bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nuclear expression of the regulatory T cell marker Foxp3 by non-small cell lung cancer (NSCLC) tumors is positively correlated with histologic grade (95.3)
Authors: Tucker Jo , Horbinski Craig , Yannelli John 
Published: January 2023

Abstract
Recently, expression of the regulatory T cell associated transcription factor, Foxp3, has been shown in a variety of tumors and tumor cell lines. The function of Foxp3 in tumor cells is currently unknown, but has implications for immune evasion and tumor progression. We have detected the presence of Foxp3 in several tumor cell lines, including 8 NSCLC lines, as well as in fresh tumor and normal adjacent tissue (NAT) samples by flow cytometry and western blot. To examine expression patterns in vivo, immunohistochemistry was performed on paraffin sections obtained from 25 NSCLC adenocarcinomas and 2 NAT. There was no evidence of Foxp3 expression in the normal lung tissues, however, all NSCLC samples included Foxp3+ tumor cells displaying either nuclear and/or cytoplasmic expression. Samples were graded 0-3, indicating no, weak, moderate or strong expression in each compartment. Strong nuclear expression was seen in 8 samples, moderate in 4 and weak in 8. Coefficient correlation analysis revealed a significant correlation (p=0.02) of nuclear expression strength with increasing histologic grade which was regardless of TNM staging. The analysis also suggests a relationship between nuclear Foxp3 expression in tumor cells and in infiltrating lymphocytes. As histologic grade has been reported as an independent prognostic factor for survival in NSCLC, we propose that Foxp3 may be an important element in promoting disease progression by inducing an immunosuppressive microenvironment.
Interleukin-2 treatment promoting T regulatory cells can inhibit the development of experimental autoimmune encephalomyelitis. (96.11)
Authors: Rouse Michael , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is a chronic and disabling autoimmune disease that affects ~400,000 people in the US. There is a pressing need for alternate and more effective treatment strategies that target the components of inflammatory cells. In recent years, regulatory T-cells (T-regs) have been found to play an important role in governing the immune system, particularly in preventing the development of autoimmunity. In our studies, we used experimental autoimmune encephalomyelitis (EAE), a murine model of MS, to investigate the potential therapeutic role of the cytokine interleukin-2 (IL-2) and its effects on FoxP3+ T-regs and IL-17 producing T-cells (Th17 cells). In our studies, clinical scores of paralysis were significantly reduced in EAE mice pre-treated with a moderate dose of IL-2. Immune cell phenotypes showed significant cellular infiltration in the brains of untreated EAE mice, which was reduced with IL-2 pre-treatment. Tissue histopathology of the central nervous system also confirmed the effectiveness of IL-2 pre-treatment by decreasing cellular infiltration in the spinal cord and preserving tissue integrity, whereas untreated EAE mice possessed numerous infiltrating cells and marked demyelination. Together, these studies demonstrate that IL-2 treatment prior to MOG administration may suppress the development of EAE by activation of T-regs and down-regulation of Th17 cells.
Safety, Efficacy and pharmacokinetics of T1h, a humanized anti-CD6 monoclonal antibody, in moderate to severe chronic plaque psoriasis - Results from a randomized phase II trial. (96.13)
Authors: Anand Arun , Assudani Deepak , Nair Pradip , Krishnamurthy Sharmitha , Deodhar Sarika , Arumugam Muruganandam , Iyer Harish , Melarkode Ramakrishnan 
Published: January 2023

Abstract
T1h, a novel humanized monoclonal antibody targeting CD6, a co-stimulatory receptor present on T cells, was evaluated as a potential therapy for psoriasis. In this multi-centric phase II, dose finding, single-blind study, 40 patients with moderate-to-severe psoriasis were randomized to receive T1h intravenously at 3 different doses across weekly, two-weekly and four-weekly schedules (n=5 per dose cohort) for 8 weeks, and followed for further 24 weeks. Safety and PK were the primary endpoints. Efficacy of T1h was evaluated using PASI and PGA. SF-36 and DLQI questionnaires were used to assess changes in quality of life. T1h was well tolerated. The most common adverse events were chills and pyrexia. Only 2 serious adverse events (both related to psoriasis) were ascribed to T1h therapy. T1h was weakly immunogenic with one patient developing an immune response. T1/2 of T1h ranged from 11.72 days to 18.51 days across different dose-schedules. Significant reductions in mean PASI score from baseline were observed at week 12 (22.32 to 6.23, P&lt; 0.0001) with the best response observed in cohort receiving 1.6 mg/kg T1h administered every 2 weeks. Overall, the proportion of patients with PASI50 and 75 responses were 72.5% and 45% respectively. 26 patients (65%) achieved a PGA score of clear or minimum at 12 weeks. A significant improvement in DLQI, SF36 and epidermal thickness was also noted. T1h exhibited a favourable safety profile in the treatment of moderate to severe psoriasis.
Negative modulation of B-cell function via inhibitory receptor signaling by using novel diabody-based Dual-Affinity Re-Targeting (DART) molecules (96.14)
Authors: Veri Maria-Concetta , Burke Steve , Huang Ling , Li Hua , Gorlatov Sergey , Tuaillon Nadine , Alderson Ralph , Rainey Jonah , Ciccarone Valentina , Zhang TengFei , Shah Kay , Jin Linda , Moore Paul , Koenig Scott , Johnson Syd , Bonvini Ezio 
Published: January 2023

Abstract
The Fc receptor, CD32B, functions as an inhibitory receptor and, when co-ligated with the B-cell antigen receptor (BCR) complex, dampens signaling and immune activation. Ligation of activating and inhibitory receptors is an obligatory event for CD32B inhibition coupling in B cells, which heightens the need for a bispecific molecule for interventional purposes. To exploit this mechanism, we have engineered a novel and stable bispecific diabody scaffold that facilitates heterodimeric assembly with high predictability. This Dual-Affinity Re-Targeting (DART) scaffold was used to couple an Fv specific for the inhibitory receptor, CD32B, with an Fv specific for the Ig-beta component (CD79B) of the BCR. The resulting CD32BxCD79B DART molecule was capable of co-ligating the activating and the inhibitory receptors on the B-cell surface, resulting in reduced BCR-induced calcium mobilization and phosphorylation of selected signaling molecules. These biochemical changes correlated with inhibition of B-cell proliferation and Ig secretion upon B-cell activation. In addition, a DART protein specific for the mouse orthologs of CD32B and CD79B reduced disease severity in a collagen-induced arthritis model. This novel approach to B-cell function modulation forms the basis for translating inhibitory signaling into therapeutic tools for managing autoimmune and inflammatory diseases.
Anti-inflammatory curcumin inhibits AID expression within cycling human B cells (96.21)
Authors: Haque Shabirul , Lee Hyunjoo , Waqas Bukhtawar , Chiorazzi Nicholas , Mongini Patricia 
Published: January 2023

Abstract
Curcumin is a natural phenolic compound extracted from the spice, Curcuma longa. It has noted anti-inflammatory effects, in part due to its suppression of NF-kB. Activation-induced cytosine deaminase (AID) is a NF-kB-regulated enzyme essential for Ig class switch recombination and somatic hyper-mutation with a demonstrated role in lymphomagenesis. This study has examined the effect of curcumin on the division-dependent upregulation of AID protein and mRNA within in vitro-activated normal human B lymphocytes and the AID-expressing B cell line, CL-01. CFSE-labeled, IgM+ human B2 cells isolated from spleen/tonsil were pre-activated for 4-5 days with stimuli likely encountered in sites of inflammation, i.e. limiting surrogate C3dg-coated antigen (anti-IgM: anti-CD21: dextran) + IL-4 + BAFF. Curcumin at doses from 6 to 50 µM, or parallel vehicle control, was pulsed into dividing B cell cultures and AID mRNA and protein were assessed after 1 or 2 d, respectively. Expression of mRNA was monitored by both quantitative and qualitative RT-PCR. AID protein was assessed, by two-color flow cytometry of CFSE-labeled cells and immunoblotting. Curcumin significantly down-regulated AID mRNA and protein, in dose dependent fashion. Accompanying this decline was a diminished recovery of IgG+ class-switched B cells within the divided population. This study suggests that curcumin could have a role in treating B cell autoimmune disease and reducing the risk of malignant transformation.
B-cell Delivered Gene Therapy for Tolerance in EAE: Role of Antigen-specific B Cells (96.27)
Authors: Zhang Ai-Hong , Onabajo Olesegun , Su Yan , Skupsky Jonathan , Scott David 
Published: January 2023

Abstract
B-cell delivered gene therapy has been useful for tolerance induction in several mouse models for autoimmune diseases. However, it is not known whether Ag specific B-cells can be transduced to serve as tolerogenic antigen-presenting cells (APC), since such cells would be present in primed hosts. To test this, LPS activated splenic B cells were transduced with a retroviral vector encoding the immunodominant peptide of myelin oligodendrocyte glycoprotein (MOG35-55) in frame with IgG (MOG-Ig). Unlike transduced B-cells from wild type C57Bl/6 (B6) donors, adoptive transfer of MOG-Ig transduced B-cells from MOG-specific BCR transgenic mice (αMOG B-cells) failed to ameliorate MOG35-55 induced EAE in either pretreatment or therapeutic protocols. However, αMOG B-cells transduced with control vector encoding OVA323-339 (OVA-Ig) were highly tolerogenic in terms of T-cell recall response to OVA323-339. Interestingly, significant protection in mice from EAE was observed when ~1% transduced αMOG B-cells were used in the EAE model (+99% MOG-Ig transduced B6 B-cells). These data suggested that Ag specific B-cells in nature can be transduced as tolerogenic APC when a non-relevant Ag was targeted, and Ag specific tolerance induction can still be achieved in the presence of low number of pathogenic antigen specific B-cells. (Supported by NIH grant RO1 AI035622 and a Pre-doctoral fellowship from the AHA)
Experimental extracorporeal photopheresis therapy prevents type 1 diabetes in non-obese diabetic mice (96.3)
Authors: Xia ChangQing , Chernatynskaya Anna , Campbell Kim , Clare-Salzler Michael 
Published: January 2023

Abstract
In our previous studies, we demonstrated that infusion of apoptotic cells significantly prevented type 1 diabetes (T1D) in non-obese diabetic (NOD) mouse. Extracorporeal photopheresis (ECP) is an apoptotic cell-based therapy in clinic for immune-mediated disorders. In this study we examined experimental ECP therapy in T1D prevention in NOD mice. We discovered that five weekly intravenous injections of ECP-treated NOD spleen cells significantly delayed diabetes onset when NOD mice started to receive treatment at 8 weeks of age. Further cell dose studies demonstrated that low dose ECP-treated spleen cells as low as 2x105/injection/mouse had similar diabetes protection compared to high dose (5x106). In contrast to ECP therapy alone, ECP therapy combined with β cell antigens appeared to improve the protective effect with markedly reduced insulitis in pancreas. ECP and ECP plus β cell antigen therapies increased Foxp3+ Tregs in spleen, and β cell antigen-specific T cell proliferation was significantly suppressed in vivo in these two groups. In addition, we found that ECP therapy did not induce global immunosuppression as well as autoimmunity against nuclear materials. In conclusion, ECP therapy is a safe and effective approach in T1D prevention and has great potential for clinical translation to treat human T1D.
Efalizumab down-regulates CD25 expression on FOXP3+ regulatory T cells and exacerbates the autoimmunity in primary Sjogren’s syndrome (96.4)
Authors: Tran Dat , Bebris Lolita , Shevach Ethan , Illei Gabor 
Published: January 2023

Abstract
Rationale: FOXP3+ regulatory T cells (Tregs) are central to prevention of autoimmunity. Tregs expressed high level of CD25 and require IL-2 signaling for their function. Since CD25 is up-regulated with activation and LFA-1 is required, we hypothesize that efalizumab treatment would result in down-regulation of CD25 on Tregs and potential exacerbation of autoimmunity. Methods: Subjects with Sjogren’s syndrome were enrolled in a phase II clinical trial for weekly injection of efalizumab (1mg/kg) up to 25 weeks. Peripheral bloods were analyzed for Tregs by flow cytometry. Clinical conditions were measured by objective improvement in salivary and lacrimal flows and minor salivary gland (MSG) inflammation. Results: All three subjects had progressive down-regulation of CD11a and CD18 on Tregs (CD4+FOXP3+), which also correlated with dramatic decrease in CD25. There was no clinical improvement but instead repeat MSG biopsy showed significant increase in inflammation. Two subjects developed anti-dsDNA; one of whom developed multiple autoantibodies and lupus-like syndrome which resolved after efalizumab discontinuation. Conclusions: Efalizumab exacerbates Sjogren’s syndrome and induces significant increase in local inflammation and systemic autoimmunity. Inhibition of LFA-1 interaction on Tregs negatively affected their CD25 without altering their FOXP3 level. This study cautions the potential detrimental effect of efalizumab on Tregs and autoimmunity.
Anti-inflammatory effects of glucosamine in regulating the development of experimental autoimmune encephalomyelitis (EAE) (96.6)
Authors: Zhou Juhua , Nagarkatti Prakash , Zhong Yin , Nagarkatti Mitzi 
Published: January 2023

Abstract
We attempted to understand the anti-inflammatory regulation of glucosamine-6-phosphate (GS-6-P) and glucosamine-6-sulfate (GS-6-S) in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Clinical symptoms in MOG35-55-induced EAE mice significantly decreased following either oral administration or intravenous injection of GS-6-P, whereas only intravenous injection of GS-6-S inhibited EAE development. After clinical symptoms of EAE were induced, intravenous injection of both GS-6-P and GS-6-S could alleviate EAE in mice although GS-6-P was more potent. Further analysis showed that both GS-6-P and GS-6-S dramatically inhibited lymphocytic infiltration in the brain and spinal cord, recovered IL-10 producing cells to a normal level, and significantly decreased total number of splenocytes, CD4 T cell populations, IFN-γ producing cells and Th17 cells in mice. Besides, both GS-6-P and GS-6-S significantly inhibited the gene expression of IL-12, T-bet and IFN-γ, suggesting that glucosamine suppressed Th1 CD4 T cell differentiation and thus blocked EAE. GS-6-P also significantly increased IL-4 producing cells in spleen, but GS-6-S did not, suggesting GS-6-P could also promote Th2 CD4 T cell differentiation and thus further inhibited EAE. Our results suggested that GS-6-P could be a new therapeutic drug for MS treatment. (Supported in part by NIH grants R01AI053703, R01ES09098, R01 AI058300, R01DA016545, R01HL058641, ES 019313 and P01AT003961).
Tumor derived gangliosides promote regulatory cell activity (98.10)
Authors: Jales Alessandra , Falahati Rustom , Herzog Dallen , Ladisch Stephan , Leitenberg David 
Published: January 2023

Abstract
Gangliosides, shed by tumor cells, have been shown to have immunomodulatory properties, suggesting that gangliosides may be a critical factor in initiating an immunosuppressive tumor microenvironment. To better define the immunomodulatory properties of gangliosides on antigen-specific T cell activation and development, independent of other tumor associated factors, we have developed an in vitro system utilizing ganglioside-treated murine bone marrow derived dendritic cells to prime and activate antigen-specific CD4+ T cells from AND T cell receptor transgenic mice. Ganglioside treatment promotes the development of a regulatory DC population characterized by decreased CD86 expression, and decreased IL-12 and IL-6 production. CD4 T cells primed with ganglioside-treated DCs proliferate normally, but have a defect in Th1 effector cell development and IL-2 production. This defect in Th1 effector cell responses is due in part to the development of regulatory T cell activity that can suppress the activation of previously primed Th effector cells in a contact-dependent manner. Depletion of CD25+FoxP3+cells, and addition of exogenous IL-2 partially rescues Th1 responses in effector T cells co-cultured with ganglioside primed T cells. Collectively, these data suggest that ganglioside-exposed dendritic cells promote regulatory T cell activity that may have long lasting effects on the development of tumor specific immune responses.
Developing regulatory dendritic cells with the pregnancy estrogen estriol (98.11)
Authors: Muth Dillon , Taylor Cassandra , Whitacre Caroline , Boyaka Prosper , Papenfuss Tracey 
Published: January 2023

Abstract
In addition to inflammatory (immunogenic) capabilities, DCs have a potent role in regulating inflammation and immunity. We have found that DCs from estriol (E3) treated mice are activated regulatory DCs (regDCs). Specifically, these splenic E3 regDCs have elevated CD80, CD86, PD-L1, PD-L2, B7-H3 and B7-H4, hypo-produce IL-12, inhibit T cell proliferation and, upon adoptive transfer, protect mice from EAE through promoting Th2 responses. In these studies, we generated regDCs in vivo and in vitro and developed an in vitro correlate to splenic E3 regDCs. Mice given murine Flt3L (mFL)-secreting cells expanded both CD11b-CD11c+ and CD11b+CD11c+ cells, demonstrated mononuclear hyperplasia within bone marrow, lymph nodes and spleens and E3-exposed DCs were phenotypically similar to human Flt3L (hFL) E3 regDCs. Bone marrow DCs (BM-DCs) were generated with mFL, hFL or GM-CSF with or without E3. E3 inhibited FL BM-DC differentiation while GM-CSF BM-DCs were less affected. Phenotypic evaluation showed elevated CD80, CD86, PD-L1 and PD-L2 and CD4+ T cells proliferated less when cultured with E3 BM-DCs. These results demonstrate that E3 generates regDCs in vitro and in vivo and demonstrate an in vitro correlate to in vivo generated E3 regDCs. Generation of regDCs has important therapeutic applications in autoimmunity and inflammatory diseases.
Maturation of dendritic cell by edible mushroom Sparassis crispa (98.15)
Authors: Kim Hyung Sook , Kim Jee Youn , Roh Eunmiri , Hong Jin Tae , Kim Youngsoo , Han Sang-Bae 
Published: January 2023

Abstract
Dendritic cells (DCs) play a pivotal role in the initiation of T cell-mediated immune response, making them an attractive cellular adjuvant for use in cancer vaccines. During the evolution of neoplastic diseases, dendritic cell (DC) functions are usually attenuated, and this presents a problem to DC-based immunotherapies against cancer. Here, we investigated the effects of beta-glucan (SCG), purified 6-branched 1, 3-beta-D- glucan obtained from Sparassis crispa, on Dc maturation. SCG efficiently increased the maturation of tlr4+/+ DCs from C57BL/6 and C3H/HeN mice, but not tlr4-/- DCs from C3H/HeJ mice. Phenotypic maturation was confirmed by the elevated expressions of CD40, CD80, CD86, MHC-I, and MHC-II molecules, and functional maturation by increased in the gene expression of IL-12, IL-1beta, TNF-alpha, IFN-alpha, IFN-beta production and decreased endocytosis. Also, SCG made DCs to activate allogenic T cells to proliferate and produce cytokines such as IL-2 and IFN-gamma. As a mechanism of action, SCG activated mitogen-activated protein kinases, proved by enhanced phosphorylation of ERK, p38 and JNK. In addition, SCG increased nuclear translocation of NF-κB p65/p50, which are signaling molecules down-stream of toll-like receptor 4 (TLR4). These results indicate that SCG induces DC maturation through TLR4.
Association of TREM2-DAP12 with DAP10 is required for the regulation of PI3K in macrophages (98.18)
Authors: Peng Qisheng , Malhotra Shikha , Humphrey Mary Beth 
Published: January 2023

Abstract
The regulation of PI3K following TREM2 ligation in macrophages is unclear and was the focus of this study. Immunoprecipitation studies show that DAP10 signaling adapter protein is required for recruitment of PI3K (p85 subunit) to a TREM2-DAP12 complex following TREM2 ligation. Once recruited to the complex, PI3K mediates TREM2-DAP12 dependent activation of AKT and ERK1/2. Compared to wild type macrophages, TREM2 stimulation failed to induce p85 recruitment to DAP12 in DAP10-deficient macrophages leading to a significant reduction in activated AKT and ERK1/2. Calcium flux induced by TREM2 ligation remained intact in DAP10-deficient macrophages, indicating that it is DAP10-independent. Both DAP10 and DAP12 could associate with TREM2 and each other in macrophages suggesting a tri-molecular complex of TREM2-DAP12-DAP10. We further show that the recruitment of PI3K to TREM2-DAP12 complexes is negatively regulated by the lipid phosphatase, SHIP1, in a DAP12 ITAM- dependent manner. Confocal study showed that DAP10 is not required for the translocation of SHIP1 or DAP12 to the membrane. Thus, our data suggests that DAP10 is required for the recruitment and activation of PI3K induced by TREM2-DAP12 signaling but not for calcium flux. Experiments are now being done to further understand the role of this tri- molecular complex (TREM2-DAP12-DAP10) leading to optimal functioning of bone marrow- derived macrophages.
PU.1 is required for generating the IL-9-producing Th9 phenotype (99.10)
Authors: Yao Weiguo , Tepper Robert , Kaplan Mark 
Published: January 2023

Abstract
IL-9 secreting Th9 cells are a newly defined subset of CD4 T cells that differentiate in the presence of TGF-β and IL-4, and that we have found have increased expression of the transcription factor PU.1. In a cohort study on infants with dermatitis, we found cultured PBMCs from atopic patients secreted higher level of IL-9 than non-atopic patients following anti-CD3 stimulation. In addition, specific cat or mite allergen stimulation of these PBMCs resulted in higher IL-9 production in cultures from atopic patients than from non-atopic patients. To investigate the underlying mechanism of IL-9 production and the development of Th9 cells in human allergic disease, we differentiated Th9 cells from naïve CD4 T cells isolated from atopic and non-atopic groups. We found that, after differentiation, Th9 cells from atopic patients have higher expression of PU.1 and IL-9 than those from non-atopic patients. Moreover, atopic samples showed increased pSTAT6 levels during differentiation, compared to samples from non-atopic patients. To determine if PU.1 is a regulator of the Th9 phenotype, we transfected Th9 cultures from normal human PBMCs with PU.1-specific siRNA. Our data showed that decreasing PU.1 expression impaired IL-9 production. In conclusion, these data demonstrate a critical role of PU.1 in the regulation of Th9 differentiation and suggest that PU.1-expressing Th9 cells may be involved in human allergic disease.
Dec2 regulates initial TH2 lineage commitment (99.12)
Authors: Yang Xuexian , Angkasekwinai Pornpimon , Zhu Jinfang , Peng Juan , Liu Zhiduo , Nurieva Roza , Liu Xikui , Chung Yeonseok , Chang Seon Hee , Sun Bing , Dong Chen 
Published: January 2023

Abstract
How naive CD4+ T cells commit to the T helper type 2 (TH2) lineage is poorly understood. Here we show that the basic helix-loop-helix transcription factor Dec2 is selectively expressed in TH2 cells. CD4+ T cells from Dec2-deficient mice exhibits defective TH2 differentiation in vitro and in vivo in an asthma model and in response to challenge with a parasite antigen. During early TH2 differentiation, Dec2 directly binds to and activates transcription of the Junb and Gata3 genes and promotes interleukin 4 expression. In addition, over-expression of GATA3 or JunB rescues TH2 cytokine expression in Dec2-deficient CD4+ T cells while optimal expression of these cytokines requires Dec2. As GATA3 induces Dec2 expression, these findings also indicate a feed-forward regulatory circuit during TH2 differentiation.