bluuebunny/crossref_metadata_2025_split huggingface dataset:
STAT5-regulated autocrine IL-6 signaling dictates IL-10-dependent regulatory functions of neonatal B10 cells
Authors: Sakai Jiro , Akkoyunlu Mustafa 
Published: August 2023

Abstract
Neonates have suboptimal immune responses to immunization, resulting in higher susceptibility to microbial infection. B cells have a central role in humoral immunity to immunization, and antigen recognition by BCRs is essential for the activation and differentiation of B cells. Neonatal B cells, however, do not respond to BCR activation as robustly as adult cells do. Our hypothesis is that unique features of neonatal BCR signaling may contribute to suboptimal humoral responses. The aim of this project is to decipher the neonatal BCR signaling pathways and identify those that may be responsible for suboptimal B cell functions.
Purified adult and neonatal B cells were stimulated with anti-IgM. RNA-seq analysis revealed that STAT3 and STAT5 signaling pathways were activated in neonatal B cells. STAT3 and STAT5 were phosphorylated in neonatal B cells. BCR-mediated STAT5 phosphorylation induces IL-6 production, which in turn activates STAT3 in an autocrine/paracrine manner. Moreover, IL-6-induced STAT3 activation led to the production of anti-inflammatory cytokine IL-10. Further underscoring the role of IL-6 in IL-10 production, neonatal B cells from IL-6-KO mice did not secrete IL-10. To assess whether the autocrine IL-6 is essential for IL-10-dependent immunosuppression, we incubated peritoneal macrophages with conditioned medium (CM) from adult, wild-type neonatal, or IL-6-KO neonatal B cells. We found that CM from wild-type neonatal B cells suppressed TNF-α production by macrophages in an IL-10-dependent manner, whereas CM from IL-6-KO neonatal B cells or adult B cells did not.
Our studies unveiled the essential role for STAT5-induced autocrine IL-6 signaling in IL-10-mediated immunosuppressive functions of neonatal B cells.
Identification of Neutralizing Anti-HMGB1 IgM Autoantibody and Its B Cell Producers
Authors: Vattikota Anirudh , Geng Yajun , Palani Sunil , Singh Nehal , Chen Aoshuang 
Published: August 2023

Abstract
Extracellular High Mobility Group Box 1 (HMGB1) is a prototypic damage-associated molecular pattern (DAMP). While a homeostatic level of extracellular HMGB1 may be beneficial for immune defense, tissue repair and tissue regeneration, excessive HMGB1 is linked to chronic inflammation and inflammatory diseases. This prompts an intriguing question: How does a healthy body control the level of extracellular HMGB1? Here we have identified, in the plasma of both healthy humans and healthy mice, an anti-HMGB1 IgM autoantibody that neutralizes extracellular HMGB1 via binding specifically to a 100% conserved epitope, namely HMW4 (HMGB1 98–112). In mice, this anti-HMGB1 IgM (i.e., anti-HMW4 IgM) is produced by peritoneal B-1 cells, and concomitant triggering of their B cell receptor and toll-like receptor 4 by extracellular HMGB1 stimulates the production of anti-HMW4 IgM. The ability of extracellular HMGB1 to induce its own neutralizing antibody suggests a feedback loop limiting the level of this DAMP in a healthy body. Currently, our studies are ongoing to identify and characterize the human counterpart B cells that produce the anti-HMGB1 IgM, by first amplifying HMW4-reactive B cells from human peripheral blood mononuclear cells (PBMCs) in NSG recipient mice, in the presence of B cell-stimulating adjuvants (such as B cell mitogens). These studies serve as the prelude to exploring human anti-HMGB1 IgM down the road for treating patients with inflammatory diseases and provide insight pertaining to the role and regulation of other DAMP molecules.
Tissue Microenvironment Reprograms the Circulating Memory T Cell Differentiation and Enhances Vaccine-Elicited Anti-Metastasis Immunity
Authors: Xu Haoran 
Published: August 2023

Abstract
During tumor ontogeny and viral infection, heterologous subsets of CD8+ T lymphocytes provide immediate clearance and durable protection. We utilized model antigen (HIV-1-Gag) expressing melanoma cell line and parabiosis model to investigate the role of different components of memory T cells, including circulating memory T cells (Tcirm) and tissue-resident memory T cells (TRM), in melanoma lung metastasis protection. We first proved that TRM generated by DNA vaccine intramuscular prime followed by influenza-vectored vaccine intranasal boost immunization regime mediated potent and long-lasting anti-lung metastasis immunity, whereas Tcirm induced in different vaccination combinations was not capable to provide sufficient protection. To further explain the mechanism behind the potent TRM generated by prime-boost immunization, we found that DNA vaccination elicited a large amount of central memory T cells (TCM) in the circulation and was preferentially differentiated into lung TRM after the intranasal booster immunization. Single-cell RNA sequencing profile illustrated the tissue microenvironment post mucosal immunization reshaped the differentiation of circulating TCM elicited by systemic immunization and enhanced the anti-metastasis T cell immunity. Thus, our research highlighted the importance of TRM in lung metastasis protection and provided insight into the mechanism of lung TRM establishment in the prime-boost vaccination.
Novel bio-signature for the topical administration of a suppressor of cytokine signaling-1 mimetic to the equine eye: implications in treatment of Recurrent Uveitis (RU)
Authors: Stafford Lauren Stewart , Vicuna Valeria , Plummer Caryn , Smith W Clay , Larkin Joseph 
Published: August 2023

Abstract
Recurrent uveitis (RU) is a leading cause of ocular decrement in both humans and horses, which can lead to blindness. Equine recurrent uveitis (ERU) serves as the only spontaneous model for human RU as the eye destruction in both diseases is guided by a dysregulated cytokine milieu mediated by T lymphocytes. We have recently shown that the topical administration of a peptide (SOCS1-KIR), which mimics a natural regulator of cytokine signaling, was correlated with a reduction in clinical pathology when applied to the eye of horses with ERU. This administration was without any observed toxicity. The purpose of this study is to establish the intraocular presence of topical SOCS1-KIR treatment. As such, we administered SOCS1-KIR to the eye of experimental horses (lacking ocular pathology) to evaluate peptide localization and detection of a biological signature. SOCS1-KIR peptide, that was intravitreally-injected, was readily detectable within the retina by immunofluorescence. Although we were unable to detect topically administered SOCS1-KIR by immunofluorescence, topical administration reduced levels of TNFa and IL-10 in the aqueous humor of treated eyes. Additionally, we found that SOCS1-KIR modulated TNFa, IL-6, IL-10, RANTES, and IL-8 levels within activated healthy equine PBMC. Together these results suggest a novel biological signature that is mediated by topical SOCS1-KIR administration to the equine eye that has implications for translation to the clinical setting.
This work was supported by the Grayson Jockey Club grant
Pre-clinical pharmacologic and tolerability characterization of a novel KIRxCD8 targeting bispecific CD8 Treg modulator
Authors: McMahan Catherine J , Pham Minh , Boster Daniel , Hermansky Gleda , Gardell Jennifer , Bowser Justin , Rachael Fasnacht , Chen Alex , Gilbertson Emily , Morgan Nadine , Childs Monica , Fitzpatrick Kristin , Tan Cong , Mauer Meghan , Meengs Brent , Therriault Jon , Patton Dan , Julien Susan , Crane Courtney , Swiderek Kristine M 
Published: August 2023

Abstract
We have characterized a subset of CD8 T cells (CD8 Treg) with immunosuppressive characteristics in inflammatory disease settings. Here we describe the binding and specificity profiles of a novel bispecific CD8 Treg modulator in vitro, ex vivo, and in vivo, and initial assessment of tolerability and pharmacology in a humanized mouse model.
We evaluated the binding, pharmacokinetics (PK), and early tolerability of the bispecific CD8 Treg modulator targeting CD8 and KIR2DL1/2/3. Despite single arm binding to NK cells via the KIR targeting arm and CD8 T cells by the CD8 targeting arm of the bispecific, we did not detect activation of immune cells or increased pro-inflammatory cytokines in vitro, nor did we observe any contribution of NK cells to the elimination of pathogenic CD4 T cells. In healthy mice, the CD8 Treg modulator had a PK profile consistent with antibody molecules; treatment delayed disease onset in an acute GVHD setting. In humanized CD34-engrafted NSG-IL-15 transgenic mice, supporting engraftment of NK cells, no activation of immune cells in peripheral blood or terminal tissues or induction of proinflammatory cytokines in the serum was observed following a single dose of the CD8 Treg modulator.
The recently described CD8 Treg network appears dysfunctional in autoimmune diseases. The KIRxCD8 targeting bispecific modulator targets this network, engages and activates CD8 Treg and reduces inflammation without increasing unwanted immune cell activation or pro-inflammatory cytokines, both in vitro and in vivo. Our early data suggest that KIR-mediated enhancement of CD8 Treg function using a bispecific modulator is a broadly applicable and a promising CD8 Treg specific therapeutic modality for the treatment of autoimmune disease.
Prevention of Type 1 Diabetes via a Lipid Nanoparticle-Based JAK inhibitor Treatment that Involves Anergy Formation
Authors: Hou Shenda , Zhang Yichuan , Wang Jialu , Calderon-Colon Xiomara , Tiburzi Olivia , Iglesias-Lozano Marcos , Patrone Julia , Raimondi Giorgio 
Published: August 2023

Abstract
Type 1 diabetes is an untreatable autoimmune disease caused by the destruction of pancreatic beta cells by autoreactive T cells. The inhibition of inflammatory cytokines signaling via JAK inhibitors like Tofacitinib (Tofa) has shown promise in the prevention of this disease. To improve on drug bioavailability and reduce deleterious systemic exposure, we identified a lipid nanoparticle (LNp) formulation with favorable Tofa encapsulation efficiency and negligible cellular toxicity. Live animal imaging indicated these particles have the unique property of accumulating in lymphoid tissues, particularly in pancreatic and mesenteric lymph nodes when administrated via oral gavage. Spectral flow analysis revealed that multiple immune cells, like dendritic cells, T cells, and B cells, uptake the particles in these tissues. Short-term administration (5 gavages once every other day) of Tofa-LNp early (3-week-old) or late (10-week-old) in disease prone NOD mice promoted a significant delay of disease onset. Importantly, the therapeutic effect was associated with a profound increase in anergic CD4 T cells in the draining sites of LNp. Anergic cells have been known to form following stimulation in absence of co-stimulation, however, additional in vitro stimulation assays suggest a distinctive path of anergy induction promoted by blocking cytokine signaling. Overall, our results suggest an unexpected and novel immunomodulatory effect of JAK inhibition that warrants further investigation for the development of an effective treatment of type 1 diabetes.
The Molecular Underpinnings of Treg Plasticity in Cancer
Authors: Friedman David J , Osman Abu , Tousinas Georgios , Marquez Daisy , Carapanceanu Nicoleta , Carapanceanu Valentin , Khazaie Khashayarsha , Gounari Fotini 
Published: August 2023

Abstract
Colorectal cancer (CRC) is one of the most common cancers in the world, yet it remains one of the most difficult to treat. Immunotherapy of CRC using checkpoint inhibitors is only efficacious in approximately 4% of patients with high microsatellite instability (MSI-H). In earlier studies we showed that in patients with inflammatory bowel diseases (IBD) and CRC as well as in the APCΔ468 murine polyposis model, Tregs overexpress β-catenin. Furthermore, we demonstrated that expression of a dominant active β-catenin in Tregs induces RORγt, compromising suppressive activity and promoting TH17-like properties. This results in a scurfy-like phenotype. By contrast loss of TCF-1 upregulated RORγt, but only compromised Treg anti-inflammatory functions. These observations suggested cooperation of β-catenin and TCF-1 in regulating Treg plasticity. We show here that in healthy mice, β-catenin expression is significantly higher in Tregs as compared to conventional CD4+ T-cells. In Tregs that express a dominant active β-catenin, ablation of TCF-1 or HEB provide partial rescue, while ablation of both TCF-1 and HEB recovers Treg numbers and prevents the scurfy-like phenotype. These observations suggest that TCF-1, HEB and β-catenin cooperate to determine Treg functions. In search for additional partners, we show that loss of TCF-1 upregulates SATB-1, a chromatin modifier that is known to determine T-cell development and function. Upregulation of SATB-1 is enhanced with the loss of both TCF-1 and HEB. All three transcription factors upregulate RORγt suggesting that they cooperatively determine Treg function and plasticity. Elucidating this cooperation will enhance our ability to control Treg plasticity in health and disease.
NIH/NIAID - R01 AI108682-0A1
Gut microbiota changed by tryptophan modulates anti-tumor CTL responses against brain tumor
Authors: Kim Hyeon Cheol , Kim Hyun-Jin , Lee Heung Kyu 
Published: August 2023

Abstract
Glioblastoma multiforme (GBM) is one of the most common brain tumors, and both conventional therapies and current immunotherapies are not effective. Thus, a novel approach is required for GBM treatment. Commensal microbiota reside in the body and are involved in both healthy and disease states of the host. To date, research into the role of microbiota has mainly focused on the gastrointestinal tract. It remains unclear how gut microbes may affect brain and how they may play a role in GBM. Here, we observed a distinct change in gut microbial composition and metabolism during GBM progression using 16S rRNA sequencing in two different animal models. The amount of tryptophan was significantly reduced in GBM-bearing mice. Based on these results, we considered tryptophan supplementation. This diet improved the survival in a commensal microbiota-dependent manner. Surprisingly, some microbiota were restored by tryptophan to levels comparable to those of normal mice. Next, we observed improved survival of GBM-bearing mice co-housed with normal mice. Furthermore, we identified a bacterial species that was present at significantly different levels depending co-housing. Colonization with this bacterium led to increased survival. This bacterium required tryptophan for its growth. Cytotoxic T cells showed more potent immune responses in the tumor microenvironment in tryptophan-supplemented mice and mice colonized with the bacterium. In addition, bacterial metabolites increased apoptosis in glioma tumor cell lines. Collectively, we identified a bacterial species that is critical for defense against GBM and demonstrated that this bacterium potentiates cytotoxic T lymphocyte effector functions and induces the apoptosis of tumor cells.
Loss of testosterone leads to impaired T cell function via glucocorticoids in mouse glioblastoma models
Authors: Lee Juyeun , Chung Yoon-Mi , Sharifi Nima , Lathia Justin 
Published: August 2023

Abstract
While sex differences in glioblastoma (GBM) are well established, the contribution of sex hormones on these differences has not been fully explored. Recently, the immunoregulatory effect of testosterone in other type of cancers has been reported. To evaluate the effect of testosterone on GBM, we performed castration or sham surgery on mice, followed by intracranial implantation of syngeneic glioma cells. Surprisingly, the castrated B6 mice had more aggressive tumors compared to sham surgery controls and the castration induced aggressive tumor growth could be rescued by exogenous testosterone administration. This was further confirmed by chemical blockade of androgen receptor signaling using enzalutamide. In contrast, castration in Rag1KO mouse models did not show a survival difference compared to controls, suggesting a role for lymphocytes. Interestingly, upregulated levels of circulating corticosterone in castrated mice was detected by mass spectrometry, and glucocorticoid receptor blocker reversed the survival of castrated mice, suggesting glucocorticoid-mediated systemic immunosuppression upon castration. Flow analysis revealed decreased cytokine production in CD4+ and CD8+ T cells from tumors and lymph nodes in castrated mice. We also found that tumor growth was delayed in castrated mice when tumor cells were subcutaneously implanted in the flank while decreased cytokine production in T cells in tumor and lymph nodes from flank tumor model as well. These data suggest brain-specific effect of steroid hormone on tumor control. Taken together, our findings demonstrate that testosterone regulates T cell function via glucocorticoids, and ultimately affects GBM tumor growth in a site-specific manner.
Supported by grants from NIH (R35 NS127083, P01 CA245705).
Differential expression of immune receptors in pediatric Acute Lymphoblastic Leukemia (ALL)
Authors: Mathew Stephen O , Ahmed Nourhan G , Powers Sheila , Jose Roslin , Mathew Porunelloor A 
Published: August 2023

Abstract
Acute Lymphoblastic Leukemia (ALL) represents the most common pediatric cancer. Significant improvements in chemotherapy regimens caused a leap in the 5-year survival rates to surpass 90%. However, relapse significantly lowers the chances of survival to less than 50% in some cases due to resistance developed by malignant cells to chemotherapy. Natural Killer (NK) cells are a promising immunotherapy alternative for their ability to recognize and kill malignant cells directly through activation or inhibition signals or through cytokine release. We have previously identified 2B4 (SLAMF4), CS1 (SLAMF7) and LLT1 that can activate or inhibit NK cells upon the interaction with their ligands. In this study, the expression of 2B4, CS1, LLT1, NKp30 and NKp46 was determined in pediatric ALL and healthy subjects. Whole blood was collected from 42 pediatric ALL subjects before and after induction chemotherapy and the surface expression of receptors/ligand on T-cells, B-cells, monocytes, and NK-cells was compared with blood samples from 20 healthy subjects. The flow cytometry data showed a significant increase in CS1 and NKp46 expression on monocytes and LLT1 in T cells and monocytes of ALL subjects before treatment. A decrease of LLT1, 2B4, CS1 and NKp46 on T-cells of ALL subjects was also observed after treatment along with elevated expression of LLT1 on ALL subjects’ NK-cells before and after treatment. Furthermore, mRNA data showed altered expression of receptors in ALL subjects pre and post induction chemotherapy treatment. The results indicate that the differential expression of the receptors/ligand may play a role in the T cell and NK-cell mediated immune surveillance of pediatric ALL.
Supported by funds from Cancer Research Foundation of North Texas and Team Connor Childhood Cancer Foundation
Analysis of the protumoral mechanisms of F.nucleatum on growth, epithelial-mesenchymal transition and the expression of immunosuppressive markers in cell line of OSCC
Authors: Munoz Camila Paz , Ferrada Luciano , Riquelme Erick , Zuñiga Felipe , González Wilfredo , Betancur Daniel , Oñate Angel , Novoa Sergio Andrés Sanhueza , Cabrera-Garcia Camilo Daniel , Quiroga Romina Andrea , Cáceres Bárbara Evelyn Antilef , Labarca Gonzalo , Nova-Lamperti Estefania , Fernandez Liliana Lampert 
Published: August 2023

Abstract

Background
Oral squamous cell carcinoma (OSCC) is the most common manifestation of oral cancer. It has been proposed that periodontal pathogens contribute to OSCC progression, and preliminary data from our laboratory has identified Fusobacterium nucleatum (F.n) and Epithelial Mesenchymal Transition (EMT) markers in the secretome of biopsies from patients with OSCC in comparison with healthy biopsies from the oral cavity. However, the mechanisms modulated by the tumoral bacteriome in OSCC remains not fully understood.

Methods
Oral cancer cells (HSC3) were infected with F.n using a MOI of 100 to evaluate the effect of the bacteria on tumor growth, expression of EMT markers and immunomodulatory properties.

Results
After infection, we confirmed the presence of bacteria inside and surrounding the cancer cells by confocal microscopy. Then, a significant increment in the size of F.n-infected tumor spheroids was found at 3-, 6- and 10-days post-infection. Related to EMT markers, MMP-9 transcripts were significantly elevated in infected cells, whereas E-cadherin transcripts were significantly downregulated post infection. In addition, the Human XL Oncology array kit revealed that several cancer proteins such as MMP-3, GM-CSF, FOXO1/FKHR, Cathepsina D-S, Amphiregulin, SerpinB5/Maspin and EGFR were upregulated and others like ICAM-1, DLL-1 and ERB2 were downregulated after F.n-infection. Finally, the expression of Galectin-9 measured by flow cytometry was significantly increased in infected cells than control cancer cells.

Conclusions
The periodontal bacterium F.n promotes tumor progression of OSCC through increased tumor growth, acquisition of ETM-associated markers and Galectin-9 upregulation.

Fondecyt Regular Project 1211480
Safety of Laparoscopic Cholecystectomy for Cholecystitis during Pregnancy
Authors: Itaimi Ahmed , Abbassi Imed , Baraket Oussama , Kotti Ahmed , Triki Wissem , Bouchoucha Sami 
Published: August 2023

Objectives:
The aim of this study is to evaluate the safety of laparoscopic cholecystectomy to treat acute cholecystitis during pregnancy.

Materials and Methods:
We conducted a retrospective multicenter study including pregnant women with acute cholecystitis managed in surgery departments in Tunisia from January 1, 2015, to December 31, 2019.

Results:
Seventeen centers of surgery department participated in this study including 107 cases of acute cholecystitis. The average maternal age was 30.5 years. Nonoperative management was performed in eight patients, whereas 99 other patients had surgery. Postoperative follow-up was uneventful in 93.8% of cases and eventful in 6.2% of cases. There was no mortality as far. A medical complication occurred in two patients with a medical morbidity rate of 1.7%. It was about thromboembolic disease. A surgical complication occurred in two other patients with a surgical morbidity rate of 1.7%. It was about intraperitoneal infection in one case and biliary collection in the other case. In univariate analysis, variables related significantly to maternal complication were: age equal or over 35 years old (P = 0.001), jaundice (P = 0.024), C-reactive protein value equal or over 20 mg/L (P
= 0.05), and biliary peritonitis (P = 0.05). In multivariate analysis, independent variable predictive of maternal complications was age equal or over 35 years old (P = 0.003), jaundice (P = 0.003), and biliary peritonitis (P = 0.011).

Conclusion:
Laparoscopic cholecystectomy for cholecystitis can be safely achieved in pregnant women with low rates of morbidity and mortality. This study showed that independent variable predictive of maternal complications was age equal or over 35 years old, jaundice, and biliary peritonitis.