Immune Modulatory Effects Research Articles

Combining low-dose regorafenib with pembrolizumab for patients with MSI-H colorectal cancer: REGPEM-CRC-01.

TPS313 Background: Currently, pembrolizumab is one of the front-line therapies for patients with MSI-H CRC. However, approximately 40% of patients who received pembrolizumab experienced disease progression early in the course of disease (KEYNOTE 177). Therefore, there is still an unmet need to enhance the efficacy of checkpoint inhibitors in MSI-H CRC. MSI-H CRC has a higher level of expression of VEGF in blood compared to patients compared to its MSS counterpart (Hansen et al. Colorectal Dis. 2011). Consistently, exploratory analysis of CALBG-80405 and PARADIGM trial showed that patients with MSI-H CRC were more likely to benefit from anti-VEGF therapy than anti-EGFR therapy regardless of the side of the tumor. NSABP C-08 also suggested that anti-VEGF therapy may have biological activity even in as adjuvant therapy for patients with MSI-H colon cancer. Regorafenib is a potent VEGF inhibitor, with preclinical evidence showing its immune modulatory effect in the tumor microenvironment. In this trial, we hypothesize that adding low-dose regorafenib to pembrolizumab may induce synergistic activity beyond their independent clinical efficacy and create deep and durable responses for patients with MSI-H CRC. Methods: In the lead arm of this prospective randomized study, 22 patients will be enrolled through Hoosier Cancer Research Network (HCRN-GI23-643). Patients with treatment naïve MSI-H CRC will be enrolled in this front-line trial. One cycle of pembrolizumab and up to 3 cycles of chemotherapy prior to determination of MMR-D/MSI-H is allowed. Patients will receive regorafenib 60 mg daily in combination with pembrolizumab 200mg IV in cycle 1, followed by regorafenib 90mg in subsequent cycles to improve treatment tolerance. The primary outcome that will be measured is ORR, defined as the percentage of partial or complete response to the treatment within 12 months. ORR will be measured using RECIST 1.1. criteria. A formal one-sided hypothesis test will be conducted for futility, assuming that we will reject the null hypothesis of a target ORR only if we have strong evidence. In this study, we assume a null hypothesis that ORR is 0.60, which would reflect significant clinical improvement over the current standard of ORR = 0.43 from KEYNOTE 177. The alternative hypothesis is that ORR is less than 0.60. For the lead-in phase of the study, the emphasis is on controlling Type I error to be small, approximately 0.05. The test statistic will be the number of ORRs in the 22 patients, which we assume to follow a binomial distribution. Clinical trial information: NCT06006923 .

Role of probiotics in skin health: Current trends and future perspectives

The human skin is a complex ecosystem that plays a crucial role in maintaining overall health and well-being. In recent years, there has been a growing interest in the potential benefits of probiotics in promoting skin health. Probiotics are live microorganisms that confer health benefits when administered in adequate amounts. Probiotics have been shown to have a positive impact on the skin microbiome, promoting the growth of beneficial microorganisms and inhibiting the growth of pathogens. In addition to their effects on the skin microbiome, probiotics have also been shown to have anti-inflammatory, antioxidant, and immune-modulating effects, which may contribute to their beneficial effects on skin health. Their role in skin health is a relatively new area of research. This review aims to provide an overview of the current state of knowledge on the role of probiotics in skin health, including their potential benefits, mechanisms of action, and future perspectives.

Establishment of iPSC-Derived MSCs Expressing hsa-miR-4662a-5p for Enhanced Immune Modulation in Graft-Versus-Host Disease (GVHD).

The immune-modulatory effects of mesenchymal stromal cells (MSCs) are widely used to treat inflammatory disorders, with indoleamine 2,4-dioxygenase-1 (IDO-1) playing a pivotal role in suppressing stimulated T-cell proliferation. Taking that three-dimensional (3D) cultures enhance MSCs' anti-inflammatory properties compared with two-dimensional (2D) cultures, the differentially expressed miRNAs were examined. Thus, we identified hsa-miR-4662a-5p (miR-4662a) as a key inducer of IDO-1 via its suppression of bridging integrator-1 (BIN-1), a negative regulator of the IDO-1 gene. The IDO-1-inducing potential of miR-4662a was conserved across primary MSCs from various donors and sources but exhibited variability. Notably, iPSC-derived MSCs (iMSCs) demonstrated superior IDO-1 induction and immune-modulatory efficacy compared with their donor-matched primary MSCs. Accordingly, iMSCs expressing miR-4662a (4662a/iMSC) exhibited stronger suppressive effects on T-cell proliferation and more potent suppressive effects on graft-versus-host disease (GVHD), improving survival rates and reducing tissue damage in the liver and gut. Our results point to the therapeutic potential of standardized, off-the-shelf 4662a/iMSC as a robust immune-modulating cell therapy for GVHD.

Immune Modulation Effect of Administration of Rice Bran Extract with Increased Solubility Fermented by Lentinus edodes UBC-V88 in Cyclophosphamide-Treated Mice Model

Immune Modulation Effect of Administration of Rice Bran Extract with Increased Solubility Fermented by Lentinus edodes UBC-V88 in Cyclophosphamide-Treated Mice Model

Extracellular vesicles from adipose-derived stem cell alleviate diabetic cardiomyopathy by regulating Chit1/NLRP3/Caspase-1-Mediated pyroptosis.

It is well-established that chronic hyperglycemia progressively destroys the heart structure, weakening function and leading to diabetic cardiomyopathy (DCM). Extracellular vesicles derived from adipose-derived stem cell (ADSC-EVs) have been reported to have anti-inflammatory and immune-modulating effects, but their role in DCM is still poorly understood. Therefore, this study investigated the impact of ADSC-EVs on DCM and potential mechanisms. ADSC-EVs were isolated from the conditioned media of ADSCs. DCM rat models were established using streptozotocin (STZ) in vivo, and high glucose (HG) stimulated H9c2 cardiomyocytes to establish in vitro model. Then mRNA sequencing identified Chit1 as a key gene. Both in vivo and in vitro experiments demonstrated that chitinase 1 (Chit1) and NLRP3/Caspase-1-mediated pyroptosis levels were significantly upregulated in myocardial tissue of rat diabetic cardiomyopathy and hyperglycemic cardiomyocytes, which was reversed by ADSC-EVs treatment. We next observed that in hyperglycemic cardiomyocytes, downregulating Chit1 also resulted in a decrease in NLRP3/Caspase-1-mediated pyroptosis proteins. To a certain extent, the inhibitory effect of ADSC-EVs on the NLRP3/Caspase-1 signaling pathway was reversed by Chit1 overexpression. Taken together, we identified a novel mechanism by which ADSC-EVs regulate NLRP3/Caspase-1-mediated pyroptosis through Chit1 to alleviate diabetic cardiomyopathy, offering an innovative strategy for DCM treatment.

Dendritic cell activation by iron oxide nanoparticles depends on the extracellular environment.

Nanoparticles can exert immune modulating effects in a host depending on composition, mode of administration, and type of disease. Although the specific mechanisms of nanoparticle-induced immune responses remain unclear, their uptake by macrophages and other phagocytic innate immune cells is considered to be a key event. Our objective here was to ascertain if nanoparticle-mediated activation of dendritic cells (DCs) occurs in vitro or in vivo when exposed to hydroxyethyl starch-coated iron oxide nanoparticles. For the present studies, our choice of nanoparticles, animal model, and experimental design is motivated by our previously published observations that systemic exposure can induce antitumor adaptive immune responses in mouse models of metastatic breast cancer. Here, we began by assessing the potential toxicity of systemic exposure to commercially available starch-coated Bionized Nanoferrite® nanoparticles (BP) by measuring body weight, complete blood count, and enzyme parameters in healthy FVB/NJ mice after repeated BP dosing. We observed no evidence of toxicity at doses up to 25 mg Fe per mouse, five-fold higher than those used in subsequent in vivo experiments. We then measured the expression of surface maturation markers (CD86, MHC II) in DCs incubated with BP in vitro. Although DCs cultured with BP revealed high levels of nanoparticle uptake, neither JAWSII dendritic cells nor bone marrow derived dendritic cells (BMDCs) showed significant changes in marker expression to indicate stimulation of maturation and effector function. To assess whether BP interactions in vivo produced different effects, we analyzed CD80, CD86, and MHC II expression of DCs recovered from the livers, spleens, bone marrows, and lymph nodes of mice injected once with BP (5 mg Fe). Interestingly, only DCs in spleens and bone marrow cells responded to BP exposure. DCs recovered from other organs showed no evidence of increased activation. These findings highlight complex interactions between living systems and nanoparticles, and their potential to mediate context-specific and selective activation of innate immune cells. Our study also emphasizes that results obtained from in vitro experiments must be interpreted with caution, as they may not faithfully represent responses in living systems.

Multi-omic Biomarkers Distinguish Rheumatoid Arthritis in Discordant Monozygotic Twins.

Although genetic factors have been identified in the pathogenesis of rheumatoid arthritis (RA), the concordance rate in monozygotic (MZ) twins is low, suggesting that other features contribute to disease development. Further, the relative contribution of such non-genetic elements in identical twins have not been characterized. Here, we aimed to measure differentiating host and microbial biomarkers of RA by studying MZ twins discordant for disease using a multi-omics approach. Eight pairs of MZ twins discordant for RA (n=16) were enrolled. Gut microbiome was assessed using shotgun metagenomic sequencing. Autoantibodies, cytokines, and other plasma proteins were measured in both plasma and feces. Levels of short and medium-chain fatty acids from serum and feces were quantified using gas chromatography mass spectrometry (GC-MS). While overall microbiome diversity and composition did not significantly differ between twins, we observed a decrease in Blautia faecis in affected twins. Affected twins had higher concentrations of both fecal and plasma citrullinated and non-citrullinated autoantibodies, as well as significantly lower concentrations of fecal butyrate and propionate. Multi-omics biomarkers differentiate MZ twins discordant for RA. Blautia faecis , which is associated with reduced inflammatory cytokine expression, was decreased in RA twins. Similarly, short-chain fatty acids, known to have immune modulatory effects, were decreased in affected twins, suggesting further bi-directional interactions between inflammation at the gut barrier and disease state. If confirmed in other cohorts, exhaustive multi-omics approaches may improve our understanding of RA pathogenesis and potentially contribute to novel diagnostics and co-adjuvant therapies.

Bacteroides fragilis capsular polysaccharide A ameliorates ulcerative colitis in rat by recovering intestinal barrier integrity and restoring gut microbiota.

Bacteroides fragilis (B. fragilis) is a Gram-negative, obligate anaerobic, commensal bacterium residing in the human gut and holds therapeutic potential for ulcerative colitis (UC). Previous studies have indicated that capsular polysaccharide A (PSA) of B. fragilis is a crucial component for its effectiveness, possessing various biological activities such as anti-inflammatory, anti-tumor, and immune-modulating effects. We previously isolated and characterized the B. fragilis strain ZY-312 from the feces of a healthy breastfed infant, and extracted its PSA, named TP2. In this study, we explored the impact of TP2 on colonic inflammation and delved into its potential mechanisms. Initially, we used 2,4,6-trinitrobenzenesulfonic acid (TNBS) to induce colitis in rats and found that TP2 treatment significantly ameliorated TNBS-induced weight loss, increased clinical scores, extensive ulcers, and intestinal epithelial damage in UC rats. Further analysis revealed that TP2 effectively restored the intestinal barrier integrity in UC rats by regulating the expression of Muc-2, tight junction proteins (ZO-1, occludin, claudin-1, and claudin-2), as well as apoptosis-related proteins Bcl-2, BAX, and Cleaved-Caspase-3. Additionally, TP2 suppressed the expression of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL23, while promoting the secretion of anti-inflammatory cytokines IL-10 and IL-22, thereby inhibiting the occurrence of inflammation. TP2 also downregulated the phosphorylation levels of AKT and PI3K, effectively inhibiting the abnormal activation of the PI3K/AKT signaling pathway. More interestingly, 16S rRNA sequencing results showed that TP2 restored the ecological imbalance of the rat intestinal microbiota, with an increase in beneficial bacteria such as Lactobacillus and Limosilactobacillus observed in the treatment group. In conclusion, TP2 through the regulation of intestinal barrier-related cells and proteins, inhibition of apoptosis, modulation of inflammation-related cytokine levels, and control of abnormal activation of the PI3K/AKT signaling pathway, restores intestinal barrier integrity. Additionally, by reshaping the ecological imbalance of the gut microbiota, TP2 ultimately alleviates ulcerative colitis in rats.

In Vivo Induction of Leukemia-Specific Adaptive and Innate Immune Cells by Treatment of AML-Diseased Rats and Therapy-Refractory AML Patients with Blast Modulating Response Modifiers.

There is a high medical need to develop new strategies for the treatment of patients with acute myeloid leukemia (AML) refractory to conventional therapy. In vitro, the combinations of the blast-modulatory response modifiers GM-CSF + Prostaglandin E1, (summarized as Kit M) have been shown to convert myeloid leukemic blasts into antigen-presenting dendritic cells of leukemic origin (DCleu) that were able to (re-)activate the innate and adaptive immune system, direct it specifically against leukemic blasts, and induce memory cells. This study aimed to investigate the immune modulatory capacity and antileukemic efficacy of Kit M in vivo. Brown Norway rats suffering from AML were treated with Kit M (twofold application). Blasts and immune cells were monitored in peripheral blood (PB) and spleen. Upon the observation of promising immune modulatory effects in the treated animals, two patients with AML refractory to multiple lines of therapy were offered treatment with Kit M on an individualized basis. Safety, as well as immunological and clinical effects, were monitored. Samples obtained from a third patient in similar clinical conditions not receiving Kit M were used as controls for immune monitoring tests. Animal experiments: Drugs were well tolerated by the treated animals. After 9 days of treatment, DCleu and memory-like T cells increased in the peripheral blood, whereas regulatory T cells, especially blasts, decreased in treated as compared to untreated control animals. Clinical courses: No severe side effects were observed. In patient 1482, PB blasts remained under the detection threshold during 27 days of treatment, thrombocytes were normalized, and (leukemia specific) immune effector cells of the adaptive and innate immune system increased up to 800-fold compared to the start of treatment. Patient 1601 responded with a 12% reduction in blasts in PB immediately after Kit M treatment. Several subtypes of (leukemia-specific) immune effector cells in PB increased up to four-fold during the 19 days of treatment. In contrast, immune-reactive cells decreased under mild chemotherapy in the PB of control patient 1511 with comparably refractory AML. Within the limitation of low numbers in both animal experiments and clinical applications, our data suggest that Kit M treatment of AML-diseased rats and patients is feasible and may induce leukemia-specific immune reactions and clinical improvement. A larger series and a prospective clinical trial will be required to confirm our observations. Beyond optimized doses and schedules of the applied compounds, the combination with other antileukemic strategies or the application of Kit M in less proliferative stages of the myeloid diseases need to be discussed. If effects are confirmed, the concept may add to the armamentarium of treatments for highly aggressive blood cancer.

Amygdalin alleviates psoriasis-like lesions by improving skin barrier function.

Psoriasis is a chronic, relapsing, inflammatory skin disease that is caused by the immune system. Amygdalin possesses immune-modulating and anti-inflammatory effects. To explore the possible effects of amygdalin on psoriasis and its pathogenesis of action, we examined the effects of amygdalin on imiquimod-induced psoriasis, tape-stripping-induced skin barrier disruption, and investigated the potential mechanism of action in vitro. The fact that amygdalin could reduce the thickness of the epidermis and inflammatory cell infiltration in two animal models inhibited the production of IL-1β, IL-6, and TNF-a, and the expression of filaggrin, involucrin, and keratin10 was increased. Also, in IL-17A and TNF-α induced HaCaT, amygdalin inhibits the expression of IL-6, IL-1β, and TNF-a, promoting the expression of skin barrier recovery-related proteins flaggrin, involucrin, and keratin10. Combined in vivo and in vitro experiments suggest that amygdalin modulates inflammation and the skin barrier in psoriasis. The same study also conducted a preliminary mechanistic exploration and found that amygdalin inhibited the phosphorylation of the p38MAPK signaling pathway. In conclusion, Amygdalin can alleviate psoriasis lesions and improve skin barrier impairment, and the research provides an experimental basis for its future development as a drug candidate for psoriasis therapy.

Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. Traditional Japanese herbal medicine (Kampo), such as Juzentaihoto (a standardized combination of 10 herbal extracts), has shown immune modulatory effects, modulation of microcirculation, and amelioration of fatigue. It is administered to patients to prevent deterioration of cachexia and counteract side effects of chemotherapy. The effect of Juzentaihoto with or without standard chemotherapy (Gemcitabine) on survival and tumor microenvironment was studied in an immunocompetent pancreatic cancer mouse model. Following tumor development ±12 days after orthotopic implantation of murine pancreatic cancer cells (KPC) into the pancreas of C57BL/6 mice, the mice were treated with Gemcitabine, Juzentaihoto, their combination (Gem/Juz) or NaCl (Ctr.). Combination treatment significantly prolonged survival (+38%) of tumor bearing mice, compared to controls as well as Gemcitabine or Juzentaihoto monotherapy. Macrophage (CD68+) infiltration in pancreatic tumors was significantly enhanced in Gem/Juz - treated animals, compared with controls (p < 0,001), with significant increases of both, macrophages (CD68+) and for lymphocytes (CD45+), especially at the tumor front. In vitro, Juz- or Gem/Juz-treated KPC tumor cells secreted significantly more macrophage-chemoattractant cytokines, e.g., CCL2, CCL20, and CXCL2, whilst Juz- and Gem/Juz-treated macrophages (MH-S) secreted cytokines of the M1 phenotype, e.g., IL6, TNF-α, and IL12. It has been shown that tumor cells recruit and polarize macrophages towards tumor-associated macrophages (TAM). Our results indicate a change in macrophage polarization which not only induced anti-tumor immune-cell activity and cytokine release, but also suggests amelioration of Gemcitabine efficacy as DNA-analogue and as partial antitumor antigen. We propose that the increased survival of tumor bearing mice after Gem/Juz combination treatment is due to the restored cytotoxicity of Gemcitabine and changes in the tumor-microenvironment - induced by Juzentaihoto - such as an increased number of M1 macrophages.

SARS-CoV-2 Spike Protein Amplifies the Immunogenicity of Healthy Renal Epithelium in the Presence of Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the most common form of kidney cancer, known for its immune evasion and resistance to chemotherapy. Evidence indicates that the SARS-CoV-2 virus may worsen outcomes for RCC patients, as well as patients with diminished renal function. Evidence suggests that the SARS-CoV-2 virus may exacerbate outcomes in RCC patients and those with impaired renal function. This study explored the unidirectional effects of RCC cells and the SARS-CoV-2 spike protein (S protein) on human renal proximal tubule epithelial cells (RPTECs) using a microphysiological approach. We co-cultured RCC cells (Caki-1) with RPTEC and exposed them to the SARS-CoV-2 S protein under dynamic 3D conditions. The impact on metabolic activity, gene expression, immune secretions, and S protein internalization was evaluated. The SARS-CoV-2 S protein was internalized by RPTEC but poorly interacted with RCC cells. RPTECs exposed to RCC cells and the S protein exhibited upregulated expression of genes involved in immunogenic pathways, particularly those related to antigen processing and presentation via the major histocompatibility complex I (MHCI). Additionally, increased TNF-α secretion suggested a pro-inflammatory response. Metabolic shifts toward glycolysis were observed in RCC co-culture, while the presence of the S protein led to minor changes. The presence of RCC cells amplified the immune-modulatory effects of the SARS-CoV-2 S protein on the renal epithelium, potentially exacerbating renal inflammation and fostering tumor-supportive conditions. These findings suggest that COVID-19 infections can impact renal function in the presence of kidney cancer.

NK cells-derived extracellular vesicles potency in the B cell lymphoma biotherapy.

Extracellular vesicles of Natural Killer cells (NKEV) exert an antitumor effect towards hematopoietic and solid tumors and have an immune modulating effect, suggesting a promising role in immune and biotherapy. In this study, a continuation of our former works, we demonstrated a network by mass spectrometry analysis between NKEV protein cargo and antitumor effects. Human healthy NKEV, both exosomes and microvesicles, have a significant and direct cytotoxic effect against human B cell lymphoma in in vitro and in vivo conditions. We isolated extracellular vesicles from in vitro amplified healthy human NK cells and their treatment efficacy was monitored by cytometry analyses, in vivo MRI/MRS measurements, ex vivo MRS analyses and immunohistochemistry. We observed a remarkable NKEV cytotoxic effect, mainly by apoptosis, on B cell lymphoma in vitro when exosomes and microvesicles were administered simultaneously. In vivo results showed metabolic alterations in SCID mice xenografts after NKEV treatment, associated with a significant reduction of tumor growth (64%). In the in vivo 1H MR spectra we found a significant increase in the tumor lipid/lactate and in taurine signals, both considered as apotosis markers. Ex vivo lymphoma metabolomics revealed a significant increase in fatty acid (FA) pool and decrease in unsaturated and mono-unsaturated FA in treated groups, as compared to control one, thus suggesting an alteration of tumor homeostasis. Immunohistochemistry analyses confirmed the reduction of B-cell lymphoma proliferation rate, as well as the induction of apoptosis following the NKEV treatment. This study underscore the importance of NKEV as a novel biological acellular tool for B-cell lymphoma treatment, probably having a greater effect on combined treatment regimens. These nanovesicles have an extraordinary potential in innovative cancer immunotherapy, representing a safe and efficient tool naturally circulating in healthy individuals and ready to maintain the immune homeostasis, and therefore a good organism healthy state.

In vitro investigation of monoglycerides and zinc glycinate: anti-inflammatory and epithelial barrier function.

The objectives of this study were to investigate the in vitro immune-modulatory effects of monoglycerides and zinc glycinate with porcine alveolar macrophages (PAM) and their impact on epithelial barrier integrity using the intestinal porcine enterocyte cell line (IPEC-J2). Cell viability was assessed using a Vybrant MTT assay to determine the appropriate dose range of monoglyceride blend (C4, C8, and C10) and zinc glycinate. In experiment 1, IPEC-J2 cells (5 × 105 cells/mL) were seeded and treated with each compound (monoglycerides: 0, 25, 100, 250, 500, and 1,000 µg/mL; zinc glycinate: 0, 2, 5, 12.5, 25, and 50 µg/mL). Transepithelial electrical resistance (TEER) was measured by Ohm's law method at 0h (before treatment) and at 24, 48, and 72h posttreatment. In experiment 2, PAM were collected from 6 clinically healthy piglets (7wk of age) and seeded at 106 cells/mL. After incubation, the cells were treated with each compound and/or lipopolysaccharide (LPS). The experimental design was a 2 × 6 factorial arrangement with 2 doses of LPS (0 or 1 μg/mL) and 6 doses of each compound (monoglycerides: 0, 50, 100, 250, 500, and 1,000 µg/mL; zinc glycinate: 0, 25, 50, 100, 250, and 500 µg/mL). Cell supernatants were collected to analyze the concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) by enzyme-linked immunosorbent assay kits. Data were analyzed by ANOVA using PROC MIXED of SAS with a randomized complete block design. IPEC-J2 cells treated with 250 or 1,000 μg/mL of monoglycerides, or 5 μg/mL of zinc glycinate had increased (P < 0.05) TEER values at 48 or 72h posttreatment, compared with control. The LPS challenge increased (P < 0.05) the production of TNF-α and IL-1β from PAM. In the non-challenge group, 50 or 100 μg/mL of monoglycerides stimulated (P < 0.05) TNF-α and IL-1β production from PAMs. Treatment with 25 or 100 μg/mL of zinc glycinate also enhanced (P < 0.05) TNF-α production from PAM. In LPS-treated PAM, 1,000 μg/mL of monoglycerides increased (P < 0.05) IL-1β production, while zinc glycinate suppressed (P < 0.0001) the secretion of TNF-α and IL-1β at the doses of 100, 250, and 500 μg/mL. In conclusion, the results of this in vitro study indicate that monoglycerides positively affect the barrier function of the epithelium, while zinc glycinate may have strong immune regulatory benefits. Future animal studies will be required to verify their impacts on animal gut health, systemic immunity, and growth performance.

Effects of probiotics on clinical manifestations and inflammatory markers in HTLV-1-associated myelopathy/tropical spastic paraparesis: A triple blind randomized, placebo controlled trial

Human T-lymphotropic virus type 1 (HTLV-1), leads to adult T-cell lymphoma/leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of infected individuals. The virus promotes inflammation, a major factor in chronic disease progression. Probiotics' immune modulation and anti-inflammatory effects present a potential therapeutic intervention for HTLV-1-related conditions. This study investigates the impact of probiotics on both clinical manifestations and inflammatory markers in HAM/TSP patients.Conducted at the HTLV-1 clinic of Ghaem Hospital (Mashhad, Iran) between 2019 and 2020, this study randomized 40 HAM/TSP patients into two groups: an intervention group receiving 500 mg LactoCare capsules twice daily and a control group receiving placebo capsules of identical appearance for 12 weeks. Baseline and follow-up assessments included muscle strength, spasticity, motor disability, urinary disturbance, and serum levels of IL-10, IL-4, and IFN-γ (measured by ELISA). Post-intervention analysis revealed no significant differences between intervention and control groups in muscle strength, spasticity, and motor disability. However, significant improvement was observed in the intervention group regarding urinary symptoms after 12 weeks of initiation of intervention (P = 0.003). No significant changes were detected in serum levels of IL-10, IL-4, and IFN-γ between the two groups. The probiotics showed positive effects on urinary symptoms in HTLV-1-associated myelopathy/tropical spastic paraparesis patients but did not significantly impact other clinical or paraclinical parameters within the 12-week study period. These findings suggest that probiotics may offer symptomatic relief for some symptoms of HTLV-1-associated myelopathy/tropical spastic paraparesis patients.

The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment.

Regulatory T (Treg) cells play key roles in cancer immunity by suppressing a range of antitumor immune responses and contributing to resistance to programmed death (PD)-1 blockade therapy. Given their critical roles in self-tolerance, local control of immunosuppression by Treg cells, such as in the tumor microenvironment (TME), has been intensively studied. Inhibition of heat shock protein 90 (HSP90), a chaperone with vital roles in regulating proteostasis in cancer cells, impedes cancer progression by interrupting oncogenic signaling pathways and potentially modulating antitumor immunity, but we have very little mechanistic insight into these immune modulatory effects. Here, we show that the number of Treg cells are selectively reduced by the HSP90 inhibitor pimitespib in animal models and patients with gastric cancer in a clinical trial (EPOC1704). Pimitespib reduced the highly immunosuppressive human FOXP3high effector Treg cells by inhibiting their proliferation and decreasing their expression of effector molecules, which improved the priming and activation of antigen-specific CD8+ T cells. Mechanistic studies revealed that pimitespib selectively degraded STAT5, a key transducer of the IL-2 signaling pathway, which is essential for Treg cell development and maintenance, and consequently compromised FOXP3 expression, leading to selective impairment of immunosuppression in the TME by Treg cells. Thus, pimitespib treatment combined with PD-1 blockade exhibited a far stronger antitumor effect than either treatment alone in animal models. Through these data, we propose that HSP90 inhibition is a promising therapeutic option for Treg cell-targeted cancer immunotherapy.

The Opportunities and Challenges of Mesenchymal Stem Cells-Derived Exosomes in Theranostics and Regenerative Medicine.

Cell-secreted nanovesicles of endosomal origin, called exosomes, are vital for mediating intracellular communication. As local or distal transporters of intracellular cargo, they reflect the unique characteristics of secretory cells and establish cell-specific interactions via characteristic surface proteins and receptors. With the advent of rapid isolation, purification, and identification techniques, exosomes have become an attractive choice for disease diagnosis (exosomal content as biomarkers), cell-free therapy, and tissue regeneration. Mesenchymal stem cell (MSC)-derived exosomes (MSC-exosomes) display angiogenic, immune-modulatory, and other therapeutic effects crucial for cytoprotection, ischemic wound repair, myocardial regeneration, etc. The primary focus of this review is to highlight the widespread application of MSC-exosomes in therapeutics, theranostics, and tissue regeneration. After a brief introduction of exosome properties, biogenesis, isolation, and functions, recent studies on therapeutic and regenerative applications of MSC-exosomes are described, focusing on bone, cartilage, periodontal, cardiovascular, skin, and nerve regeneration. Finally, the review highlights the theranostic potential of exosomes followed by challenges, summary, and outlook.

Small intestinal derived Prevotella histicola simulates biologic as a therapeutic agent

A role of gut microbiome in pathogenesis as well as response to treatment is documented in rheumatoid arthritis. Using a novel duodenal derived Prevotella histicola strain MCI 001, we have shown that it suppresses disease progression in a collagen-induced arthritis (CIA), a model for rheumatoid arthritis (RA) using humanized mice expressing HLA-DQ8 gene in the absence of endogenous class II genes. Here we compared efficacy of P. histicola MCI 001 with tumor necrosis factor inhibitor (TNFi) for treating arthritis. DQ8 arthritic mice treated with P. histicola by oral gavage or TNFi, were compared for disease onset, incidence and severity. We demonstrate that oral treatment with P. histicola mimics treatment with TNFi in arthritic DQ8 mice. A pangenome comparison of our P. histicola MCI 001 with its closest available neighbors depicted it as a novel strain with unique gene sequences that may contribute to immune modulatory effects. Notably, it possesses a unique sequence of an outer membrane protein, BtuB, which is involved in vitamin B12 transport. Our data indicate that P. histicola MC001 is an attractive candidate to prevent the progression of disease in RA patients with ongoing disease.

Cigarette smoke-induced disordered microbiota aggravates the severity of influenza A virus infection.

Cigarette smoke (CS) promotes the development of chronic pulmonary disease and has been associated with increased risk for influenza-related illness. Here, we directly addressed the impact of CS disordered microbiota on the severity of influenza A virus (IAV) infection. Specific and opportunistic pathogen-free (SOPF) C57BL/6J mice were exposed to CS or room air (RA) for 5.5 months. Each exposed mouse was then cohoused with a group of recipient germ-free (GF) mice for 1 month for microbial transfer. Colonized GF mice were then infected intranasally with IAV and disease development was monitored. Upper and lower airway and fecal microbiota were longitudinally investigated by 16S rRNA gene sequencing and bacterial cultures in donor and recipient mice. The bacterial family Streptococcaceae accounted for the largest difference between CS- and RA-exposed microbiota in the oropharynx. Analysis of the oropharynx and fecal microbiota indicated an efficient transfer to coprophagic recipient mice, which replicated the differences in microbiota composition observed in donor mice. Subsequent IAV infection revealed significantly higher weight loss for CS microbiota recipient mice at 8-10 days post infection (dpi) compared to control recipient mice. In addition, H1N1 infection inflicted substantial changes in the microbiota composition, especially at days 4 and 8 after infection. In conclusion, mice with a CS-associated microbiota suffer from higher disease severity upon IAV infection compared to mice colonized with a normal SOPF microbiota. Our data suggest that independently of CS exposure and concomitant structural lung damage, microbial distortion due to CS exposure may impact the severity of IAV disease course.IMPORTANCEIt has been reported that chronic exposure to CS is associated with a disordered microbiota composition. In this study, we colonized germ-free (GF) mice with the microbiota from SOPF mice which were chronically exposed to CS or RA. This allowed disentangling the effect of the disordered microbiota from the immune-modulating effects of actual CS exposure. We observed a successful transfer of the microbiotas after cohousing including specific microbiota differences induced by CS exposure in formerly GF mice, which were never exposed to CS. We then investigated the effects of IAV infection on the disease course and microbiotas of formerly GF mice. We found that mice with CS-associated microbiota reveal worse disease course compared to the control group. We hypothesize that CS-induced disordering of the microbiota may, indeed, impact the severity of influenza A disease.

Cholecystokinin and gastrin as immune modulating hormones: Implications and applications

Cholecystokinin (CCK) and gastrin are gastrointestinal hormones traditionally recognised for their roles in digestion. However, it has been recognised that these hormones may also modulate immune function. Here, we examine the immune-modulating effects of CCK and gastrin, and explore the functional significance of this dual role. In addition to the direct effect of these hormones on immune cell function, we discuss why hormones that regulate complex physiological and behavioural aspects of digestion might also influence immune responses. Notably, recent findings highlight the importance of these hormones in promoting a tolerogenic hepatic environment, particularly as the liver encounters gut-derived inflammogens following a meal. Additionally, the neuro-immune crosstalk mediated by CCK suggests that this hormone may influence immune responses indirectly via the gut-brain axis, especially in the context of infection or inflammation. Furthermore, the role of CCK in inducing feeding cessation and satiety appears to be repurposed during sickness behaviour, such as the loss of appetite during infection. Collectively, these observations suggest that nutritional strategies, including permissive underfeeding or fasting, could have important clinical implications. A deeper understanding of the dual roles of CCK and gastrin in digestion and immunity may pave the way for novel therapeutic approaches that leverage these pathways for improved disease management and treatment outcomes.