bluuebunny/crossref_metadata_2025_split huggingface dataset:
GenSci120, a humanized PD-1 agonistic monoclonal antibody, enhances the binding of both PD-L1 and PD-L2 to PD-1, and mitigates the symptoms of GVHD in a mouse model
Authors: Jiang Wenbo , Chu Xuebin , Song Lei , Li Xue , Xue Weili , Li Lingyun , Zhao Ranran , Gu Fei , Xu John 
Published: November 2024

Abstract
Background: Autoimmune diseases impose tremendous health and economic burden to the individuals and families they affect. The fundamental mechanism of autoimmune diseases is a break in immune tolerance and homeostasis. PD-1 plays an important role in maintaining immune tolerance by antagonizing CD28/TCR signaling in autoreactive T cells. Stimulating the PD-1 co-inhibitory pathway by an agonistic antibody would suppress pathogenic immune responses and restore immune homeostasis. Methods: A PD-1 agonistic monoclonal antibody, GenSci120, was generated by Beacon single plasma cell cloning and murine antibody humanization technologies. In vitro T cell inhibition, ADCC and ligand blocking activities of GenSci120 were characterized. In vivo efficacy in a mouse GVHD model and PK in the human FcRn transgenic mice were evaluated. Results: GenSci120 exhibited potent T cell inhibition activity in a luciferase reporter assay and a primary T cell proliferation assay. GenSci120 also showed ADCC activity in an LDH release assay. Remarkably, GenSci120 enhanced the binding of both PD-L1 and PD-L2 to PD-1 in a flow cytometry assay. In a mouse model, GenSci120 significantly alleviated the symptoms of GVHD. Furthermore, GenSci120 demonstrated longer half-life than competitors’ antibodies in the human FcRn transgenic mice. Conclusion: These data suggest the potential of GenSci120 as a novel therapy to treat autoimmune disorders and support the evaluation of this molecule in clinical studies.
Phenotypic and Therapeutic Evaluation of Humanized C3 Transgenic Mice as a Model for C3 glomerulopathy-Like Autoimmune Disease
Authors: Liang Juan , Zi Kaiyuan , Xu Qiuping , Xu Shuxin 
Published: November 2024

Abstract
C3 glomerulopathy (C3G) encompasses a range of kidney disorders with autoimmune and genetic origins, where dysregulated alternative pathway (AP) complement activation stands as the underlying cause. This study develops a transgenic mouse strain that overexpresses human C3, thereby spontaneously generating a rapidly progressing and severe murine model of C3G.
The C3G phenotype observed in humanized C3 transgenic mice may arise from a dysregulated interaction between human C3 protein and various mouse complement proteins, resulting in uncontrolled C3 activation via the AP. Male humanized C3 transgenic mice exhibit increased morbidity early in life. Proteinuria initiates at 4 weeks of age, accompanied by an elevation in the albumin/creatinine ratio. Significantly increased serum levels of ALT, AST, ALP, LDH, and CK in humanized C3 transgenic male mice compared to wild-type mice indicate liver and heart injuries. Moreover, serum T-CHOL and HDL levels are significantly reduced, suggesting anemia and malnutrition. Pathohistological analysis of the kidney reveals various renal lesions. Oral administration of Lnp023, a small-molecule inhibitor of complement factor B, effectively increases body weight and serum hC3 levels, improves anemia, and preserves liver, heart, and renal function.
In conclusion, this novel model contributes significantly to unraveling the mechanisms underlying C3G and exploring potential therapeutic interventions.
The combined use of statin and rapamycin treatments synergistically inhibit the proliferation of B cell Lymphoma
Authors: Zhu Zhenhan 
Published: November 2024

Abstract
Sterol Regulatory Element-Binding Protein (SREBP) signaling plays a crucial role in maintaining sterol homeostasis during B cell activation and the proliferation of germinal center B cells. It is unclear whether this pathway can be targeted to effectively treat B cell lymphoma. We discovered that inhibiting SREBP signaling or its downstream target 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) using Fatostatin or Simvastatin effectively restrains the proliferation of B cell lymphoma cells. However, B cell lymphoma cells activate the mTORC1-pS6 pathway in response to statin treatment, suggesting a possible mechanism to counteract statin-induced cell cycle arrest. Combining statin treatment with the mTOR inhibitor rapamycin demonstrates a synergistic effect in inhibiting B cell lymphoma proliferation, impeding cell cycle progression, and regulating sterol production. These findings emphasize the potential of a combined therapy approach targeting both SREBP and mTORC1 as a treatment strategy for B cell lymphoma.
The tumor immune environment in advanced breast cancer following treatment with pembrolizumab and nab-paclitaxel
Authors: Tyagi Apoorvi , Voloshyna Iryna , Klar Natalie , Darvishian Farbod , Hao Yuan , Zhurova Anastasia , Cynthia Loomis , Marks Douglas K , Adams Sylvia , Krogsgaard Michelle 
Published: November 2024

Abstract
Metastatic breast cancer poses significant clinical challenge, necessitating improved treatment options. Immune checkpoint blockade approval for PD-L1+ triple-negative breast cancer highlights potential for durable response. However, PD-L1 diagnostics can be discordant and responses in PD-L1 low/negative patients emphasize the need for deeper understanding of tumor microenvironment (TME). In a single center phase II trial, specimens were obtained from 70 breast cancer patients at baseline, treatment cycle 1 featuring monotherapy using nab-paclitaxel (ER+/HER2- BC, cTNBC) or pembrolizumab (iTNBC), followed by combination therapy in cycle 2. We used PhenoImagerHT and NanoString for spatial phenotyping and gene expression analysis of ER+ cohort. Preliminary multiplex imaging (qMIF) showed correlation in cell phenotype, activation state, and spatial location. NanoString revealed transcriptional differences between responders and non-responders at baseline. Moreover, a positive relationship (r=0.8) was found between CTLs and macrophage count, validating qMIF targets. Our research extends to study tumor immune infiltrates and gene expression in cTNBC (n= 30) and iTNBC (n= 20) cohorts. The final results will determine intrinsic subtype signatures of each cohort and study crosstalk between different cell types in the TME. In conclusion, our approach aims to enhance the understanding of treatment response and TME's role in metastatic breast cancer for improved therapeutic strategies.
The EGFR inhibitor exerts a suppressive influence on the response of CD8+ T cells in Non-Small Cell Lung Cancer
Authors: Ko Chun-Jung , Chi Hao-Chen 
Published: November 2024

Abstract
Lung cancer is the leading cause of death worldwide, predominantly characterized by non-small cell lung cancer (NSCLC). The foremost treatment for NSCLC patients with EGFR mutations involves EGFR-tyrosine kinase inhibitors (EGFR-TKIs), demonstrating notable enhancements in patient survival and the preservation of quality of life. Immune checkpoint blockade (ICB) that reinvigorates T cell response is a promising immunotherapeutic approach to treat NSCLC patients with an efficacy of approximately 20%. Thus, comprehending the intricate interplay between EGFR-TKIs and immune regulation is pivotal, laying the groundwork for strategic combination therapies. Despite its critical importance, the relationship between EGFR-TKIs and immune regulation remains elusive, necessitating further investigation into the immunomodulatory role of EGFR-TKIs. This study unveils that EGFR-TKIs contribute to the reduced proliferation and effector cytokine production of CD8+ T cells. Treatment with EGFR-TKIs suppresses the response of tumor-infiltrating T cells in two syngeneic tumor mouse models. Furthermore, employing EGFR-TKI-specific antibodies and mass spectrum analysis, we identified the target profile of EGFR-TKIs. Remarkably, NSCLC patients undergoing EGFR-TKI therapy exhibited a diminished frequency of IFNγ-producing CD8+ T cells. These findings significantly inform the future development of therapeutic strategies and the optimization of drug administration timing for NSCLC patients.
The functional role of KLRG1+ Tregs in Non-small Cell Lung Cancer.
Authors: Oluwatola Oluwaseyi , Bag Arup , Oseni Saheed , Pilon-Thomas Shari , Adeegbe Dennis 
Published: November 2024

Abstract
Killer cell lectin-like receptor G1 (KLRG1) is a co-inhibitory receptor and upon engagement with its ligand, E-, N-, or R-cadherins, Akt phosphorylation is inhibited leading to proliferative dysfunction in T and NK cells. This study aims to investigate how E-cadherin engagement affects KLRG1 function.
KLRG1 fl/fl and cKO mice were orthotopically implanted with KP tumor cell line. T cells were isolated and stimulated for intracellular staining. KLRG1+ and KLRG1- Tregs sorted from lung suspensions of KPM tumors were stimulated with α-CD3+α-CD28 in the presence or absence of soluble E-cadherin for 24hours. CD4+CD25- effector T cells were labelled with cell-trace violet (CTV) and then co- cultured with graded numbers of each population of Tregs in the presence/absence of soluble E-cadherin. Finally, KLRG1+ and KLRG1- Tregs were sorted from lung tumors of KP mice for single-cell RNA sequencing.
We show that GZB is upregulated in KLRG1+ Tregs upon engagement with E-cadherin as confirmed by RNA sequencing, and this GZB expression by KLRG1+ Tregs is associated with enhanced death of effector T cells. Also,Treg-specific deletion of KLRG1 in the cKO mice does not impact Treg development or peripheral homeostasis; instead it permits enhanced anti-tumor responses in lung adenocarcinoma-bearing mice.
NSCLC-associated KLRG1+ Tregs are armed with a functional program that drives their enhanced immunosuppressive activity and attenuates effector function compared to KLRG1- Tregs.
A microbiota derived metabolite and pediatric celiac disease pathogenesis
Authors: Kelley Kristina , Girdhar Khyati , Dogru Yusuf , Yang Yi , Tolstikov Vladimir , Kiebish Michael , Palm Noah , Ludvigsson Johnny , Soto Genesis , Zhang Michelle , Altindis Emrah 
Published: November 2024

Abstract
Celiac Disease (CD) is an autoimmune condition triggered by gluten ingestion and defined by small intestine inflammation leading to villous atrophy in genetically predisposed individuals. 20-40% of the general population possess the predisposing HLA-DQ2 or HLA-DQ8 alleles, however only 1-2% of the population develops CD, indicating that there are additional environmental factors at play in the pathogenesis of the disease.
In a prospective cohort study using fecal and plasma samples from children at ages 2.5 and 5 years, before the onset of celiac disease (CD progressors), we found that CD progressors have an altered gut microbiome, plasma metabolome and cytokine profile years before diagnosis. IgA sequencing revealed an increased IgA response and unique microbial targets of IgA. One metabolite increased in CD progressors is taurodeoxycholic acid (TDCA), a secondary bile acid produced by gut microbes. Treating C57BL/B6 mice with TDCA caused villous atrophy as well as upregulated CD4+T-cells in intraepithelial lymphocytes and natural killer cells in the lamina propria (LP). TDCA increased the expression of Qa-1 and NKG2D on T-cells.
The DQ8-Dd-villin-IL-15tg mouse model of CD possesses the predisposing HLA-DQ8 molecule and overexpresses IL-15 in the LP. Treating these mice with TDCA caused the villi/crypt ratio to decrease in the treatment group of pooled villi. Our results indicate that TDCA and TDCA-producing bacteria could potentially contribute to the pathogenesis of CD.
Infection of the human lymphoid organ on-a-chip with Borrelia burgdorferi reveals novel mechanisms of immunosuppression and autoimmunity in Lyme disease
Authors: Goyal Girija , Ku Min Wen , Zhai Yunhao , Menon Kavya , Laforest Demi , Gould Russell , Gulati Aakanksha , Feigenson Marina , Feitor Jessica , Morton Shad , Shanmugam Nandhinee , Singh Rohini , Patil Aditya , Prabhala Pranav , Gharpure Supriya , Horvath Viktor , Isaacs Abdul 
Published: November 2024

Abstract
In mice and one human case study, Borrelia burgdorferi (Bb), the causative agent of Lyme disease (LD), disrupts germinal center architecture and function. Bb proteins also mimic self-antigens. Thus, the antibody response may be of poor quality and target self antigens. To understand this pathology and its relevance to human infection-induced autoimmune diseases, we infected human lymphoid organ chips (Goyal et al., Adv Sci., 2022) created from healthy volunteers with Bb. We discovered unexpected and severe suppression of the adaptive immune system by Bb. T cell and B cell activation were absent in all of the donors (n&gt;10) activated by Bb. Further, T cell proliferation was suppressed by Bb. Yet, some donors displayed hypergammaglobulinemia (hyperIg), seen in many antibody-mediated autoimmune diseases.
We collected the exosomes secreted from the lymphoid organ chips and performed mass spectrometry to identify proteins associated with Bb infection and hyperIg. A heat-killed, fixed suspension of Staph. aureus Cowan I (SAC), commonly used to benchmark patient immune responses, was used as a control. We identified complement and coagulation factors, chaperone proteins, and immunological synapse proteins as key players in discriminating between successful activation, immunosuppression, and hyperIg (Bb). Our studies establish an innovative way to study human infectious diseases and their role in autoimmunity and reveal novel therapeutic targets to treat post-treatment Lyme disease.
COMPOUND 1 is a first-in-class small molecule cGAMP competitive oral STING antagonist that reduces lung inflammation and fibrosis in chronic bleomycin and silica mouse models
Authors: Banerjee Monali , Middya Sandip , Shrivastava Ritesh , Basu Sourav , Ghosh Rajib , Middya Anindita , Mane Nagaswamy , Sharma Priti , Rawat Nidhi , Soram Thanilsana , Mansuri Rubeena , Yadav Dharmendra , Gautam Anuj , Shinde Vaibhav , Padaliya Manisha , Bano Shahnaj , Roy Sneha 
Published: November 2024

Abstract
Background: STING activation by cGAMP leads to canonical Type I IFN responses and non-canonical signaling that increase inflammation, pyroptosis, autophagy, senescence and fibrosis in conditions such as Idiopathic Pulmonary Fibrosis. COMPOUND 1 is a novel cGAMP competitive synthetic small molecule STING antagonist discovered at Curadev. Materials and Methods: Competitive binding was established using radioligand binding assays. Anti-fibrotic activity was established in Bleomycin and Silica induced lung fibrosis models in mice. PK and safety studies were evaluated in rodents. Results: COMPOUND 1 inhibits the binding of cGAMP to STING and causes reductions in the level of Type I interferons and pro-inflammatory cytokines from immune cells as well as in mice treated with a STING agonist. Once a day oral administration of COMPOUND 1 that commenced one week after intratracheal injury with bleomycin or silica in C57/Bl6 mice ameliorated lung inflammation and fibrosis with concomitant decreases in collagen load and inflammatory cytokines. Orally administration of the compound was well tolerated at high doses in a 14-day non-GLP rat safety study. Conclusions: COMPOUND 1 is an orally administered novel first-in-class cGAMP competitive STING antagonist with promising single agent anti-inflammatory and anti-fibrotic activity in chronic lung injury models making it is well suited for IND directed studies.
Highly Motile Neutrophil Cytoplast ameliorate Bacterial Pneumonia
Authors: Tsukasaki Yoshikazu , Prasad Nithish , Vellingiri Vigneshwaran , Mehta Dolly , Malik Asrar 
Published: November 2024

Abstract
Polymorphonuclear neutrophils (PMN) function as innate immune cell through rapid mobilization at site of infection and prompt phagocytosis and bactericidal activity. We addressed in vivo in mouse lungs the function of cytoplasts (PMNcyt), the PMN generated following release of extracellular traps (NETs). We found ~50% of PMN lost their nucleus post-NETosis following pneumonia induced by Pseudomonas aeruginosa (PA), and become PMNcyt. Interestingly, , PMNcyt in lung microvessels showed &gt;2 greater velocity and &gt; 3 greater deformability as compared to PMN. PMNcyt were also 9x more efficient in killing airway PA as compared to PMN. Using the protein arginine deiminase 4 (PAD4) inhibitor (Cl-amidine) to prevent NET formation in mice, we prevented the generation of PMNcyt demonstrating that PMNcyt were derived post-vital NETosis. We also showed PMNcyt retained the ability to phagocytose PA. Moreover, the inhibition of PMNcyt generation by PAD4 blocker induced severe lung injury in the pneumonia model, indicating an important anti-bacterial protective role of PMNcyt. Adoptive transfer of PMNcyt in PA infected mice also significantly reduced bacterial load and prevented lung tissue injury in mice. The results suggest a crucial host-defense function of PMNcyt generated post vital NETosis and their usefulness as cell-based therapy in inflammatory diseases such as pneumonia.
Identify new Foxp3 regulators in human primary regulatory T cells using a whole-genome CRISPR screening
Authors: he huan , chen mingkuan , chanda sumit 
Published: November 2024

Abstract
Regulatory T (Treg) cells are crucial in maintaining immune homeostasis. However, they can also promote tumor progress by suppressing anti-tumor immunity. Conversely, Treg instability, marked by the loss of the key transcription factor Foxp3, can facilitate effective tumor immunity. Therefore, gaining a deeper understanding of the pathways that regulate Foxp3 could offer promising therapeutic opportunities for cancer treatment. In this study, we performed a genome-wide CRISPR screening on human in vitro induced Treg cells to identify Foxp3 regulators. Our preliminary results have identified 191 potential positive and 75 potential negative regulators of Foxp3 in human Treg cells. Gene ontology analysis revealed several important functional clusters, including chromatin organization, histone modification, and transcription regulator complex. In particular, we identified many genes encoding components of the INO80 complex and the Sin3-type complex. Next, we aim to conduct further validation and analysis of the INO-80 and Sin3 complexes to gain insight into their role in regulating Foxp3 expression and the functioning of Treg cells. Given that Treg cells can promote tumor growth by inhibiting anti-tumor immunity and Foxp3 is the master regulator for Treg cells, obtaining a comprehensive understanding of the regulation of Foxp3 can reveal novel therapeutic targets to modify the number and function of Treg cells, leading to potential cancer treatment strategies.
Gamma-delta T cells suppress microbial metabolites that activate striatal neurons and induce repetitive/compulsive behavior in mice
Authors: Rezende Rafael , Cox Laura , LeServe Danielle , Mayrink Julia , Oliveira Marilia , Fonseca Roberta , Lanser Toby , Rosa Ana , Schwerdtfeger Luke , Moreira Thais , Weiner Howard 
Published: November 2024

Abstract
Intestinal gamma-delta (gd) T cells play an important role in shaping the gut microbiota, which is critical not only for maintaining intestinal homeostasis but also for controlling brain function and behavior. Here, we found that mice deficient for gd T cells (gd-/-) developed an abnormal pattern of repetitive/compulsive (R/C) behavior, which was dependent on the gut microbiota. Colonization of WT mice with gd-/- microbiota induced R/C behavior whereas colonization of gd-/- mice with WT microbiota abolished the R/C behavior. Moreover, gd-/- mice had elevated levels of the microbial metabolite 3-phenylpropanoic acid in their cecum, which is a precursor to hippurate (HIP), a metabolite we found to be elevated in the CSF. HIP reaches the striatum and activates dopamine type 1 (D1R)-expressing neurons, leading to R/C behavior. Altogether, these data suggest that intestinal gd T cells shape the gut microbiota and their metabolites and prevent dysfunctions of the striatum associated with behavior modulation.
Fc-Optimized Agonistic Anti-Human CD40 mAb Demonstrates Strong Antitumor Activity in hCD40/hFcγRIIB Dual Humanized Mice
Authors: Hong Juan , Hong Jane , Han Boang , Li Tao , Feng Dongxiao , Sun Ruilin , Qing Shuang , He Daniel 
Published: November 2024

Abstract
As a promising antitumor immunotherapy, the agonistic anti-CD40 antibody is limited by its clinical response and toxicity. The selective binding of anti-CD40 antibodies to FcγRIIb has been reported to improve the anti-tumor efficacy. Therefore, we developed the CD40 single humanized and CD40/FcγRIIB dual humanized mouse model, and characterized the expression and pathway activation of chimeric h/m CD40 and FcγRIIB by FACS. Moreover, to evaluate the efficacy and toxicity of anti-hCD40 in vivo, the hCD40 and hCD40/hFcγRIIB mice were engrafted with MC38 syngeneic tumors and treated with anti-human CD40 antibody (MIL97) with mouse or human Fc domain. The binding epitope of MIL97 has a strong potential to rely on cross-linking CD40 signaling activation, and the functional modification of Fc enhances the binding to FcγRllB, resulting in stronger cross-linking and agonistic effects on CD40 signaling. Notably, in comparison with MIL97-mFc, the MIL97 with human Fc domain failed to inhibit the tumor growth in hCD40 mice, but led to ~50% tumor growth inhibition in MC38 tumors in hCD40/hFcγRIIB dual knockin mice. Meanwhile, we observed the toxicity indicated by the body weight change and liver function damage of the MIL97-hFc in hCD40/hFcγRIIB mice, mirror clinical toxicities. Collectively, the hCD40/hFcγRIIB mice provide a powerful preclinical model to predict the activity and safety of anti-hCD40 antibodies in vivo, especially of human-specific Fc-engineered antibodies.
Harnessing a potent combination to address a pandemic virus: SARS-CoV-2-specific antiviral and anti-inflammatory activity of BromAc
Authors: Coelho-dos-Reis Jordana , Marques Ferreira Geovane , Reis Erik , Clarindo Felipe , Lopes-Ribeiro Ágata , Gomes-de-Pontes Letícia , Carvalho Luciana , Martins-Filho Olindo , Guimaraes da Fonseca Flavio , Teixeira Mauro , Sabino Adriano , Eapen Mathew , Morris David , Valle Sarah 
Published: November 2024

Abstract
Herein, the impact of BromAc on the SARS-CoV-2-specific inflammatory response was evaluated. A reduction of the cytokine storm, composed of chemokines, growth factors, proinflammatory and regulatory cytokines produced after short-term in vitro culture with the inactivated virus (iSARS-CoV-2). The immunophenotypic analysis showed that BromAc was able to downmodulate CD16+ neutrophils and CD14+ monocytes observed after stimulation with iSARS-CoV-2. Conversely, BromAc treatment increased steady-state HLA-DR expression in CD14+ monocytes and preserved this activation marker in this subset upon iSARS-CoV-2 stimuli, indicating improved monocyte activation upon BromAc treatment. Additionally, BromAc downmodulated the iSARS-CoV-2-induced production of TNF-α by the CD19+ B-cells. System biology approaches, utilizing comprehensive correlation matrices and networks show distinct patterns of connectivity in groups treated with BromAc, suggesting loss of connections promoted by the compound and by iSARS-CoV-2 stimuli. In addition, BromAc seems to disengage proinflammatory responses and their interactions with other soluble factors and axis orchestrated by SARS-CoV-2. These results give new insights on the mechanisms for the robust anti-inflammatory effect of BromAc in the steady state as well SARS-CoV-2-specific immune leukocyte responses, indicating its potential as a therapeutic strategy for COVID-19.