bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new compound isolated from Vitex rotundifolia Linn fil., pyranopyran-1,8-dione, suppresses airway epithelial cell inflammatory responses in a murine model of asthma (140.14)
Authors: Lee Heekyung , Keum Dongjune , Kim Haejeong , Shin Min-Kyu , Hong Moo-Chang , Kim Yangseok , Bae Hyunsu 
Published: January 2023

Abstract
The new natural compound, pyranopyran-1,8-dione (PPD), was isolated from Vitex rotundifolia L. To elucidate the mechanism by which the anti-asthmatic responses of PPD occurred in vitro, A549 cells were stimulated with TNF-¥á, IL-4 and IL-1¥â to induce the expression of chemokines and adhesion molecules involved in eosinophil chemotaxis. PPD treatments reduced the expression of eotaxin, IL-8, IL-16 and VCAM-1 mRNA significantly. Additionally, PPD reduced eotaxin secretion and significantly inhibited eosinophil migration toward A549 medium. In addition, PPD treatment suppressed the phosphorylation of p65 and ERK1/2, suggesting that it can inhibit the MAPK/NF-¥ê b pathway. To clarify the anti-inflammatory and antiasthmatic effects of PPD in vivo, mice were sensitized and challenged with OVA and then examined for the following typical asthmatic reactions: an increase in the number of eosinophils in BALF; the presence of Th2 cytokines such as IL-4 and IL-5 in the BALF; the presence of allergen-specific IgE in the serum; and a marked influx of inflammatory cells into the lung. Taken together, our results revealed that PPD exerts profound inhibitory effects on the accumulation of eosinophils into the airways while reducing the levels of IL-4, IL-5, and IL-13 in the BALF.
Anti-Malarial Drug Artesunate Attenuates Allergic Airway Inflammation in A Murine Asthma Model (140.18)
Authors: Cheng Chang , Ho Eugene WX , Chu Kai Ling , Wong WS Fred 
Published: January 2023

Abstract
Artesunate is a derivative of artemisinin isolated from a Chinese herb Artemisia annua L. It is used clinically for the treatment of malaria. There are recent evidences supporting an immune-regulatory role by artesunate. We investigated potential anti-inflammatory actions of artesunate in a mouse asthma model. BALB/c mice sensitized and challenged with OVA developed airway eosinophilia and mucus hypersecretion, and elevations in serum IgE level and in bronchoalveolar lavage (BAL) fluid cytokine level. Artesunate significantly inhibited OVA-induced increases in BAL fluid eosinophil count, and IL-5 and IL-13 levels. It also reduced the serum level of OVA-specific IgE. Histologic analysis reveals that artesunate suppressed OVA-induced inflammatory cell infiltration and airway mucus production. Besides, artesunate markedly attenuated OVA-induced mRNA expression of ICAM-1, VCAM-1, Muc5ac and chitinases. Furthermore, artesunate inhibited TNF-α-induced phosphorylation of phosphoinositide 3-kinase (PI3K) and its downstream Akt and p70 S6 kinase, as well as nuclear factor (NF)-κ B DNA binding activity in normal human bronchial epithelial cells. Taken together, our results clearly demonstrate anti-inflammatory effects of artesunate in a mouse asthma model, and it may act by inhibiting PI3K/Akt signaling pathway. (This work was supported by a BioMedical Research Council grant BMRC06/1/21/19/443)
Reduction of serum IgE by depletion of the IgE B cell lineage - a novel approach for the treatment of allergic diseases (140.7)
Authors: Wu Lawren C , Brightbill Hans D , Jeet Surinder , Lin Zhonghua , Yan Donghong , Zhou Meijuan , Tan Martha , Nguyen Allen , Yeh Sherry , Delarosa Donnie , Leong Steven R , Wong Terence , Chen Yvonne , Jackman Janet , Dennis Mark S , Chuntharapai Anan , DeForge Laura , Meng Y Gloria , Xu Min , Lee Wyne P , Refino Canio J , Balazs Mercedesz 
Published: January 2023

Abstract
Anti-IgE antibody targeting of serum IgE is an efficacious treatment for asthma and other allergic diseases. Currently, therapeutic anti-IgE antibodies neutralize free serum IgE, but do not affect IgE production. We have developed monoclonal antibodies that disrupt IgE production by binding to the M1' domain of human membrane IgE, a 52 amino acid extracellular segment on human IgE-switched B cells and plasmablasts that is not present in serum IgE. Using genetically modified mice that contain the human M1' domain knocked into the mouse IgE locus, we demonstrate that our anti-M1' antibodies reduce serum IgE and IgE plasma cells, but not other immunoglobulin isotypes, in vivo. Anti-M1' antibodies are effective when delivered prophylactically and therapeutically in mouse immunization, asthma, and Nippostrongylus infection models. Moreover, the anti-M1' antibodies are active on primary human cells in vivo, reducing serum IgE and IgE plasma cells in a human PBMC-SCID mouse model. In vitro and in vivo studies indicate that anti-M1' antibodies trigger apoptosis of IgE B cells and may therefore abolish IgE memory. Anti-M1' targeting of IgE B cells is a promising new therapy for the treatment of asthma and allergy.
Fullerene C70 derivatives inhibit eosinophilia associated with chronic asthma (140.8)
Authors: Norton Sarah K , Conrad Daniel H , Kepley Christopher L 
Published: January 2023

Abstract
Fullerenes are nanospheres of carbon that are extremely stable and highly reactive with oxygen free radicals. While native fullerenes are insoluble in water, the carbon cage can be derivatized by the addition of polar chemical groups, thus generating water soluble molecules. Water soluble fullerene derivatives have been shown to inhibit mast cell degranulation and cytokine release (J. Immunol. 179: 665-672), demonstrating a potential role in controlling mast cell diseases such as allergic asthma. In order to observe the effects of derivatized fullerenes on chronic features of asthma in vivo, we used a murine model of asthma pathogenesis. Mice were sensitized to ovalbumin by intraperitoneal injection and then challenged by directly introducing the protein into the lungs. Fullerene treated mice did not exhibit any acute toxicity, and when compared to PBS or vehicle treated controls, showed a significant reduction in airway eosinophilia. The data also suggest a reduction of IL-4, IL-5, and KC in the bronchoalveolar lavage fluid of fullerene treated mice, but further investigation is necessary. Finally, we are investigating the effect of fullerenes on B cell IgE production in vitro as a possible mechanism of inhibition. Together, these results suggest that fullerenes can control chronic inflammation characteristic of asthma pathogenesis, indicating the potential for their use in the treatment of chronic asthma.
The T Cell Cytolytic Molecules FasL and TRAIL are Required for Thymic GVHD (141.14)
Authors: Lu Sydney X , Na Il-Kang , Goldberg Gabrielle L , King Christopher G , Smith Marsinay , Suh David , Rao Uttam , Yim Nury , Holland Amanda M , Penack Olaf , Jenq Robert R , Ghosh Arnab , Houghton Alan , van den Brink Marcel RM 
Published: January 2023

Abstract
Thymic graft-versus-host-disease (tGVHD) is an important contributor to impaired T cell reconstitution in patients with GVHD. We analyzed molecules relevant for T cell trafficking and cytolytic function in tGVHD.
Thymic output and cellularity were inversely proportional to numbers of mature donor T cells in the allograft, suggesting that tGVHD severity was inversely associated with thymic function. Upon adoptive transfer of CFSE-labeled donor T cells, we noted that thymus-infiltrating alloreactive donor T cells were largely fast-proliferating and highly activated. These T cells infiltrated the thymus within one week after allogeneic bone marrow transplantation.
We analyzed T cells in tGVHD with mice deficient for certain molecules, and found that the trafficking molecules CCR9, β7 integrin, and PSGL-1 were all partially required for tGVHD, while L-selectin and αE integrin subunit may be dispensable. Similarly, we examined the role of T cell cytolytic pathways for tGVHD, and found that FasL and tumor necrosis factor associated apoptosis inducing ligand (TRAIL) were required for tGVHD, but that perforin and TNF were dispensable.
As host thymic stroma may be an important target for donor alloreactive T cells, we assessed the expression of the death receptors Fas and DR5 in thymic stroma from normal and irradiated mice, and found that endothelium and fibroblasts, as well as epithelial cells upregulated the expression of both Fas and DR5 after irradiation. FLIP, which is a negative regulator of Fas ligand and TRAIL mediated apoptosis, was also downregulated after irradiation.
Our study suggests that TRAIL, which has previously been shown to be important in graft-versus-tumor activity, may also be important for mediating GVHD.
Simultaneous bone marrow and tissue transplantation in rats treated with a nonmyeloablative conditioning regimen promote tolerance to composite tissue allografts (141.18)
Authors: Ramsey Deborah M. , Bozulic Larry D. , Wu Shengli , Adamson Larry A. , Rahhal Dina N. , Swearingen Bruce J. , Xu Hong , Ildstad Suzanne T. 
Published: January 2023

Abstract
Approaches to safely induce graft acceptance through bone marrow chimerism and limited immunosuppression are currently being pursued. Here we evaluated the effect of nonmyeloablative conditioning on the establishment of tolerance and mixed chimerism in recipients of bone marrow transplantation (BMT) and reconstructive tissue allotransplantation (RTA). Twenty Wistar-Firth rats were treated with a short course of immunosuppressive therapy (anti-ab-TCR mAb, tacrolimus, and anti-lymphocyte serum). One day prior to BMT, rats received total body irradiation followed by transplantation of heterotopic osteomyocutaneous flaps taken from hind limbs of ACI rats. Following BMT, rats were monitored for rejection and mixed chimerism (&gt;2% donor cells). Fifteen rats rejected their RTA, and five rats accepted the graft. Mixed chimerism was detected in peripheral blood at one month after RTA, but chimerism was lost in all transplant recipients by four months. After 1.5 years post-RTA, the number of donor cells in spleen, mesenteric lymph node, recipient bone marrow and thymus was &lt;2%. To determine the tolerance mechanism, ten rats were given donor skin grafts at one year post-RTA and examined for anti-donor antibodies by flow cross-match assay. Acceptors of RTA were tolerant of donor skin and no anti-donor antibodies were detectable, which points to a deletional mechanism. These studies suggest that nonmyeloablative conditioning can establish long-term tolerance and indefinite allograft survival in rats. (Research supported by a grant from the US Department of Defense).
MHC class I restriction in DiGeorge anomaly patients after allogeneic thymus transplantation (141.22)
Authors: Li Bin , Li Jie , Devlin Blythe H , Markert Mary Louise 
Published: January 2023

Abstract
Purpose: The aim of this study is to determine whether antigen specific T cells are restricted to host or donor MHC after human allogeneic thymus transplantation for complete DiGeorge anomaly. Methods: Tetramers composed of HLA-A*0201, B*0801, or B*0702 with an Epstein Barr virus (EBV) peptide or HLA-B*0702 with a respiratory syncytial virus (RSV) peptide were used in flow cytometry to detect CD8 T cells restricted to these specificities. After thymus transplantation, DiGeorge anomaly subjects were screened and identified for infection by EBV and RSV. Healthy adults serologically positive for EBV or RSV were identified. EBV and RSV specific CD8 T cells were detected by flow cytometry. Results: We found binding of recipient CD8 T cells to tetramers in 4 of 4 subjects with host HLA:EBV peptide and in 1 subject with host HLA:RSV peptide after thymus transplantation. Donor-restriction was not seen in 5 of 5 subjects receiving thymus unmatched for the tested specificity. This implies that host cortical epithelium is present in the donor thymus to effect host selection, that host selection can occur on cell types other than cortical epithelium (such as on thymocytes), or that host selection can result from initial restriction on totally disparate MHC molecules on donor cortical epithelium. We are assessing host HLA expression in thymic epithelial cell cultures derived from allograft biopsies. The presence of host thymic epithelium could explain the HLA restriction to host seen in the tetramer studies.
This study was supported by NIH grant R01 AI 47040 and grant FD-R-002602 from the FDA Office of Orphan Products Development.
Interruption in Dendritic Cells Paracrine Delivery of IL-2 to Treg Cells Impairs Their Function. (141.30)
Authors: Nasr Mohamed E , Kulhankova Katarina , Rouse Todd , Field Elizabeth H 
Published: January 2023

Abstract
Regulatory T cell plays an important role in controlling immunity to self and foreign antigens. CD4+CD25+ require T cell receptor and IL-2 receptor activation for in vivo / in vitro expansion and function, but the source of IL-2 remains unknown. In identifying the important paracrine source of IL-2 for Treg cells, we concentrated on the dendritic cell as the paracrine source, because in vitro imaging studies demonstrated fine localization of CD25 at the membrane interface between RD6 and dendritic cells. We used ELISPOT assay to detect IL-2 production by the freshly isolated splenic and bone marrow dendritic cells Dendritic cells secrete a small fraction of IL-2 early in culture, CpG-B enhances the IL-2 production of DCs. Coculture with regulatory cells reduces the level of detectable IL-2.We examined the direct effect of dendritic cell IL-2 on Treg function, CD4+CD25+ cells suppressed CD4+CD25- effectors cells when stimulated with WT dendritic cells, but not when stimulated with IL-2KO DCs. Anti-CD25 abrogates the function of both Treg and RD6 co-cultured with WT DCs, suggesting that CD25 is required for delivery of IL-2 into the Tregs for processing and the addition of high doses of exogenous IL-2 can restore the inhibitory function of Treg and RD6 cells co-cultured with IL-2 -/- dendritic cells. These data suggest that DC IL-2 is essential for Treg function.
Contact-dependent suppression pathways in non-human primate Tregs expanded ex vivo in the presence of Rapamycin (141.36)
Authors: Johnson Jennifer Lynn , Hennessy Emily A , Pahuja Anil , Graham Melanie , Blazar Bruce , Hering Bernhard , Bansal-Pakala Pratima 
Published: January 2023

Abstract
Regulatory T cell therapy offers a safe and effective alternative to achieve long-term graft survival by establishing a state of operational tolerance in the transplant recipient. Prior to use in human clinical trials, Treg therapy must be tested in non-human primate (NHP) pre-clinical models. To assess tolerogenic potential of Treg therapy, we used CD3/CD28 costimulation and frequent, low doses of IL-2 to expand natural CD4+CD25hi Tregs purified from NHP peripheral blood, with and without rapamycin. We achieved 500-800 fold expansion in 21 days and maintained high levels of CD25 and Foxp3.The ex vivo expanded Tregs were capable of inhibiting CD4 proliferation to anti-CD3 and allostimulation by 90%. Preliminary analyses of potential regulatory mechanisms employed by ex vivo expanded Tregs show high expression of CTLA4 and Granzyme B but little or no expression of TGF-b and IL-10 suggesting that these Tregs may function primarily through contact-dependent pathway. To our knowledge this is the first report of potential suppressive pathways used by ex vivo expanded NHP Tregs. Further investigations into suppressive molecules used by freshly isolated Tregs and whether ex vivo expansion selectively induced CTLA4 and Granzyme B are underway. These data establish the feasibility of using ex vivo expanded Tregs as part of a tolerogenic protocol in NHP model of islet transplantation.
Induction of Regulatory T-cells by Donor-Specific Blood Transfusion in the Absence or Presence of Liver Allograft Transplantation (141.43)
Authors: Grisham Matthew B. , Abe Yuta , Ostanin Dmitry V. , Zibari Gazi 
Published: January 2023

Abstract
Donor-specific blood transfusion (DST) has been shown to be effective at inducing tolerance and long-term survival in animals transplanted with MHC-mismatched tissue. The objective of this study was to ascertain how DST alone or in combination with liver allograft transplantation (LTx) affects the generation and function of regulatory T-cells in vitro and in vivo. We found that DST alone generates CD4+ T-cells that when transferred into naïve recipients suppress liver allograft rejection despite expressing little or no Foxp3 at the time of adoptive transfer. In addition, we present the novel finding that DST plus LTx (but not DST alone) increases the formation of Foxp3-expressing regulatory T-cells (Tregs) that suppress alloantigen-induced activation in vitro as well as induce long term tolerance to liver allografts when adoptively transferred into naïve recipients prior to LTx. Finally we demonstrate that virtually all Foxp3-expressing Tregs reside within the CD4+CD45RC- population whereas these Tregs are equally distributed between the CD4+CD25+ and CD4+CD25- populations. Taken together, our data suggest that DST administration, in the absence of allograft transplantation, induces the formation of CD4+ T-cells that are not Tregs themselves but develop into fully functional Foxp3+ Tregs or help to induce the formation of Foxp3+ Tregs following allograft transplantation.
Species Variation in the Mechanisms of Mesenchymal Stem Cell-Mediated Immunosuppression (141.45)
Authors: Ren Guangwen , Zhang Liying , Su Juanjuan , Zhao Xin , Ling Weifang , Roberts Arthur I , Shi Yufang 
Published: January 2023

Abstract
Bone marrow derived mesenchymal stem cells (MSCs) hold great promise for treating immune disorders, although the immunoregulatory mechanisms remain largely controversial. Here we show that the mechanisms of MSC-mediated immunosuppression vary in different species. Under the same culture conditions, immunosuppression by MSCs derived from human or monkey was mediated by indoleamine 2, 3 dioxygenase (IDO), while immunosuppression by mouse MSCs depended on nitric oxide (NO). When the expression levels of inducible nitric oxide synthase (iNOS) and IDO were examined in mouse and human MSCs stimulated with their respective inflammatory cytokines, we found that human MSCs expressed high levels of IDO, but very low levels of iNOS, while mouse MSCs expressed high levels of iNOS and very little IDO. Except the executor molecules, moreover, the human and mouse MSCs shared some similarities. Like in mouse MSCs, immunosuppression by human MSCs was not intrinsic, but inducible by inflammatory cytokines. Additionally, IDO-mediated immunosuppression by human MSCs is also chemokine-dependent. These findings help to explain the apparently conflicting reports in the literatures and provide critical information to allow better application of human MSCs in treating immune disorders.
Modulation of extracellular redox remodeling by regulatory T cells (33.11)
Authors: Yan Zhonghua , Garg Sanjay , Kipnis Jonathan , Banerjee Ruma 
Published: January 2023

Abstract
T cell activation and proliferation requires a reducing microenvironment that is provided by dendritic cells (DC). Naturally occurring CD4+CD25+ regulatory T cells (Treg) can suppress autoimmunity by inhibiting CD4+CD25- effector T cells (Teff). The mechanism is not fully understood. In this study, we have tested the hypothesis that inhibition by Treg cells of DC-induced extracellular redox remodeling is a component of the Treg immunosuppressive mechanism. We demonstrate that the increase in extracellular Cys concentration upon co-culture of DCs with Teff cells results from the system xc--dependent import of cystine, its conversion to glutathione, which is subsequently exported and degraded by γ-glutamyltranspeptidase and a dipeptidase, to furnish Cys. Suppression of DC-dependent Teff cell proliferation by Treg cells is correlated with a significant diminution in extracellular Cys concentration and is abrogated by addition of exogenous Cys. The decrease in the extracellular redox potential during T cell activation is associated with an increase in the levels of exofacial surface thiols in both DCs and T cells, which is diminished in the presence of Treg cells. This study elucidates the pathway of thiol release by DCs in response to T cell stimulation, demonstrates that Treg cells interfere with the process of extracellular redox remodeling and identifies a novel mechanism for immunomodulation.
Characterization of isoquinolinium salt derivatives as potent inhibitors of transcription factor NFAT (33.20)
Authors: Park Jungchan , Kim Jung-Ho , Lee Mina 
Published: January 2023

Abstract
Transcription factor NFAT plays critical roles in gene expression during the immune response. NFAT activation is regulated by calcineurin (CaN), a target of the immunosuppressive drugs such as cyclosporin A (CsA) and FK-506. CsA blocks phosphatase activity of CaN, which results in inactivation of NFAT. In search for novel immunosuppressive drug candidates, we have screened an organic chemical library and identified several isoquinolinium salt derivatives as novel inhibitors of NFAT. These compounds inhibited proliferation of peripheral blood mononuclear cell (PBMC) and T-lymphocytes by a mixed-lymphocyte reaction. Their inhibitory effect was specific to transcription factor NFAT, but in contrast with CsA, they neither affect the phosphatase activity of CaN nor nuclear localization of NFAT upon ionomycin stimulation. The DNA binding assay reveals that these compounds strongly attenuated DNA binding activity of NFAT. Taken together, these results indicate that these novel compounds inhibit NFAT activity without any significant change in CaN activity, which is a different mechanism from that of CaA, and suggest as potential candidates for immunosuppression
Effect of vitamin C on the activation of T cell in Gulo(-/-) mice (33.23)
Authors: Maeng Hyung Gun , Kang Jae Seung , Kim Hye Min , Lee Na Eun , Kong Joo Myoung , Bae Se Yeon , Kim Hang Rae , Hwang Young Il , Lee Wang Jae 
Published: January 2023

Abstract
It is known that vitamin C has anti-viral and anti-tumor activity via the activation of immune cells including T and NK cells. Even though the mechanisms of vitamin C on the activation of NK cells were extensively studied, but the effect of vitamin C on the activation of T cells is poorly understood, especially in vivo system. Therefore, we compared the surface marker and cytokine profiles of T cells from Gulo (-/-) mice, which cannot synthesize endogenous vitamin C, upon vitamin C depletion. First, we examined the phenotype and cytokine secretion of naïve T cells from wild type C57BL/6 mice, and vitamin C-depleted and supplemented Gulo(-/-) mice. Interestingly, the number of regulatory T cells were increased in vitamin C depleted Gulo(-/-) mice. Next, we investigated the changes on activated T cells in Gulo(-/-) mice upon vitamin C depletion. As a result, the expression of activation markers, CD25 and CD69, were relatively low, but there was no change on the level of IFN-gamma production. Taken together, when there was insufficient amount of vitamin C, the immune system might be suppressed by the increase of regulatory T cell population. In addition, T cells are not effectively activated when antigens were administered in vivo. Therefore, our results suggest that vitamin C maintains cell-mediated immunity via the suppression of the regulatory T cell development and plays a pivotal role during the process of T cells activation.