bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pneumocystis jiroveci pneumonia in rheumatoid arthritis patient treated with methotrexate but without prednisolone: A case report
Authors: Noh Jungwon , Han Seungtae 
Published: January 2023

Abstract

Background/Purpose
Methotrexate (MTX) is an anchor drug for rheumatoid arthritis (RA) if there is no contraindication. However, MTX can increase the risk of opportunistic infections including Pneumocystis jiroveci pneumonia (PCP) if combined with other immunosuppressive drugs such as prednisolone. Herein, we report a case of an RA patient who developed PCP during MTX treatment without prednisolone.

Methods
A 63-year-old woman with RA was admitted with high fever and shortness of breath. She had demonstrated stable RA activity after taking MTX 12.5 mg/week in addition to leflunomide 10mg daily for RA; however, about five months ago, she stopped taking low dose prednisolone. Computerized tomography (CT) of the chest demonstrated diffuse ground glass opacities in bilateral middle and lower lung fields. Laboratory examinations showed β-D-glucagon 140.2 pg/ml. A polymerase chain reaction (PCR) assay of bronchoalveolar lavage (BAL) fluid showed Pneumocystis carinii (PC). MTX and leflunomide were immediately discontinued. High dose trimethoprim/sulfamethoxazole (TMP-SMX) and methylprednisolone pulse therapy were administered. Following treatment, clinical and radiographic improvement were noted.

Results
The risk factors for RA-PCP have been reported by several studies. However, in this case, the patient had not taken prednisolone for more than five months before the occurrence of PCP and was considered low risk for PCP. In the RA patient, with or without risk factors, PCP should be considered in the differential diagnosis for respiratory infection and interstitial pneumonitis, including MTX-induced pneumonitis.

Conclusion
In the RA patient, MTX should be considered an important risk factor of PCP.
Generation of islet antigen-specific engineered Treg for use in T1D therapy via homology-directed gene editing of conventional CD4+ T cells
Authors: Yang Soo Jung , Singh Akhilesh , Cook Peter , Honaker Yuchi , Tappen Tori , Mauk Kelsey , Smith Jessica , Sommer Karen , Rawlings David J , Buckner Jane H 
Published: January 2023

Abstract
Adoptive transfer of regulatory T cells (Treg) is therapeutic in T1D mouse models. Notably, Treg specific for pancreatic islets are more potent than polyclonal Treg in blocking disease. However, the frequency of antigen-specific Treg is extremely low and ex vivo expansion has the potential to destabilize Treg leading to an effector phenotype. Here, we developed methods to generate durable, antigen-specific engineered (ed)Treg from primary human CD4+ T cells using a combination of lentiviral TCR transduction and FOXP3 homology-directed repair (HDR)-editing. Using TCRs derived from clonally expanded CD4+ T cells in T1D, we generated islet-specific edTreg that exhibit a Treg-like phenotype. Islet-specific edTreg effectively suppress proliferation and cytokine production by islet-specific effector T cells (Teff). Notably, edTreg suppress Teff recognizing the identical peptide as well as bystander Teff recognizing alternative islet antigens. Consistent with this, islet-specific edTreg suppress polyclonal islet-specific T cells derived from PBMC. Further, edTreg expressing TCR with high avidity have superior suppressive capacity to those expressing TCR with low avidity. To directly assess the capacity of edTreg to modulate T1D in vivo, we established an identical HDR-editing strategy in islet-specific murine cells. Adoptively transferred islet-specific mu-edTreg homed to the pancreas and blocked diabetes triggered by islet-specific Teff in recipient mice. Collectively, our approach enables the production of edTreg specific to pancreatic islets with the capacity to efficiently suppress islet specific responses. This approach has the capacity to deliver targeted islet specific therapy to treat or prevent T1D.
CD126 negative regulatory cells represents a superior Treg subset in treating autoimmune diseases
Authors: Zheng Song Guo , Chen Ye , Jarjour Wael , Wang Julie 
Published: January 2023

Abstract
Treg cells play an important role in maintaining immunologic homeostasis. Abnormal Treg were found in some autoimmune diseases. Infusion of natural Treg (nTreg) prevents some autoimmune disease but usually fails to treat established diseases. Several studies demonstrated nTreg could be transdifferentiated into Th17 cells and lost its function under inflammatory condition. Given IL-6 is an important inflammatory cytokine and it binds to its receptor (CD126) to exert functional role, whereas nTreg express CD126, we hypothesize that CD126− Foxp3+ cell subsets could be more stable and functional in the inflammatory condition.
CD126+ and CD126− nTreg were sorted from collagen-induced arthritis (CIA) and then were analyzed for transcript difference via RNA-sequence. They were cultured in the presence of IL-6 to determine the stability and function following a colitis model in vivo.
Compared to normal mice, the proportion of CD126+ nTreg in CIA was significantly higher. CD126− nTreg express higher immunosuppressive molecules and present stronger function than CD126+ nTreg in both normal condition and presence of IL-6. Moreover, CD126− nTreg was stable while CD126+ nTreg lost Foxp3 expression and trans-differentiated into Th17 in the presence of IL-6. In addition, CD126− nTreg exhibited reduced Hif-1a and glucose transporter 1(Slc2a1) expression, which are two key regulators of glycolytic metabolism and play an important role in the balance of Th17 and Treg. Finally, CD126− Treg more potent treat colitis compared to control.
We show CD126− nTreg present stronger function and stability under inflammatory conditions Our results suggest that manipulation of CD126− nTreg might be a novel strategy for the treatment of autoimmune diseases.
Antigen-specific suppression of previously activated T cell responses via polymeric GalNAc antigen conjugation
Authors: Tremain Andrew C. , Wilson D. Scott , Hubbell Jeffrey 
Published: January 2023

Abstract
Current treatments for autoimmunity, allergy, and drug hypersensitivity require continuous global immune suppression. Here we demonstrate in vivo therapeutic efficacy of antigen-specific T cell tolerance induction following prior immunization in various models of murine immunity. Our lab has engineered an N-acetylgalactosamine polymer (pGal) that can be conjugated to protein antigen and delivered intravenously to immunosuppressive hepatic antigen presenting cells, thereby inducing lasting immune regulation without off target effects. In this work, we show treatment with pGal-ovalbumin (OVA) conjugates can suppress previously activated T cells in an antigen-specific fashion. We describe the suppressive effects and underlying signatures of tolerogenic T cell reprogramming by comparing treatment with native OVA to pGal-OVA. Therapeutic treatment with pGal-OVA results in reduced T cell expansion and activation after secondary challenge, higher expression levels of suppressive/exhausted markers such as PD1 and TOX, and markedly lower production of cytokines including IFNg, TNFa, and IL-17 following in vitro restimulation with antigen. Further investigation of antigen-specific tolerance induction utilizing pGal-conjugates can lead to potentially curative approaches for controlling aberrant immunity to self or innocuous foreign protein.
Lidocaine improves psoriasis by calming down inflammatory cells
Authors: Wang Honglin , YIN Qianqian 
Published: January 2023

Abstract
Psoriasis is an incurable chronic skin disease. In addition to immune system participation, cutaneous nervous system has long been reported to play a role in psoriasis pathogenesis. However, the clinical application and underlying mechanism of how peripheral sensory nervous system works during psoriasis pathogenesis are largely unknown. Here we report a new and straight-forward clinical strategy using epidural injection of lidocaine to directly manipulate peripheral sensory nervous system, resulting in significant PASI score improvement of psoriasis patients. Imiquimod-induced rat model of psoriasis shows consistent therapeutic effect with epidural injection of lidocaine. Transcriptome analysis of lidocaine-treated rat primary sensory neurons indicates that lidocaine may function through calming down neuronal proinflammatory chemokines (CCL2, CCL7 and CCL21), cytokines (IL-34 and TSLP). Collectively, our results reveal that direct modulation of peripheral sensory nervous system by epidural treatment with lidocaine reveals a novel and promising therapy for psoriasis treatment.
High affinity oligoclonal TCRs define effective adoptive T-cell therapy targeting mutant KRAS-G12D
Authors: Sim Malcolm John Wyness , Lu Jinghua , Spencer Matthew , Hopkins Francis , Tran Eric , Rosenberg Steven A , Long Eric O , Sun Peter Daopin 
Published: January 2023

Abstract
Complete regression of cancer has been observed in a subset of patients following adoptive T-cell transfer (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TIL). However, the low success rate of ACT presents a great challenge to broader clinical application. To provide a rational approach to TIL-based immunotherapy, we developed a three-pronged approach to comprehensively evaluate clinically relevant traits of TIL-TCR. We applied the approach to a successful case of ACT where regression was observed against tumors carrying the hotspot mutation KRAS-G12D. We show that only G12D mutant peptides (a nonamer and a decamer) but not wildtype peptides can be presented by HLA-C*08:02. Structurally, the mutated Asp formed a salt bridge necessary for HLA-C binding. Therapeutic TCRs exhibited high affinity anti-tumor binding both in solution and on reconstituted T-cells. The nonamer G12D is recognized by multiple TCR9 through conserved contacts on their shared CDR2β and CDR3α, allowing CDR3β variation to generate an oligoclonal response. The decamer G12D is recognized by TCR10 through an induced peptide conformation. Interestingly, the antigen binding affinities of these TIL-TCR inversely correlated with their persistence in vivo. Importantly, the successful ACT contained TCRs specific for two non cross-reactive conformationally distinct tumor epitopes. We conclude that successful ACT requires high affinity oligoclonal TCRs with specificity for multiple antigens to optimize tumor clearance and in vivo persistence. This approach has the potential to transform current trial and error aspect of TIL-based immunotherapy to a rational selection of TCRs with optimal therapeutic properties.
Synthetic MyD88 co-stimulation in donor CD8+ T cells enhances T cell activation, function, and tumor control in experimental hematopoietic cell transplant
Authors: Ciavattone Nicholas G , Wu Long , O’Neill Rachel , Davila Eduardo , Cao Xuefang 
Published: January 2023

Abstract
Allogeneic hematopoietic cell transplantation is a potentially curative treatment for blood cancers. Nevertheless, some patients will relapse and succumb to their cancer. Donor lymphocyte infusion of CD8+ T cells with transplant evidently provides further protection from recurrent malignancies. Further engineering the donor CD8+ T cells to respond to the tumor may provide even further protection in patients. Novel co-stimulation through Toll-like Receptors in CD8+ T cells enhances T cell activation and function through the MyD88 adaptor protein. Previously, we developed a synthetic MyD88 linked to CD8 which drives MyD88 signaling with T cell activation. This tool enables assessment of the role of MyD88 in CD8+ T cell function and helps determine the benefit of this pathway in T cell immunotherapies. Our studies show that donor CD8+ T cells transduced with this construct (CD8-MyD88 T cells) increase the graft-versus-tumor response in experimental mouse transplants with A20 lymphoma. Further studies show engineered CD8-MyD88 T cells proliferate better in the host and elicit greater production of functional cytokines and Granzyme B compared to controls. Increased granzyme B production from CD8-MyD88 T cells did not hinder their activation and these cells displayed enhanced survival. Using in vitro cytotoxicity assays we determined that the tumor control is a direct result of T cell cytotoxicity and that this effect is enhanced with host-Antigen Presenting Cells. Increases in GvHD were indicated in host mice, specifically relating to weight loss, however the symptoms occurred with no mortality. Future experiments will explore the specific mechanism of tumor killing and delineate the cause of GvHD symptoms from donor CD8-MyD88 T cells.
Modulating extracellular TCR-CD3 interaction to identify new immunotherapy targets against cancer
Authors: Krogsgaard Michelle , Natarajan Aswin , Velmurugu Yogambigai , Yuan Zhou , Ge Chenghao , Nadarajah Vidushan , Cardozo Timothy , Bracken William C. , Zhu Cheng 
Published: January 2023

Abstract
T cell recognition of antigen and resulting proximal signaling are key steps in the initiation of the adaptive immune response. Previous studies targeting antigen binding site for enhancing T-cell responses to tumor antigens often lead to off-target effects and toxicity. Recently, we used nuclear magnetic resonance (NMR) spectroscopy, mutational analysis and computational docking to derive a 3D structure of the extracellular TCR-CD3 assembly. Further, biomolecular force probe (BFP) measurements allowed us to determine how 2D affinity and force-modulated TCR-pMHC kinetics depend on TCR-CD3 interaction sites and affect transduction of extracellular pMHC-TCR ligation into T cell function. Based on our TCR-CD3 structural model and binding data, we generated TCR libraries for a melanoma-specific TCR (DMF5) using site-specific mutagenesis in the Cbhelix 3 and helix 4-F strand regions of the TCR to optimize the TCR-CD3 interaction and to select for mutants with enhanced T-cell effector function. One Cb helix 4-F strand mutant, NP202203AA showed increased T cell response to antigen and showed enhanced TCR-pMHC bond lifetime (catch-bonds) in BFP assays leading to prolonged T cell signaling. In the future, DMF5 TCR with reengineered CD3 binding regions will be used in tumor rejection in pre-clinical mouse melanoma models for efficacy and toxicity to develop more effective T cell therapies for human targets.
Bispecific anti-CD22 T-cell engager efficiently promotes cell-mediated cytotoxicity of lymphoma, leukemia and sarcoma targets
Authors: Barisone Gustavo A , Vang Daniel P , Murphy William J , Tuscano Joseph 
Published: January 2023

Abstract
Immunotherapy has revolutionized cancer therapy. Two of the most recently FDA-approved immunotherapies for B-cell malignancies target CD19, in the form of a Bispecific T-Cell Engager (BiTE) antibody construct or CAR-T cells. Blinatumomab, and FDA-approved BiTE, binds to CD19 on B cells and to CD3 on T cells, mediating killer-target cell contact and T cell activation that results in effective elimination of B cells. Although CD19 is expressed by essentially all cases of B cell malignancies at clinical presentation, relapses with loss or reduction of CD19 surface expression are increasingly recognized as a cause of treatment failure.
We have developed a novel BiTE consisting of humanized anti-CD22 and anti-CD3 single chain variable fragments, expressed as a single molecule and purified from tissue culture supernatant. Binding of the anti-CD22 and anti-CD3 moieties to B and T cells, respectively, was confirmed by flow cytometry. CD22-BiTE promoted cell-mediated cytotoxicity in a dose and E:T-dependent fashion, with a maximum NHL and ALL-specific killing activity of 90% in vitro. Besides canonical expression in B cells, CD22 has been reported in non-hematologic malignancies. Our analysis of TCGA data suggests CD22 is expressed in a variety of solid tumors, including sarcoma. We verified expression of CD22 message and protein in solid tumor cell lines. Accordingly, our CD22-BiTE mediated killing of HT1080 sarcoma cells in vitro.
In conclusion, we report here the development of a new BiTE with killing activity against CD22+ malignancies which could represent a therapeutic option for B-cell malignancies and potentially solid tumors.
Heteroclitic peptide cancer vaccine counters MHC-I skewing in mutant calreticulin-positive myeloproliferative neoplasms
Authors: Gigoux Mathieu , Zappasodi Roberta , Park Joseph J , Pourpe Stephane , Ghosh Arnab , Bozkus Cansu Cimen , Mangarin Levi M.B. , Redmond David , Verma Svena , Schad Sara , Duke William , Leventhal Matthew , Jan Max , Ho Vincent , Hobbs Gabriella , Knudsen Trine Alma , Skov Vibe , Kjær Lasse , Larsen Thomas Stauffer , Hansen Dennis Lund , Lindsley R Coleman , Hasselbalch Hans , Grauslund Jacob H , Andersen Mads H , Holmström Morten O , Chan Timothy , Rampal Raajit , Abdel-Wahab Omar , Bhardwaj Nina , Wolchok Jedd D , Mullally Ann , Merghoub Taha 
Published: January 2023

Abstract
The majority of JAK2WT myeloproliferative neoplasms (MPN) have disease-initiating frameshift mutations in calreticulin (CALR) resulting in a common novel C-terminal mutant fragment (CALRMUT), representing an attractive source of neoantigens for cancer vaccines. However, studies have shown that CALRMUT-specific T cells are rare in CALRMUT MPN patients, but the reasons for this phenomenon are unknown. In this study, we examine class-I major histocompatibility complex (MHC-I) allele frequency in CALRMUT MPN patients from two independent cohorts and observed that MHC-I alleles that present CALRMUT neoepitopes with high affinity are under-represented in CALRMUT MPN patients. We speculate that this is due to an increased chance of immune-mediated tumor rejection by individuals expressing one of these MHC-I alleles. As a result of this MHC-I allele restriction, we reasoned that CALRMUT MPN patients would not efficiently respond to cancer vaccines composed of the CALRMUT fragment, but could do so with a properly modified CALRMUT heteroclitic peptide vaccine approach. We found that heteroclitic CALRMUT peptides designed for CALRMUT MPN patient MHC-I alleles elicited a cross-reactive CD8+ T cell response in human PBMC samples otherwise unable to respond to the matched weakly immunogenic CALRMUT native peptides. We also modeled this effect in mice and observed that C57BL/6J mice, which are unable to mount an immune response to CALRMUT, can mount a cross-reactive CD8+ T cell response against a CALRMUT peptide upon heteroclitic peptide immunization and this was further amplified by combining with anti-PD-1. Together, our data underscore the therapeutic potential of heteroclitic peptide-based cancer vaccines in CALRMUT MPN patients.
Tumor-derived lactate inhibits methylation levels of SGK1 in myeloid-derived suppressor cells to promote GLUT1-mediated glucose uptake and metabolic reprogramming
Authors: Ma Jie , Shen Hua , Xu Huaxi , Wang Shengjun 
Published: January 2023

Abstract

Objective
Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-associated immunosuppressive function, our previous results have confirmed that MDSCs in the tumor microenvironment have stronger glucose uptake capacity and higher glycolysis activity compared with MDSCs in the spleen of mice lung cancer xenograft model. This may be related to metabolic reprogramming, but little is known about the metabolic reprogramming of MDSCs and its regulatory mechanism in the tumor microenvironment.

Methods
We screened changes in gene expression levels before and after lactate treatment in MDSCs by transcriptome sequencing. The methylation levels of SGK1 were confirmed by BSP sequencing.

Results
we found that lactate, a metabolite found in high concentration within the anaerobic tumor environment, increased the glycolysis activity and immunosuppressive function of mouse spleen MDSCs. After the treatment of lactate, the expression of SGK1 was significantly up-regulated, and the methylation level of SGK1 was greatly reduced. Furthermore, methylation of SGK1 increases expression of GLUT1 and transfers to cell membrane, thereby increasing glucose uptake and glycolytic activity of MDSC.

Conclusions
We believe this is a new mechanism through which tumor cells up-regulate the expression of SGK1, thereby promoting the glucose uptake and metabolic reprogramming of MDSCs by regulating the cell localization of GLUT1. Together, our results highlight the ability of tumor cells to alter the metabolic reprogramming and function of tumor infiltrating MDSCs to optimize the tumor growth microenvironment.
Pathways from glutamine to apoptosis: ROS and PP2A in SKW6.4
Authors: Kim YunKyu , Yang Hun Ji , Yeo Myeong Gu , Lee Kyung Jin 
Published: January 2023

Abstract
Altered glutamine metabolism is emerging target of cancer therapy. Glutamine deprivation has been proposed to induce apoptosis in multiple cancers. Dependency on glutamine metabolism of skw 6.4 lymphoma cell was investigated in vitro and in vivo. Glutamine deprivation induces apoptosis of skw 6.4 cell. Intracellular concentration of metabolites in tricarboxylic acid cycle and glutathione concentration were reduced and concentration of reactive oxygen species (ROS) and expression of PP2A were increased in glutamine-deprived skw6.4 cell. Reduction of ROS by antioxidants and knockdown of PP2A inhibited apoptosis induced by glutamine deprivation. Glutamine antagonist reduces skw6.4 tumor size in mouse xenograft model in PP2A-dependent manner. Overall, these results suggest survival of skw6.4 cells depends on the supply of glutamine in PP2A-dependent manner.
Apigenin modulates immune checkpoint molecules in pancreatic cancer enhancing anti-tumor immunity
Authors: Villalobos-Ayala Krystal , Luongo Jessica , Marsh Ari , Areas Javier , Miller Bradley , Williamson Tanika , Husain Kazim , Ghansah Tomar 
Published: January 2023

Abstract
Pancreatic cancer (PC) remains as a very aggressive malignancy with an extremely poor prognosis and an overall 5-year survival rate of only 8%. Immunotherapies are promising against solid tumors with exception of PC. This poor prognosis is partly due to PC’s inflammatory tumor microenvironment, resulting in an increased expression of both Programmed Death-Ligand (PD-L1) in tumors and Programmed cell death protein 1 (PD-1) on effector CD8+ T cells. Upon PD-L1/PD-1 interaction, CD8+ T cells exhibit anergy, allowing PC evasion and tumor progression. We hypothesize that reducing PC-induced inflammation will increase anti-tumor immune responses and promote tumor regression. Therefore, we examined the expression of checkpoint molecules (PD-L1, PD-L2, PD-1, Major Histocompatibility Complex-I, etc.) in different murine PC cell lines (i.e. Panc02, UN-KPC-960, UN-KC-6141) and modulation by an anti-cancer natural bioflavonoid called apigenin (API). To do this, we treated the PC cell lines, in vitro, with and without API along with interferon-γ (potent inducer of PD-L1) to detect the expression profiles of these checkpoint molecules using flow cytometry. Subsequently, we tested T cell proliferation in response to untreated/treated PC cells. Our results show that API down-regulated PD-L1 expression on PC cell lines, which coincides with increased T cell responses. Our results suggest that API may reduce PC-induced immunosuppression allowing increased anti-tumor immunity. Therefore, clinical application of API as an adjuvant may potentiate the efficacy of current PC immunotherapies.