bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of Protein Tyrosine Phosphatase Non-receptor 13 in Myofibroblast Apoptosis and Pulmonary Fibrosis (98.25)
Authors: Bamberg Alison B , Frankel Steve , Wynes Murry , Riches David W.H. 
Published: January 2023

Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal, fibrotic lung disease of unknown origin. Fibrogenesis is mediated in part by the accumulation and persistence of myofibroblasts in fibroblastic foci wherein they secrete collagen and other matrix components. Impaired apoptosis is thought to contribute to myofibroblast accumulation in IPF. Human lung myofibroblasts basally express Fas but are resistant to Fas induced apoptosis; however, exposure to TNFα and IFNγ prior to Fas ligation overcomes basal resistance. In this study we address the hypothesis that exposure to TNFα and IFNγ down-regulates the expression of a Fas-associated inhibitory protein, Protein Tyrosine Phoshatase Non-receptor 13 (PTPN13), thereby enabling the formation of the death-inducing signaling complex (DISC). Exposure of lung myofibroblasts to TNFα and IFNγ decreased PTPN13 mRNA and protein expression and also increased assembly of the Fas DISC. In addition, specific knockdown of PTPN13 expression in human lung fibroblast cell lines sensitized cells to Fas induced apoptosis. Understanding the regulation of PTPN13 expression in lung tissues may reveal new approaches to treating this currently incurable disease.
IMMUNE RESPONSES IN AUTOIMMUNE HEPATITIS: EFFECT OF PREDNISONE AND AZATHIOPRINE TREATMENT (98.31)
Authors: Bluth Martin H , Kohlhoff Stephan , Nowowitz Kevin B , Silverberg Jonathan I , Chice Seto , Nowakowski Maja , Durkin Helen G , Smith-Norowitz Tamar A 
Published: January 2023

Abstract
Rationale: The role of the immune response in autoimmune hepatitis has not been studied before and after prednisone and azathioprine treatment.Methods: Distributions of blood lymphocytes (CD4+, CD8+, CD19+, CD23+, CD16/56+), levels of serum immunoglobulins (IgM, IgG, IgE, IgA) and cytokines (IFN-ã, IL-4, IL-12, TNFá ) were studied in a child (f/14 y/o) with autoimmune hepatitis before and after prednisone (20 mg/d) and azathioprine (50 mg/d) treatment (nephelometry, UniCAP Total IgE Fluoroenzymeimmunoassay, flow cytometry, cytokine ELISA). Patient was studied for 0-2.5 yrs; treatment was initiated 12 weeks post diagnosis.Results: Numbers of CD4+ T cells increased (50%), while CD19+ and CD23+ cells decreased (&gt;50%) post treatment; other lymphocyte subsets were unaffected by treatment. Serum IgG and IgE levels decreased (&gt;50%) after treatment; serum IgM and IgA were within normal range and were not affected by treatment High levels of IFN-ã (5-23 pg/ml) were initially detected in serum, which decreased after treatment (&lt;0.1 pg/ml). In contrast, low levels of IL-4 (0.2 pg/mL) were detected before treatment, which were not detected after treatment (&lt;0.1 pg/ml). Before treatment, IL-12 and TNFá were not detected in serum; however after treatment the levels of IL-12 and TNFá dramatically increased.Conclusions. Prednisone and azathioprine treatment decreased total serum IgG, IgE, IFN- â and IL-4 levels, and blood CD19+ and CD23+ cells; however serum IL-12, TNFá and blood CD4+ T cells increased with treatment. Understanding immunomodulation in autoimmune hepatitis will provide better insight and mechanisms of this disease and may tailor more effective therapeutic intervention.
Interphotoreceptor retinoid-binding protein (IRBP)-specific Th1 and Th17 cells in monophasic and recurrent experimental autoimmune uveitis (EAU) (99.10)
Authors: SHAO HUI , Bian Yang , Ke Yan , Wang Yali , Kaplan Henry J. , Sun Deming 
Published: January 2023

Abstract
Emerging evidence supports the notion that the IL-17 producing T cells (Th17 cells) play an important role in the inflammatory response of autoimmune diseases. We wished to determine whether eye-infiltrating autoreactive T cells differ between monophasic and relapsing uveitis, and whether Th1 and Th17 autoreactive T cells play distinctive roles in monophasic versus recurrent uveitis. Analysis of the cellular components of eye-infiltrating cells revealed that within the inflamed eye of m-EAU, Th17 cells were dominant in the earlier stage, and declined gradually with disease resolution. In contrast; the number of Th1 cells was lower than Th17 cells in the early stages of disease but gradually increased during the peak and remission of eye inflammation. During r-EAU, abundant IFN-r single positive cells and IFN-rIL-17 double positive T cells were found in the early stage of disease; the double positive cells gradually declined, while the IFN-r T cells persisted in the entire disease process. Only a few IL-17 single positive T cells were found in the inflamed eye during the entire disease episode. Our studies indicate that a change in the ratio of autoreactive T cell subsets between Th17 and Th1 appears to correlate with disease recovery of m-EAU. The appearance of IFN-rIL-17 double positive autoreactive T cells may correlate with the acute attack of eye inflammation in r-EAU. The pathogenic and immunoregulatory function of single positive and double positive autoreactive T cells remain to be further investigated.
Defective programmed death ligand-1 (PD-L1) expression on monocytes from systemic lupus erythematosus (SLE) patients can be corrected by a soluble T lymphocyte factor (99.15)
Authors: Ou Jing-Ni , Mozaffarian Neelufar , Wiedeman Alice , Stevens Anne 
Published: January 2023

Abstract
PD-L1 is an inhibitory protein expressed on monocytes (Mo) to maintain peripheral T cell tolerance. We previously reported deficient expression of PD-L1 on Mo from patients with active SLE. To investigate the mechanisms for dysregulated PD-L1 expression in SLE we isolated peripheral blood mononuclear cells (PBMC) from juvenile SLE patients and age-matched controls. PD-L1 expression was measured by flow cytometry and realtime quantitative RT-PCR. Cytokines were analyzed by Luminex.
We found that PD-L1 expression on SLE Mo was significantly induced by PBMC or CD4+ T lymphocytes from healthy subjects, and also by supernatant from healthy PBMC. Conversely, PD-L1 expression was decreased in healthy donor Mo by addition of SLE PBMC or supernatant. SLE cells had an increased rate of apoptosis, and inhibition of caspase activity led to decreased apoptosis and upregulation of PD-L1. PD-L1 mRNA expression did not correlate with protein expression. Among 15 cytokines tested, only IL-2 and IL-10 were elevated in plasma of SLE patients with active disease.
These results suggest that expression of PD-L1 in juvenile SLE is controlled by caspases at the protein level via soluble factors normally produced by T lymphocytes. Abnormal T lymphocyte activity in SLE may prevent induction of PD-L1, leading to loss of peripheral tolerance.
Supported by the Lupus Foundation and the Lupus Research Institute
Altered PD-1-PD-L1 Pathway in CD8+ T cells of (New Zealand Black x New Zealand White) BWF1 Mice with Anti-PD-1 antibody (99.29)
Authors: Wong Maida , Hahn Bevra , La Cava Antonio , Singh Ram P 
Published: January 2023

Abstract
PD1-PD-L1 is a costimulatory pathway that regulates self-tolerance by providing negative signals to T cells, resulting in anergy and decreased cytotoxicity. We have shown that induction of suppressive CD8+ T cells (CD8+Ti) reduces PD-1 expression on suppressor cells, which links to increased Foxp3 and TGF-£] expression. These induced CD8+Ti suppress proliferation of CD4+CD25- T cells; however, suppression is abrogated by silencing of PD-1. In untreated mice, the number and percentage of CD8+Ti in PBMC decreased over time, with increased PD-1. Blocking PD-1 increased TGF-ƒÒ expression and decreased anti-DNA and total IgG production Untreated mice developed &gt;2+ proteinuria at week 30, and began to expire at week 39. Yet, mice treated with anti-PD-1 Ab had &lt;2+ proteinuria until 45 weeks old, and survival was 100% until 50 weeks old.
PD-1 is likely one of the core participants in inherent autoreactivity of CD8+Ti and in the mechanisms of immune tolerance in our model. Blocking PD-1 in untreated mice delays autoantibody production and nephritis for weeks. TGF£] up-regulation suggests that blocking PD-1 may affect on CD8+ T cell suppression by TGF£] secretion. However, PD-1 abrogation 1 prevents the suppressive capacity of tolerized CD8+Ti. Downregulation may be needed to release the inhibitory capacity of the cells to permit full generation of inhibitory and cytotoxic CD8+ T cells. PD-1 expression has to be finely tuned to enable CD8+Ti to control autoimmunity.
Analysis of gender-based disparity in Treg populations in young lupus-prone mice (99.30)
Authors: Tucker Colleen F , Parnell Sarah A , Alard Pascale , Kosiewicz Michele M 
Published: January 2023

Abstract
Females have a higher incidence of autoimmune disease than males. There is a consistently greater disparity in Foxp3+ Treg% between young females and males in autoimmune- vs non-autoimmune prone strains of mice, i.e., lupus-prone BWF1 female mice had lower Treg% than males. This disparity was not due to differences between female and male BWF1 mice in thymic production or homeostatic proliferation of Tregs in vivo, or the ability to convert Tregs in response to TGFβ, but could be due to the significantly higher rates of non-Treg CD4+ cell proliferation in vivo in female mice. These data also raised the interesting possibility that female BWF1 Tregs are less effective at controlling CD4 cell proliferation in vivo than males. However, Tregs from female and male BWF1 mice exhibited no differences in regulatory function in vitro. Likewise, no differences in the sensitivity of female and male CD4+ responders to suppression by Tregs or in the ability of splenic APC from female and male mice to activate regulatory cell function in vitro were detected. These data suggest that the failure to control CD4 cell activation in female BWF1 mice very likely contributes to disease development; this failure is due not to defects inherent in either the cells that regulate or are regulated, but rather to environmental factors that actively and transiently affect either or both cellular components of the response. Supported by LRI
Immune stress-induced generation of tumor variants deficient in CXCL9/Mig expression (100.11)
Authors: Gorbachev Anton , Petro Marianne , Fairchild Robert 
Published: January 2023

Abstract
Mechanisms promoting expansion of non-melanoma skin cancers remain poorly understood. Studies using a murine model of cutaneous fibrosarcoma demonstrated that although primary tumor growth is suppressed by IFN-g-dependent host immunity, the tumor eventually escapes this immunosurveillance. To investigate mechanisms of this process we used ELISPOT assays to demonstrate that the ability of tumor cells to produce the IFN-g-inducible chemokine CXCL9/Mig decreased during progression of cutaneous fibrosarcomas in immunocompetent wild type mice, but not in immunodeficient RAG1-/- mice. Tumor cell suspensions obtained from tumors excised at different time points were subcloned by limiting dilution and clones tested for IFN-g induced Mig. The frequencies of Mig-deficient tumor cells were higher in tumors growing in wild type mice vs. from RAG1-/- mice. Mig-deficient variants were highly tumorigenic in comparison to Mig-producing tumor clones when implanted into wild type mice. Furthermore, Mig-deficient tumor variants appeared within tumors induced by implantation of Mig-producing tumor clones into wild type mice, but not within tumors implanted into RAG1-/- mice. The results suggest that Mig-deficient variants arise from Mig-producing tumor cells and expand as a result of T cell-mediated immune stress that eliminates Mig-producing tumor cells faster than Mig-deficient tumor variants
Calcineurin Aβ signalling is required for Treg-cell generation and prevention of T-cell activation and B-cell lymphomagenesis (100.13)
Authors: Bommireddy Ramireddy , Chen Dora , Gard Connie , Molkentin Jefferey , Rimsza Lisa , Doetschman Tom 
Published: January 2023

Abstract
Introduction: Calcineurin (CN), a protein phosphatase activated by Ca2+-calmodulin, is involved in activation of NFAT. CN inhibitors such as cyclosporine A (CsA) and FK506 are potent inhibitors of T-cell responses and are commonly used to prevent graft rejection. Consistently, CNAβ-deficient mice exhibit defective thymocyte maturation in young mice. However, T cells undergo spontaneous activation in older Cnab-/- mice, and succumb to B-cell lymphomas. Methods: Splenocytes are cultured in the presence of anti-CD3/CD28 beads, TGFβ1 and IL-2 for 3 days. Cytokines in culture supernatants are determined by ELISA, CBA and MSD methods. Cells are stained with CD4, CD25, CD62L and intracellular FOXP3. Results: We observed that FOXP3+ Treg cells are decreased while mature activated T cells (CD62L-CD44+) are increased in KO mice compared to control mice. While TGFβ1 induced the expression of FOXP3 in WT cultures, it failed to induce FOXP3 in KO cultures. Cytokine profiles revealed that CNAβ is required to inhibit IL-4, IL-6, IL-10, IL-17 and IFNγ by TGFβ1. IHC analyses of lymphomas revealed that the lymphomas are of B cell origin and they do not express FOXP1, a marker for activated B cells (ABCs). Discussion: These data show that CNAβ is important for the development and homeostasis of mature T cells and Treg cells. The data also suggest that in the absence of CNAβ, a defective T-cell regulation results in activation of T cells, production of inflammatory cytokines and cause cancer.
Myeloid-derived suppressor cells express the death receptor Fas and apoptose in response to T cell-expressed FasL (100.18)
Authors: Sinha Pratima , Chornoguz Olesya , Clements Virginia , Artemenko Konstantin , Zubarev Roman , Ostrand-Rosenberg Suzanne 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSC) accumulate to high levels in individuals with a variety of conditions including cancer, chronic inflammation, and stress, where they are potent inhibitors of adaptive and innate immunity. Some of the factors that induce their accumulation are known; however, physiological conditions that regulate their turn-over have not been identified. Mass spectrometry analysis revealed prominent expression of apoptosis pathway proteins by MDSC and led us to hypothesize that Fas/FasL-mediated apoptosis may be a key mechanism that regulates MDSC turn-over. This hypothesis was confirmed by the findings that MDSC levels significantly regress after removal of primary mammary tumors from STAT6-deficient or CD-1-deficient mice, but do not regress in mice doubly deficient for FasL and STAT6 or CD-1. Flow cytometry and confocal microscopy studies examining activated caspase 3 expression and cytochrome C localization revealed that MDSC apoptosis is triggered via the extrinsic, and not the intrinsic, pathway. Surprisingly, activated FasL+ T cells mediated MDSC apoptosis in vivo, demonstrating a retaliatory relationship between these two cell populations, and suggesting that Fas-FasL interactions could be exploited as a strategy to reduce in vivo levels of MDSC.
Administration of cannabinoids enhances growth and metastasis of 4T1 murine breast cancer through the induction of myeloid derived suppressor cells. (100.2)
Authors: Jackson Austin , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Breast cancer is the most prevalent type of cancer afflicting women with more than 190,000 new cases diagnosed per year and over 40,000 deaths. The active ingredient in marijuana (Cannabis sativa), delta9-tetrahydrocannabinol (THC) as well as endogenous cannabinoids, such as anandamide, have been shown to exert effects on immune cells that express the cannabinoid(CB) receptors. We have previously shown that when mice are inoculated with 4t1 murine mammary carcinoma and treated with THC, the tumor grows and metastasizes more rapidly when compared to vehicle controls, resulting from immunosuppression. However, the mechanism for the loss of immune surveillance following THC treatment is not clear. Upon treatment of tumor-bearing mice, there was a significant increase in primary tumor size following THC treatment when compared to controls. Histopathological analysis demonstrated more tumor nodules in the lungs in groups exposed to THC. The splenocytes and pulmonary lymphocytes were assessed for the presence of MDSCs. There was an increase in MDSC in the lungs and spleens in cannabinoid-treated mice when compared to controls. Our studies therefore demonstrated that 4T1 mammary tumor-bearing mice elicited the development of MDSC in the spleens and lungs and the frequency of these cells was enhanced following administration of THC. Thus, we suggest a role for MDSCs in the cannabinoid-induced immune suppression in breast cancer patients that may result in enhanced tumor growth.
Defective antigen-presenting cell function of MDSCs from late stage tumor-bearing mice can be recovered by ATRA treatment. (100.3)
Authors: Lee Jung-Mi , Kim Eun-Kyung , Kim Yeon-Jeong , Kim Yun-Sun , Kang Chang-Yuil 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs), which accumulate during tumor progression, have recently been shown to function as the main suppressor cells. In our previous study, we showed that poorly immunogenic MDSCs could function as immunogenic antigen presenting cells (APCs) with the help of activated natural killer T (NKT) cells. However, depending on the tumor stage, we found that MDSCs had variable capacity as APCs. NKT ligand-loaded MDSCs from late stage tumor-bearing mice (late MDSCs) were less immunogenic as APCs compared to those from early stage tumor-bearing mice. As tumor growth progresses, surface molecule expression required for APC function on MDSCs was largely down-regulated. NKT ligand-loaded late MDSCs were also poorly differentiated and induced decreased NKT activation and antigen-specific cytotoxic T lymphocyte (CTL) response. However, these functional defects were recovered by the treatment of all-trans retinoic acid (ATRA). NKT ligand-loaded, ATRA-treated late MDSCs were able to be transformed into immunogenic APCs to induce incremental immune responses. These effects were accompanied by the recovered activation and differentiation of late MDSCs. Collectively, we concluded that although the functional defect of MDSCs as APCs was found with tumor progression, it can be recovered by treatment with ATRA. Therefore, these findings suggest that late MDSCs can function as effective APCs.
A population of lymphoid progenitor cells inversely correlated with outcome in canine non-Hodgkin B-cell lymphoma (100.34)
Authors: Modiano Jaime , Ito Daisuke , O’Brien Timothy 
Published: January 2023

Abstract
Disease progression and response to treatment in people and in pet dogs with non-Hodgkin B-cell lymphoma (NHL) can be unpredictable, even for patients with the same subtype of disease, reflecting the heterogeneous nature of these tumors. Tumor angiogenesis has been correlated with stage and progression of lymphoid tumors in humans and in dogs, but the prognostic value of mature endothelial cells (ECs) and endothelial progenitor cells (EPCs) as surrogate markers for angiogenesis in NHL is unclear. Furthermore, the significance of lymphoid progenitor cells (LPCs) in this disease has not been addressed. Here, we evaluated the predictive value of ECs, EPCs and LPCs in dogs with naturally occurring NHL. We used flow cytometry to identify prospectively cells that co-expressed CD34, c-Kit, and/or CD133 with αvβ3-integrin (EPCs); or with CD45 and lymphoid lineage markers (LPCs), as well as cells that expressed CD146 (ECs), in blood and lymph nodes from dogs with NHL treated using standard of care multi-agent chemotherapy. The normalized frequency of ECs, EPCs and LPCs was compared with patient outcomes. ECs, EPCs, and LPCs were routinely present in all lymph node samples. No correlation was observed between ECs and EPCs and patient outcomes; conversely, there was a significant (p&lt;0.05) inverse correlation between LPCs and overall survival. Our results suggest that a population of cells with lymphoid progenitor phenotypes is predictive for survival outcomes in spontaneous canine NHL.
Expression of CD39 and CD73 as a means of evading anti-tumor immune reponses in lung cancer (100.7)
Authors: Meyer Christian , Rosinsky Carolyn , Alme Angela , Powell Jonathan 
Published: January 2023

Abstract
A major hurdle for cancer immunotherapy is the ability of tumors to inhibit anti-tumor immune responses. CD39 and CD73 are ectonucleotidases that promote the generation of extracellular adenosine from ATP. In light of the ability of adenosine to inhibit T cell responses by activating the adenosine A2a receptor (A2aR) we wanted to explore the expression of these two molecules on the surface of cancer cells. We investigated CD39 and CD73 expression and function utilizing murine and human tissues. In vitro studies revealed that Murine Lewis Lung Carcinoma cells did not express ectonucleotidases. However, upregulation of CD39 was found in vivo at multiple time points after injection into C57BL/6 mice. This expression was not T or B cell mediated as injection into RAG knockout mice produced the same expression patterns. Interestingly, characterization of multiple human lung cancer cells lines in vitro revealed near universal expression of CD73 and no CD39 expression. To determine if the upregulation of adenosine could have consequences in vivo, we injected Lewis lung carcinoma cells into A2aR knock out mice or wild-type mice treated with an adenosine receptor antagonist. In both cases improvements in tumor free and overall survival were observed. Overall our data suggests that CD39 and CD73 expression on the surface of lung cancer cells may contribute to their resistance to immunotherapy and that successful immunotherapy in lung cancer might include A2aR antagonists.
Enhanced Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) and Soluble TREM-1 Levels in the Myeloid Cells of Tumor-Bearing Mice and Patients with Renal Cell Carcinoma (100.8)
Authors: Ford Jill , Howard O.M. Zack , Subleski Jeff , Yang Youfeng , Rayman Pat , Weiss Jon , Linehan W. , Sayers Tom , Finke James , McVicar Daniel 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) contribute to cancer-related inflammation and tumor progression. TREM-1 amplifies the innate immune response and is thus emerging as an important player in inflammation and disease. Soluble TREM-1 (sTREM-1) is found in plasma of those with various inflammatory conditions and is associated with disease progression. Because TREM-1 is expressed on myeloid cells in healthy donors, we predicted TREM-1 would be expressed on MDSC and TAM within tumors and sTREM-1 would be elevated in the periphery. In this study, we examined TREM-1 and sTREM-1 levels in mice and patients with cancer. Using the 4T1 tumor model, we found that TREM-1 was present on blood and splenic MDSC in tumor-bearing mice and that levels increased over time after tumor challenge. TREM-1 was expressed on MDSC and TAM in the tumor. Ligation of TREM-1 on MDSC enhanced TNF release, indicating that the TREM-1 is functional. sTREM-1 was elevated in plasma of tumor-bearing mice and correlated with tumor volume. In renal cell carcinoma patients, TREM-1 was expressed on both tumor-infiltrating monocytes and neutrophils and plasma sTREM-1 levels increased with cancer stage. Taken together, these data show that TREM-1/sTREM-1 is regulated during tumor development, define TREM-1 as a novel MDSC marker, and demonstrate that TREM-1 on MDSC is functional. Future studies are needed to determine if TREM-1 can modulate tumor-associated inflammation.