and lead to synergistic NK cell activation as highlighted by an increase in TNFα and IFNγ production and upregulation of multiple activation markers, including CD25, CD69, and degranulation marker CD107a. NK cell proliferation is enhanced in the presence of both anti-CD16 antibody and IL-12 compared to giving IL-12 separately. Finally, we demonstrate that the IF platform is suitable for in vivo applications, as immunofilaments readily activate human NK cells upon administration to mice. Statement of SignificanceIL-12 is a potent cytokine that stimulates IFNγ responses in NK cells, which supports an anti-tumor immune response. Due to its high potency, the delivery of IL-12 needs to be highly controlled to prevent severe adverse side effects, which can be achieved by using biomaterials. This study shows that nanosized polymers termed Immunofilaments can be used to immobilize IL-12 and effectively target and activate NK cells by co-conjugation of anti-CD16 antibodies. This work is a prime example of careful engineering of innovative biomaterials to improve immunotherapy.

Maternal separation alters peripheral immune responses associated with IFN-γ and OT in mice

The co-evolution of social behavior and the immune system plays a critical role in individuals' adaptation to their environment. However, also need for further research on the key molecules that co-regulate social behavior and immunity. This study focused on neonatal mice that were separated from their mothers for 4 hours per day between the 6th and 16th day after birth. The results showed that these mice had lower plasma levels of IFN-γ and oxytocin, but higher levels of plasma glucocorticoids (GC), then impacting their social abilities. Additionally, maternal separation led to decreased levels of BDNF, IGF2, and CREB mRNAs in the hippocampus, while levels in the prefrontal cortex (PFC) remained unaffected. Maternal separation also resulted in increased levels of oxytocin and CRH mRNA in the hypothalamus, as well as an increase in CD45+ lymphocyte subsets in the meninges and choroid plexus (CP), with CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP showing an increase. In IFN-γ-/- mice, a decrease in social preference was observed alongside lower plasma oxytocin levels. Moreover, IFN-γ-/- mice exhibited reduced numbers of oxytocin neurons in the paraventricular nucleus of the paraventricular nucleus of hypothalamus (PVN), decreased BDNF levels in the PFC and hippocampus, and alterations in CD45+ lymphocytes in CP and meninges, with an increase in CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP. These findings highlight the immunological impact of social stress on IFN-γ regulation, suggesting that the immunomodulatory molecule IFN-γ may influence social behavior by affecting synaptic efficiency in brain regions such as the hippocampus and PFC, which are linked to oxytocin in the PVN.

Lactic Acid Bacteria Surface Proteins in the Mechanisms of Cell Adhesion and Immunoregulation.

This study delves into the role of lactic acid bacteria (LAB) surface proteins in cell adhesion and immunoregulation. Using fluorescence microscopy, we observed distinct adhesion patterns on various cell types. LAB surface proteins demonstrated concentration-dependent inhibition of Salmonella adhesion, with LAB69 exhibiting potent antagonistic effects. Genetic expression analysis revealed nuanced responses in key genes (MD2, TLR4, IL-10, MUC3, MIF) across different cell types, highlighting the diverse immunomodulatory effects of LAB surface proteins. Modulation of pro-inflammatory (TNF-α) and anti-inflammatory (IL-10) cytokines further emphasized the complex interplay. In conclusion, this study underscores the pivotal role of LAB surface proteins in mediating cell adhesion and immunoregulation, providing a foundation for isolating specific immunomodulatory molecules within LAB surface proteins for potential applications in microbial ecological agents.

Gingival mesenchymal stem cells derived from patients with rheumatoid arthritis treat experimental arthritis

AbstractA therapeutic strategy using mesenchymal stem cells (MSCs) has been accepted as a novel therapy for treating rheumatoid arthritis (RA). Human gingiva‐derived MSCs (GMSCs) are superior in regulating immune responses. Autologous MSCs are the optimal candidate to avoid the potential risks of allogenic MSCs. However, whether autologous GMSCs from RA patients are therapeutic remains unknown. In this study, we compared the therapeutic efficacy of GMSCs derived from patients with RA (RA‐GMSCs) and that from health donors (H‐GMSCs) in vivo and in vitro. Then, we utilized RNA‐sequencing, the molecular and cellular assays to determine the immunomodulatory molecules that contribute to the therapeutic effect of RA‐GMSCs on both collagen‐induced arthritis (CIA) and humanized synovitis models. We demonstrated that GMSCs derived from patients with RA (RA‐GMSCs) and health donors (H‐GMSCs) shared a similar expression of immunomodulatory molecules. Moreover, RA‐GMSCs were as effective as H‐GMSCs in suppressing T‐cell proliferation, proinflammatory cytokines secretion, as well as osteoclast differentiation in vitro. In addition, RA‐GMSCs had a robust therapeutic effect on the CIA model. Importantly, RA GMSCs can survive for at least 24 days in a CIA mouse model and can be distributed in the spleen, lymph nodes, and joints. Specifically, RA‐GMSCs decreased the frequency of Th1 and Th17 cells whereas enhanced Treg cells, reducing the joint histopathological scores of lymphocytes, osteoclasts, and cartilages. Moreover, RA‐GMSCs were also effective in suppressing inflamed synoviocyte proliferation, migration, and invasion in vitro, and cartilage invasion in a humanized synovitis model in vivo. Our study implies that manipulation of RA‐GMSCs is therapeutic in CIA mice and humanized synovitis models and may have therapeutic potential in RA patients using autologous GMSCs in the future.

PROTECTION OF MICE AGAINST CECAL LIGATION AND PUNCTURE-INDUCED POLYMICROBIAL SEPSIS BY A FASCIOLA HEPATICA HELMINTH DEFENSE MOLECULE.

Sepsis results from a dysregulated host immune response to infection and is responsible for ~11 million deaths each year. In the laboratory, many aspects of sepsis can be replicated using a cecal ligation and puncture model, which is considered the most clinically relevant rodent model of sepsis. In the present study, histological and biomarker multiplex analyses revealed that the cecal ligation and puncture model initiated a large-scale inflammatory response in mice by 24 h, with evidence of acute organ damage by 48-72 h. While many typical proinflammatory cytokine/chemokines were systemically elevated, a specific array including IL-10, eotaxin, MIP-1α, MIP-1β, MCP-1, and RANTES noticeably increased just prior to animals reaching the humane endpoint. Treatment of mice with 10 μg of a synthetic 68-amino acid peptide derived from an immunomodulatory molecule secreted by a parasitic worm of humans and livestock, F. hepatica , termed F. hepatica helminth defense molecule, potently suppressed the systemic inflammatory profile, protected mice against acute kidney injury, and improved survival between 48 and 72 h after procedure. These results suggest that the anti-inflammatory parasite-derived F. hepatica helminth defense molecule peptide has potential as a biotherapeutic treatment for sepsis.