bluuebunny/crossref_metadata_2025_split huggingface dataset:
Schisandrin B and Alantolactone ameliorates experimental autoimmune encephalomyelitis in mice
Authors: Eken Ahmet , Cakir Mustafa , Karayigit Mehmet Onder , Altuntas Hamiyet Donmez 
Published: January 2023

Abstract
Schisandrin B (Sch-B) and Alantolactone (ALT) are two distinct molecules each of which could be extracted from herbs Schisandra chinensis and Inula helenium, respectively, commonly used in traditional Chinese medicine. Previous studies have revealed that both molecules impact STAT3, Nrf2 and Smad-mediated signaling pathways, and that Sch-B has protective effects in dextran sulfate sodium (DSS)-induced colitis models. However, besides a single paper studying Sch-B’s impact on murine Th17/Treg balance, the effects of Sch-B and ALT on human and murine Th17/Treg cells’ ontogeny and functions have not been investigated. In this study, we demonstrated that every other day administration of Sch-B or ALT during induction phase of myelin oligodendrocyte (MOG)35–55-induced experimental autoimmune encephalomyelitis (EAE) dramatically and significantly reduced EAE disease scores, demyelination, disease incidence, and infiltration of leukocytes into central nervous system, particularly IFN-γ+, IL-17+, GM-CSF+ T cells in C57BL/6 mice. Protection from disease correlated with elevated Treg and IL-10 levels. To our knowledge this is the first report demonstrating a prophylactic benefit for Sch B and ALT in a Multiple Sclerosis model and our results warrant further studies as to the use of both molecules after disease onset and mechanism of action.
A Phase 1 study comparing subcutaneous and intramuscular routes of administration of peginterferon beta-1a: macrophage-producing neopterin levels as biomarker
Authors: Butts Cherie L , Ramia Nancy , Zhao Yuan , Chen Kun 
Published: January 2023

Abstract

Background
Developing effective therapies for patients can be difficult as many fail due to safety concerns. Changes in route of administration (ROA) for approved therapies offers options to patients while mitigating known side effects. Peginterferon beta-1a (PEG) is approved for subcutaneous (SC) administration at 125 mcg every 2 weeks for patients with relapsing forms of multiple sclerosis. Intramuscular (IM) administration is associated with a different safety profile from SC and could offer patients receiving PEG an additional treatment option. To confirm efficacy is maintained, neopterin – a reliable pharmacodynamic measure for IFN therapies that is produced by macrophages – was tested in a bioequivalence study.

Methods
A two-period, crossover study with healthy volunteers who received a single dose of PEG administered SC followed by a single dose administered IM (or vice versa) was conducted. Blood samples were collected up to 504 hours post dose to evaluate pharmacokinetic and pharmacodynamic measures, including neopterin.

Results
The study enrolled 136 participants. Serum neopterin concentrations following SC and IM administration were similar, with maximal concentrations (Epeak) reached at a median ETmax of 40.1 hours and 44.0 hours, respectively. Geometric mean neopterin levels increased from baseline to maximum concentration similarly between both routes, with an increase from 8.0 to 22.6 nmol/L for SC and from 8.1 to 23.2 nmol/L for IM. The overall exposure to neopterin was also similar between both routes.

Conclusion
These results demonstrate no major difference in PEG activity; therefore, PEG administered SC or IM is expected to have a comparable pharmacological impact on the body.
Allo and autoimmune response following cardiac progenitor cells transplantation in rat myocardial infarction model
Authors: Gunasekaran Muthukumar , Mishra Rachana , Sharma Sudhish , Saha Progyapramita , Wang Lina , Davidson Lauren , Shah Aakash , Arfat Mir Yasir , Fu Xuebin , Abdullah Mohamed , Li Deqiang , Kaushal Sunjay 
Published: January 2023

Abstract
Cardiac progenitor cells (CPCs, c-kit+) are well-characterized stem cell type shown to potentiate cardiac regeneration in myocardial infarct (MI) model. However, auto and allo immune response to transplanted adult CPCs (aCPCs) reduces cell retention and MI recovery. We aimed to increase the regenerative potential of aCPCs by reducing immune response directed to the transplanted aCPCs using cyclosporine A (CSA).
Adult CPCs isolated from Wister Kyoto rat was transplanted into Brown Norway MI rats. MI rats transplanted with aCPCs+CSA demonstrated significant increase in MI recovery and cell retention compared to MI rats with aCPCs, CSA and Iscove Modified Dulbecco Media controls (p&lt;0.05). MI rats transplanted with aCPCs showed increased infiltration of CD68+ cells and apoptotic cells in the infarcted myocardium compared to aCPCs+CSA group (p&lt;0.05) analyzed by immunohistochemistry. Sera collected on day 2 and 7 of aCPCs group showed increased inflammatory cytokines (IL-2, IL-17, IFN-γ, TGF-β), antibodies to cardiac SAgs (Troponin-T and Myosin) allo antigens (RT1A, RT1B and RT1D) and reduced anti-inflammatory cytokines (IL-10). In contrast MI rats transplanted with aCPCs+CSA showed reduced inflammatory cytokines, abs to SAgs, allo antigens and increased anti-inflammatory cytokine IL-10 (p&lt;0.05).
In conclusion, MI rats transplanted with allogeneic aCPCs with immune suppressant CSA showed increased cell retention, reduced inflammatory cells and cytokines compared to aCPCs, CSA and IMDM control. Therefore, CSA reduces auto and allo immune response and increases regeneration potential by increased transplanted aCPCs retention that resulted in increased myocardial recovery.
B cell-derived IL-1β and IL-6 drive homeostatic T cell recovery following lymphoablation
Authors: Hasgur Suheyla , Fan Ran , Valujskikh Anna 
Published: January 2023

Abstract
T cell reconstitution after lymphoablation in allograft recipients may lead to acute rejection and poor graft outcome. Using a mouse model of heart transplantation and murine anti-thymocyte globulin (mATG) we showed that while T cell recovery depends on B cells, B cell MHC expression is dispensable. The goal of this study was to investigate the role of B cell-derived IL-1β and IL-6 in T cell homeostatic reconstitution after mATG lymphoablation. The NanoString analysis showed that mATG upregulated IL-1β and IL-6 gene expression in recipient B cells. To validate NanoString findings, IL-1β and IL-6 expression was measured by intracellular flow cytometry. Following heart allograft placement and mATG treatment, B cells are the main source of IL-1β and IL-6, and these cytokines mutually regulate each other’s production. Either treatment with anti-IL-1β mAb or the use of IL-1R1 KO, caspase-1 KO and MyD88 KO recipients diminished both CD4+ and CD8+ T cell recovery along with improved heart allograft survival and decreased donor-reactive IFN-γ producing cells after mATG treatment. Similarly, in vivo IL-6 neutralization with mAb or using IL-6 KO recipients delayed CD4+ and CD8+ T cell recovery, markedly prolonged heart allograft survival and decreased donor-specific T cell responses suggesting that IL-1β and IL-6 are essential for optimal T cell recovery. Adoptive B cell transfers into μMT mice showed that B cell-derived IL-1β and IL-6 supported CD8+ T cells recovery. The absence of either IL-1R or IL-6R on CD8+ T cells markedly impaired their homeostatic recovery following mATG depletion. These findings reveal the essential role of B cell-derived IL-1β and IL-6 during homeostatic T cell expansion in a clinically relevant model of lymphoablation.
Novel insights into high alloantibody production in CCR5 KO recipient mice
Authors: Han Jing Light , Zimmerer Jason M , Zeng Qiang , Ringwald Bryce A , Cassol Clarissa , Warren Robert T , Abdel-Rasoul Mahmoud , Breuer Christopher K , Bumgardner Ginny L 
Published: January 2023

Abstract

Purpose
Conventional immunosuppressants do not effectively control development of humoral alloimmunity in a substantial proportion of kidney allograft recipients. CCR5 KO (H-2b) mice are a useful model to study antibody-mediated rejection: A/J (H-2a) kidney transplant (KT) recipients produce 10x more alloantibody (alloAb) versus wild-type (WT, H-2b) mice. CXCR5+IFNγ+CD8+ T (Tab-supp) cells are a novel regulatory CD8+ T cell subset that can kill alloprimed IgG+ B cells and mediate suppression of in vivo alloAb in an allogeneic hepatocellular transplant (HcT) model. We hypothesize that high alloAb-producing CCR5 KO KT mice have reduced CD8+ Tab-supp cells.

Methods
Investigate CD8+ Tab-supp cells in peripheral blood and splenocytes of CCR5 KO compared to WT HcT and KT recipients using flow cytometry.

Results
CCR5 KO compared to WT HcT recipients had fewer splenic Tab-supp cells (8.75±2.73×103 vs 19.1±3.07×103; p=0.03). CCR5 KO compared to WT KT mice produce higher alloAb by postoperative day (POD) 14 (5,800±700 vs 1,200±100; p=.0003) and have reduced peripheral CD8+ Tab-supp cells (650±400 vs 11,500±450 per 106 PBMC; p=0.002). Alloprimed CD8+ Tab-supp cells injected into CCR5 KO KT mice are detected in the peripheral blood, spleen, and lymph nodes, but not in the allograft. CCR5 KO KT mice that receive adoptive transfer of CD8+ Tab-supp cells on POD5 produce significantly less alloAb than WT KT mice (1,200±200 vs 5,800±700; titer assayed on POD 14; p&lt;0.0001).

Conclusion
Deficiency of CD8+ Tab-supp cells is likely an important mechanism driving high alloAb production in CCR5 KO KT recipients. This subset exerts antibody suppressor function in lymphoid depots rather than in the kidney allograft.
DNA-PKcs Inhibition Extends Allogeneic Skin Graft Survival and Suppresses EGR1 and NFκB-mediated IL6 Production
Authors: Burdine Marie , Harrison David , Waldrip Zachary , Burdine Lyle 
Published: January 2023

Abstract
Organ transplantation is the only option for patients in end-stage organ failure. Therefore; it is imperative that immunological mechanisms that foster graft rejection be elucidated to develop more effective immunosuppressants for transplant patients.
In recent studies, the double-strand DNA break repair kinase, DNA-dependent protein kinase catalytic subunit(DNA-PKcs) has been implicated as a signaling molecule necessary for both B and T cell activity highlighting its potential role in graft rejection. In this study, we performed a phospho-proteomic screen to identify immunological targets of DNA-PKcs and a murine allogeneic skin graft study using DNA-PKcs inhibitors to investigate its effects on graft rejection. We identified a mechanism whereby DNA-PKcs is required for the protein stability of EGR1, a transcription factor known to promote NFκB expression. In primary splenocytes, DNA-PKcs inhibition abrogated EGR1 expression causing a decrease in NFκB-p65 levels and a reduction in the levels of the pro-inflammatory cytokine IL6 which can promote maturation of plasma cells. DNA-PKcs inhibition significantly reduced skin graft necrosis and extended graft survival compared to controls. DNA-PKcs inhibition reduced the infiltration of CD3+ lymphocytes into the grafts and the level of circulating CD19+ CD138+ lymphocytes. Additionally, DNA-PKcs inhibition reduced the production of donor-specific IgG and IgM antibodies. These results highlight a novel function for DNA-PKcs in the immune system and support further investigations into the use DNA-PKcs inhibitors in transplant therapy.
STING pathway mediated immunologic consequences of DNA damage repair gene losses in high-grade serous ovarian tumors
Authors: Shakfa Noor E. , Lightbody Elizabeth , Afriyie-Asante Afrakoma , Li Deyang , Chenard Stephen , Hamade Ali , Koti Madhuri 
Published: January 2023

Abstract
High grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy with high rates of chemotherapy resistance and poor outcomes. Our previous studies have demonstrated the variable tumor immune microenvironment states that associate with platinum chemotherapy response. We further showed the significance of the interferon induced chemokine CXCL10 as a key mediator of tumor infiltrating immune cell recruitment. Using the ID8-Trp53−/− murine model of HGSC, we demonstrated the potential of Stimulator of Interferon Genes (STING) pathway activation in enhancing response of HGSC tumors to carboplatin chemotherapy and sensitizing them to immune checkpoint blockade. Notably, CXCL10 production via IFN1 is also governed by genes that regulate cellular DNA damage repair pathways. Evolving evidence indicates a role of BRCA1 and PTEN genes in mediating cellular IFN1 responses. Losses in the function of these genes is widely prevalent in a large proportion of HGSC tumors, where tumors with BRCA1 mutations have higher CD8+ T cell infiltration in contrast to those with loss of PTEN. We hypothesized that HGSC tumors with loss of PTEN expression can be rendered susceptible to immune mediated killing via activating the STING pathway. Tumors generated from ID8-Trp53−/−; Brca1−/− cells and those from ID8-Trp53−/−; Pten−/− cells in C57BL6 mice showed significant immunologic differences. STING agonist treatment significantly increased chemosensitivity and improved overall response in mice implanted with ID8-Trp53−/−; Pten−/− cells compared to those treated with carboplatin alone, altering immune responses. This study is foundational to guide rationalistic combinations of STING pathway activating therapies in HGSC.
CARD9 Induces Metabolic Reprogramming and Mediates the Immune Cascades in Dendritic Cell Against Pancreatic Cancer Progression
Authors: Lu Yi , Tian Chen , Gou Jing , Xiang Ming 
Published: January 2023

Abstract
Caspase recruitment domain family member 9 (CARD9), a signaling adaptor protein, transduces the immune signals from pattern recognition receptors (PRR) and induces the cascaded immune response, which plays a critical role in innate and adaptive immunity. In order to explore the role of CARD9 in DCs during pancreatic cancer (PC) progression and its underlying mechanism, samples of PC in patients with different clinical stages, animal model of PC, simulated immune microenvironment in vitro were employed. We found that the immunogenicity of bone marrow-derived DCs decreased in the progression of PC, which was accompanied with downregulated CARD9 expression. And the glycolysis in DCs was attenuated accompanied with diminishing glucose uptake and reducing acidic metabolites production after CARD9 knockdown, while fatty acid oxidation (FAO) was lifted. Further, CARD9 deficiency weakened the DCs migration, antigen presentation and stimulation to CD8+ T cell immune response. Mechanically, activated CARD9 recruited Bcl10 and MALT1 and constructed CARD9-Bcl10-MALT1 signalosomes, followed by the PI3K/AKT/mTOR pathway mediated metabolic switching and NF-κB pathway induced inflammatory cascades. Furthermore, DCs with CARD9 overexpression loading antigenic peptide mucin 1 (MUC1) curbed tumor growth in mice with PC subcutaneously implanted tumor. These results reveal a new role of CARD9 as a molecular switch of glycolysis in DCs that triggers the metabolic reprogramming, antigen presentation and antitumor effects of CD8+ T cells.
Immune landscape of genetically-engineered murine models of glioma relative to human glioma by single-cell sequencing
Authors: Zamler Daniel Bernard , Shingu Takashi , Heimberger Amy , Hu Jian , Draetta Giulio F. 
Published: January 2023

Abstract
Glioblastoma (GBM) is the most frequent and deadliest primary brain tumor, with a &lt;10% 5-year overall survival rate. Despite promising results in other disease contexts, deployment of immune system-targeted therapies against GBM has not been successful thus far. In this regard, few preclinical models effectively recapitulate the human GBM immune microenvironment, hindering our ability to identify potentially targetable vulnerabilities. In this study, we characterized tumor immune microenvironment of the Qk/trp53/Pten (QPP) triple-knockout mouse model, harboring alterations common in human GBM and found that tumor infiltrates contain a predominantly myeloid cell population of monocytes, macrophages, and resting dendritic cells, with minor populations of T, B, and NK cells. Notable differences between spontaneous QPP tumors and tumors derived by implanting established QPP cell lines included T-cell enrichment and a larger proportion of myeloid-derived suppressive cells (MDSCs) in implanted tumors. Profiles of myeloid cells subtypes in QPP tumors paralleled findings in human GBMs, suggesting that this model effectively recapitulates the complexity of the myeloid-cell compartment and other human GBM immune cell populations.
Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual co-stimulation of CD8 T cells and enables sMIC tumors respond to PD1/PD-L1 blockade therapy
Authors: Dhar Payal , Zhang Jinyu , Larrocha Pablo Saenz-lopez , Zhang Bin , Wainwright Derek A , Wu Jennifer D 
Published: January 2023

Abstract
Insufficient co-stimulation has been demonstrated to account for the suboptimal activation of cytotoxic CD8 T cells (CTLs) and presumably unsatisfactory clinical expectation of PD1/PD-L1 blockade therapy. Tumor-derived soluble NKG2D ligands are associated with poor clinical response to PD1/PD-L1 blockade therapy in cancer patients. One of the most frequently occurring tumor-derived soluble NKG2D ligands, the soluble MHC I chain related molecule (sMIC) can impair co-stimulation to CD8 T cells. We investigated whether co-targeting sMIC can provide optimal co-stimulation to CTLs and enhance the therapeutic effect of PD1/PD-L1 blockades. Single agent therapy of a PD1/PD-L1 blockade antibody or a sMIC-targeting non-blocking antibody or a combination therapy of the two antibodies were implied to well-characterized pre-clinical MIC/sMIC+ tumor models that closely resemble the NKG2D-mediated onco-immune dynamics of MIC+ cancer patients. Therapeutic efficacy and associated effector mechanisms were evaluated. We show that antibody co-targeting sMIC enables or enhances the response of sMIC+ tumors to PD1/PD-L1 blockade therapy. The therapy response of the combination therapy was associated with enhanced antigen-specific CD8 T cell enrichment and function in tumors. Co-targeting sMIC with a nonblocking antibody provides antigen-specific CD8 T cells with NKG2D and CD28 dual co-stimulation, in addition to elimination of inhibitory signals, and thus amplifies antigen-specific CD8 T cell anti-tumor responses. Our findings provide the proof-of-concept rationale and previously undiscovered mechanisms for co-targeting sMIC to enable and enhance the response to PD1/PD-L1 blockade therapy in sMIC+ cancer patients.
Glial TIM-3 shows distinct expression patterns and functions in brain tumor microenvironment
Authors: Kim Hyung-Seok , Kim Ki Sun , Yoon Hee Jung , Park Eun Jung 
Published: January 2023

Abstract
T-cell immunoglobulin and mucin domain containing molecule-3 (TIM-3) is a transmembrane glycoprotein. TIM-3 has diverse immune functions, which differ according to the specific cell type and cell status and appears to play both positive and negative roles in a context-dependent manner. In this study, we questioned whether TIM-3 could be involved in immune surveillance against brain tumor, and thereby affect tumor immunity. To explore whether and how TIM-3 responds to brain tumor and whether it could play a role in specific immune cells of the brain tumor microenvironment, we used an intracranial mouse brain tumor model system. Here, we present that TIM-3 is expressed on both growing tumor cells and their surrounding cells including glial and T cells in an orthotopic mouse glioma model. Comparison of cells from tumor-bearing and contralateral hemispheres of a mouse glioma model shows that TIM-3 level is distinct in tumor-infiltrating CD45midCD11b+ glial cells. We find that TIM-3 affects the expression of several immune-associated molecules in primary glia-exposed conditioned media (CM) from brain tumors. Collectively, these findings suggest that glial TIM-3 actively and distinctively responds to brain tumor, and plays specific immunoregulatory roles in the brain tumor microenvironment.
T cell intrinsic DNA damage and repair response as a novel marker associated with clinical response to PD-1 blockade
Authors: Muroyama Yuki , Huang Alexander C. , Manne Sasikanth , Herati Ramin S. , Mathew Divij , Xu Caiyue , Chilukuri Lakshmi , Zamarin Dmitriy , Friedman Claire F , Wherry E John 
Published: January 2023

Abstract
Despite the high tumor mutational burden (TMB), immune checkpoint blockade (ICB) still fails in some microsatellite instability-high (MSI-H) tumors, suggesting the underlying T cell dysfunction. Immune profiling of PBMC from chemotherapy-resistant MSI-H uterine cancer patients treated with nivolumab identified the proliferative T cell response 2–4 weeks post PD-1 blockade. However, this “immunological response” to ICB was observed regardless of clinical response, suggesting the additional determinants of clinical outcome beyond the proliferative response or high TMB. To test the hypothesis that the gap between immunological and clinical response to ICB was related to T celI-intrinsic response to genotoxic and/or proliferative stress, a novel high dimensional cytometry platform was developed. The platform enables simultaneous analysis of T cell differentiation state and interrogation of multiple DNA damage and repair response (DDR) pathways at single cell resolution. This DDR-Immune platform revealed consistent T cell subset specific patterns of DDR, as well as specific DDR pathways induced by different types of DNA damage. Application of the DDR-Immune platform to this cohort revealed that, in clinical responders, Ki67+ CD8 T cells had rapid increase of pATM, presumably in response to proliferative stress induced by PD-1 blockade. This DDR was not clearly observed in clinical non-responders. In addition, Tregs from clinical non-responders had elevated DDRs compared to responders, suggesting their greater resistance to genotoxic/proliferative stress. Collectively, the new platform reveals previously unrecognized roles for T cell-intrinsic DDR as a novel determinant of immune responsiveness and clinical outcome.