bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential modulation of NK and NKT cells in the liver and spleen following IL-18 + IL-12 treatment of mice (98.9)
Authors: Subleski Jeff John , Hall Veronica L , Weiss Jonathan M , Ortaldo John R , Wiltrout Robert H 
Published: January 2023

Abstract
IL-18 + IL-12 treatment elicited significant antitumor activity in the liver via an increase in NK cells and a concurrent decrease in the detectable number of NKT cells. To determine both the fate of NKT cells and the origins of NK influx into the liver following IL-18 + IL-12 treatment, we optimized liver leukocyte isolation techniques and determined that IL-18 + IL-12 was not causing NKT cells to down-modulate their TCR, as was previously reported with anti-CD3 or α-GalCer activation. Also, no discernable apoptosis was detected at 6 or 24 hours. However, IL-18 + IL-12 treatment caused an increase in NKT cells in the spleen that coincided with a decrease in these cells in the liver. We also observed a decrease in NK cells in the spleen that coincided with an increase of these cells in the liver. These findings suggest that IL-18 + IL-12 induces a well coordinated but opposing relocation of selected subsets. To identify potential genes involved in cell migration, we used a chemokine array and identified the differential gene expression in the spleen and liver. In the spleen, we found that IL-18 + IL-12 induced CCL19 in the spleen which is the ligand for CCR7 on NKT cells. In contrast, in the liver this treatment induced CCL9 and CCL20 which are respective ligands for CCR1 and CCR6 on NK cells. These data delineate potentially novel, redistribution mechanisms whereby proinflammatory cytokines may modulate the liver leukocyte repertoire.
Effects of TH17 cell transfer on the airways (99.1)
Authors: McKinley Laura , Magill Amy , Logar Alison , Kolls Jay 
Published: January 2023

Abstract
A distinct subset of CD4+ T helper cells characterized by the production of IL-17A, IL-17F, and IL-6 has recently been discovered. The differentiation of TH17 cells is dependent on transforming growth factor-β and IL-6 while IL-23 is involved in function of TH17 cells in host defense. TH17 cells have been shown to contribute to the pathogenesis of some autoimmune disorders and models of allergic asthma show TH17 cells are involved in the development of allergic responses. In order to investigate the function of TH17 cells we polarized naïve CD4+ T cells from DO11.10 TCR transgenic mice by culturing in conditioned media containing OVA peptide, TGF-β, IL-6, IL-23, anti-IFN-γ and anti-IL-4. For comparisons we also generated TH0 cells (grown in IL-2 only) and polarized TH1 and TH2 cells.TH17 cells secreted &gt; 5 ng/ml IL-17 in an antigen-recall response when stimulated with OVA peptide. Only transfer of TH17 cells into mice challenged with OVA protein resulted in increased chemokine secretion in the BAL fluid, including substantial levels of the IL-8 homolog KC whereas only transfer of Th2 cells resulted in eosinophil emigration into the lung. Both TH17 and TH2 cells resulted in increased mucous secreting cells in the airway. These data demonstrate that the polarized antigen specific T-cells result in specific lung pathologies.
Differential expression of beta2-integrins, CNS trafficking, and cytokine production between gamma/delta and alpha/beta T cells in EAE (99.4)
Authors: Smith Sherry Susan , Barnum Scott R 
Published: January 2023

Abstract
A critical step in the development of EAE is trafficking of leukocytes into the CNS. Several families of adhesion molecules, including the b2-integrins, contribute to leukocyte trafficking in EAE. However, the expression of these integrins on gd T cells in naïve mice or those with EAE remains poorly characterized. Using multiparameter flow cytometric analysis, we compared b2-integrin expression, kinetics of CNS trafficking, and cytokine production between gd and ab T cells in C57BL/6 mice over the acute course of MOG-induced EAE. We observed that b2-integrin expression on gd T cells significantly increased from baseline, peaked at day 10, and remained unchanged in the DLN or declined in the spleen and CNS by day 15. CD11a and CD11d expression on ab T cells fluctuated throughout disease in all tissues examined, while CD11b and CD11c expression peaked 10 days post-immunization then declined. Ab T cells infiltrated the CNS prior to gd T cells and were more abundant in the CNS. However, early in disease gd T cells infiltrated the CNS at a significantly higher rate than ab T cells. In addition, gd T cells, particularly those in the CNS, produced more IFN-g and TNF-a than ab T cells throughout the course of EAE. These results suggest unique roles for b2-integrins in the trafficking of gd versus ab T cells during EAE. Furthermore, our data suggest that gd T cells rapidly infiltrate the CNS early in EAE and produce cytokines that modulate acute disease.
This work was supported by grants from the National MS Society (RG-3437-A-6) and from the NIH (NS46032) to S. Barnum and (T32 AI07051-30) to S. Smith.
CD80 blockade suppresses inflammatory response to syngenic flora in TNBS colitis. (B100)
Authors: Srinivasan Mythily , Eri Rajaraman , Eri Rajaraman 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD) is an immune-mediated inflammatory disorder of the gastrointestinal organ system characterized by chronic inflammation of the bowel with periods of exacerbation and remission. Considerable evidence suggests that IBD is a result of abnormal activation of CD4+ T cells to intestinal microflora. Therapies targeting T cell costimulation such as anti-CD80 (B7-1), anti-CD86(B7-2) mAb and CTLA-4 mAb have provided some insights on the control of intestinal mucosal inflammation. Recently short polyproline helical peptide designed to selectively inhibit CD80: receptor interactions has been reported. We investigated the therapeutic potential of this peptide in animal models of colitis. When administered at the time of transfer, the CD80 blocking peptide (500μg i.v.) protected the SCID mice from CD4+ CD45Rbhi mediated transfer colitis efficacy of this peptide. Significantly when administered at the time of boosting (day 6, 500μg i.v.), the CD80 binding peptide suppressed clinical and microscopic inflammation in TNBS colitis. The lamina propria lymphocytes isolated from CD80 binding peptide treated mice secreted significantly less IL-12p40 and IFN-g when stimulated with syngenic normal colon flora. Increased number of CD4+ mesenteric lymph node cells were annexin positive in CD80 binding peptide treated mice suggesting that peripheral deletion activated T cells as the mechanism of mediating protection.
Pulmonary Expression of Vasoactive Intestinal Peptide in a Murine Model of Allergic Asthma (B107)
Authors: Samarasinghe Amali Eashani , Hoselton Scott Alan , Schuh Jane Marie 
Published: January 2023

Abstract
Chronic allergic asthma is maintained by a Th2-type immune response and is characterized by persistent inflammation of the airways, goblet cell metaplasia, smooth muscle cell hyperplasia, and airway remodeling. Among its many roles, Vasoactive Intestinal Peptide (VIP) is a cytokine known to regulate lymphocytes, macrophages, mast cells, and natural killer cells. We investigated the distribution of VIP in naïve versus allergic mice that had been sensitized and challenged with live Aspergillus fumigatus fungal spores. In situ staining revealed that, although naïve animals produced VIP in the vascular endothelium, the presence of VIP-positive cells in and around the airways is minimal. Allergic mice, however, displayed exaggerated VIP expression in the bronchial epithelium of large and small airways, Type II alveolar cells, and resident macrophages. Recruited macrophages, eosinophils, and lymphocytes were also VIP-positive. Expression of VIP in allergic mice was maximal at days one and three after antigen challenge. Airborne delivery of spores increased the VIP production in distal airways above that seen when the challenge was delivered intratracheally in liquid. The basal epithelial cell layer was conspicuously and persistently negative for VIP expression in all samples. We hypothesize that cells in this layer secrete neutral endopeptidase (NEP) which is responsible for cleaving VIP in the healthy lung.
A post-allergen challenge inhibition of PARP prevents airway eosinophilia and reduces Th2 cytokines and mucus production in animal model of asthma: a clinical potential in the treatment of asthma (B109)
Authors: Naura Amarjit Singh , Oumouna Mustapha , Zerfaoui Mourad , Hans Chetan , Suzuki Yasuhiro , Boulares Hamid 
Published: January 2023

Abstract
Identifying therapeutic drugs that block the release or effects of Th2 cytokines after allergen exposure is an important clinical goal for treatment of allergic inflammatory diseases such as asthma. An important portion of pre-clinical research is predominantly focused on prevention rather than treatment of symptoms associated with diseases. We recently showed, using a murine model of allergic airway inflammation, that poly(ADP-ribose) polymerase (PARP) plays an important role in the pathogenesis of asthma-related lung inflammation and that PARP inhibition, by a novel inhibitor (TIQ-A), prevented airway eosinophilia in ovalbumin-challenged mice. TIQ-A injection before ovalbumin challenge in C57BL/6 mice resulted in significant suppression of Th2 cytokines production including IL-4, IL-5, and IL-13 and secretion of mucus by airway goblet cells. In the present study, we show that a single injection of TIQ-A 1 or 6 hour after ovalbumin challenge conferred a marked reduction in ovalbumin-challenge-induced eosinophilia. The reduction in eosinohilia was accompanied with an even more pronounced suppression of IL-4, IL-5, and IL-13. Such suppression was closely associated with a more pronounced reduction in mucus production by airway goblet cells. The observed protection, as late as 6 hour after the allergen challenge, may be of a great clinical importance in our search towards novel therapeutic drugs in the treatment of asthma.
Support@ NIH-HL072889 and 1P20RR18766 to HB.
NALT CD11b+ Dendritic Cell Migration Contributes to Induction of Ag Specific Immunity (B111)
Authors: Sekine Shinichi , Kataoka Kosuke , Asanuma Hideki , Fukuiwa Tatsuya , Davydova Julia , Adachi Yasuo , Kobayashi Ryoki , Fujihashi Keiko , Shizukuishi Satoshi , Yamamoto Masato , Fujihashi Kohtaro 
Published: January 2023

Abstract
Our previous study showed that targeting nasopharyngeal-associated lymphoreticular tissue (NALT) dendritic cells (DCs) with an adenovirus vector expressing Flt3 Ligand (Ad-FL) induced Ag-specific mucosal immunity that mediated by increased numbers of DCs and CD4+ Th1- and Th2-type cytokine responses. In this study, we examined the kinetics of DC subset formation and intracellular cytokine production in NALT and in cervical lymph nodes (CLNs). C57BL/6 mice were nasally immunized with Ad-FL and OVA three times at weekly intervals. As controls, mice were given Ad expressing the firefly luciferase protein (Ad-Luc). Mononuclear cells were isolated at various time points and the frequencies of DC subsets and intracellular cytokine production by CD4+ T cells were determined by FACS. An Increased frequency in CD11b+ DCs was seen in nasal passages (NPs) and submundibular glands (SMGs) at day 21. On the other hand, the frequency as well as the actual numbers of DCs in NALT was the highest 3 days after the second nasal immunization. Further, peak cell numbers of CD11b+ DCs in CLNs were seen at day 14. Of importance, intracellular cytokine FACS analysis showed highest IFN- γ and IL-4 production in CLNs at day14.
These results suggest that NALT CD11b+ DCs migrate into NPs and SMGs via the CLN and play an important role in the induction of both Th1- and Th2-type cytokine responses in mice given Ad-FL as nassal adjuvant.
Supported by DE 12242, AI 18958, AI 43197, and AG 025873.
The PD-1/PD-L costimulatory pathway plays a key role in Histoplasma capsulatum pathogenesis (B122)
Authors: Lazar-Molnar Eszter , Gacser Attila , Nosanchuk Joshua D , Freeman Gordon J , Almo Steven C , Nathenson Stanley G 
Published: January 2023

Abstract
The PD-1 costimulatory receptor negatively regulates T cell receptor signaling upon interacting with its ligands PDL1 and PDL2 expressed on antigen presenting cells (APCs) and has a key role in maintaining self-tolerance. In the present study we examined the role of PD-1 in Histoplasma capsulatum (Hc) infection. Hc is a human pathogenic dimorphic fungus that replicates within macrophages in vivo. To characterize immune responses in murine histoplasmosis, macrophages, as well as splenocytes were analyzed after intranasal infection with Hc. qRT-PCR and FACS analysis showed significant, IFN-γ-mediated up-regulation of PDL1 on both macrophages and splenocytes. The role of the PD-1 pathway in Hc pathogenesis is further demonstrated by the significant (100%) survival of PD-1 deficient mice infected with a lethal dose of Hc. Although initially inflammatory reactions developed in the lungs, the mice were disease free by day 10, as shown by histological analysis and cfu values. Also, when Hc infected C57BL/6 mice were treated with blocking anti-PD-1 monoclonal antibody, there was a significant increase in the survival of the animals (70%), whereas all untreated mice died. Our results show for the first time the importance of the PD-1/PDL pathway in anti-fungal immunity, and offer novel strategies for immunotherapy in clinical histoplasmosis.
Identification of an MHC class Ib-restricted CD8 T cell response to polyoma virus infection (B136)
Authors: Swanson Phillip Alan , Stroynowski Iwona T. , Jensen Peter E. , Lukacher Aron E. 
Published: January 2023

Abstract
While MHC class Ia-restricted CD8 T cell responses to viral infections have been extensively characterized, little is known about MHC class Ib-restricted CD8 T cells during viral infection. Mouse polyoma virus establishes a persistent low-level infection and induces tumors in MHC class Ia + class Ib deficient (i.e., b2m−/−) mice. Unexpectedly, mice selectively deficient for MHC class Ia molecules (i.e., Kb−/−Db−/−) mice efficiently control polyoma viral replication and are resistant to polyoma virus-induced tumors. Polyoma virus-specific CD8 T cell cloned lines were isolated from immune Kb−/−Db−/− mice. Using these cloned lines, we mapped their MHC restriction to H2-Q9, an MHC Class Ib molecule of the Qa-2 family. We identified the Q9-restricted viral epitope as a 9mer peptide from a viral capsid protein. In preliminary studies, we found that the magnitude of the Q9-restricted antiviral CD8 T cell response progressively inflates over the course of infection. Experiments are underway to visualize this novel virus-specific class Ib-restricted CD8 T cell response in vivo.
This work was supported by R01CA71971.
Vaccination with recombinant adenoviruses and dendritic cells expressing prostate-specific antigens is effective in eliciting CTL and suppresses tumor growth in the experimental prostate cancer (B153)
Authors: Kim Sol , Lee Jee-Boong , Chang Jun 
Published: January 2023

Abstract
Prostate cancer is currently the most commonly diagnosed cancer in men and the second leading cause of cancer-related death in men in the US. Immunological approaches may provide an alternative option for prevention and treatment of prostate cancer, since the malignant cells overexpress many unique antigens that can be targeted by immune cells. To develop vaccine candidate against prostate cancer using mouse model, we constructed three recombinant adenoviruses expressing prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA) and six-transmembrane epithelial antigen of the prostate (STEAP), that were specifically upregulated in the TRAMP-C1 cancer cell line as well as the orthotopic murine prostate cancer. Male C57BL/6 mice were immunized by intravenous injection of these recombinant adenoviruses and subsequently by subcutaneous injection of dendritic cells pulsed with TRAMP-C1 cell lysate. After subcutaneous challenge with TRAMP-C1 cells, tumor growth was significantly delayed in the immunized mice compared to the control group. Surprisingly, high levels of STEAP-specific CD8 T cell responses were detected using MHC I tetramers in the peripheral blood and the spleen, which is inversely correlated with tumor growth in tumor-challenged mice. In addition, the therapeutic effect of our vaccine regimen was also accessed and induced significant delay in growth of established tumors. Together, our results suggest that STEAP is a good immunologic target against prostate cancer and our vaccine regimen successfully elicits effective tumor-specific CD8 T cell responses and suppresses tumor growth. Further study will improve the efficacy of our vaccine candidate and could be applied for the human disease in the future.
Memory and protective cellular immunity induced by the murine orthologue of metastasis associated protein TPD52 (B155)
Authors: Bright Robert K , Lewis Jennifer D , Payton Laura A 
Published: January 2023

Abstract
Tumor protein D52 (TPD52) is involved in tumor cell proliferation, trafficking and metastasis. TPD52 over expression has been demonstrated in prostate, breast, lung and colon carcinomas. Murine TPD52 (mD52) has been shown to induce transformation and metastasis, and mirrors the known function and expression patterns of the human orthologue. We believe TPD52 represents a self, non-mutated tumor associated antigen (TAA) with direct relevance to human cancers. The Transgenic Adeno-carcinoma of the Mouse Prostate (TRAMP) model was employed to study mD52 as a vaccine antigen. Naïve mice were immunized with plasmid DNA encoding the full length cDNA of mD52. Following the final immunization, mice were challenged s.c. with a tumorigenic dose of mD52 positive, autochthonous TRAMP-C tumor cells. Greater than 60% of mice were tumor free 85 days post challenge with TRAMP-C1 and 40% were tumor free post challenge with TRAMP-C2 tumor cells, without induction of observable autoimmunity. Survivors of TRAMP-C2 initial tumor challenge rejected a second TRAMP-C2 tumor challenge 73 days later and remained tumor free greater than 90 days. The T cell cytokine secretion patterns from tumor challenge survivors indicated that a TH1 cellular immune response was involved in tumor rejection. These data suggest that mD52 vaccination induced a memory immune response that resulted in rejection of mD52+ tumors without inducing autoimmunity.
4-1BB and 4-1BB ligand interaction increases IL-10 during acute inflammation of mice (B162)
Authors: Shin HH , Lee JE , Kyung TW , Oh SR , Choi HS 
Published: January 2023

Abstract
The cell influx in the peritoneal cavity after the inflammatory stimulus lipopolysaccharide (LPS) was analyzed from wild-type and 4-1BB-deficient mice. The peritoneal injection of LPS resulted in an increase of influx of polymorphonuclear leukocytes (PMN) and macrophages in the peritoneal cavity with significantly higher number of macrophages in 4-1BB-deficient mice. Anti-4-1BBL Ab, which blocks the interaction between 4-1BB and 4-1BBL, resulted in higher number of cell influx, suggesting that blocking of 4-1BB and 4-1BBL interaction can increase PMN and macrophages influx after acute inflammation. The level of IL-10 production in wild type mice was significantly higher than that of 4-1BB-deficient mice. The peritoneal macrophages of 4-1BB-deficient mice expressed lower level of IL-10 at the mRNA and protein levels than did those of wild-type ones after LPS treatment, suggesting that peritoneal macrophages are main source of IL-10 in response to LPS. Significantly lower numbers of macrophages and PMN were recruited in PEC of 4-1BB-deficient mice after IL-10 injection, comparing with after PBS injection.
This work was supported by SRC fund to IRC, University of Ulsan from KOSEF and Ministry of Korea Sciences and Technology.
Functions of Notch signaling-dependent Thy1-expressing dendritic cells in immune response (B164)
Authors: Ishifune Chieko , Maekawa Yoichi , Yasutomo Koji 
Published: January 2023

Abstract
Dendritic cells (DCs) are one of key regulators in immune response through antigen presentation and producing several cytokines. Although recent studies have shown that several DC subsets have different phenotypes and functions, it is still unclear how differentiation of various DC subsets is regulated and determined. We here investigated whether Notch signaling contributes to DCs development and their functions. Thy1-expressing DCs (Thy1-DCs) dominantly differentiated by co-culture of bone marrow cells and OP9 cells overexpressing Delta1 in the presence of GM-CSF. Thy1-DCs had different phenotypes from those of reported DCs and developed in Notch signaling dependent manner. The Thy1 expressing DCs were also found in vivo and the proportion of Thy1-DCs was markedly increased in both spleen and liver of mice infected with Trypanosoma cruzi (T.cruzi). The Thy1-DCs from mice infected with T. cruzi were capable of producing high amount of IFN-gamma. Considering that IFN-gamma is a crucial cytokine for excluding T.cruzi, Notch signaling might have an important role in controlling T.cruzi infection by expanding Thy1-DCs.
CD1d-dependent activation of NKT cells by Cryptococcus neoformans-pulsed dendritic cells (B172)
Authors: Aoyagi Tetsuji , Nakamura Kiwamu , Miyazato Akiko , Nakagawa Kiyotaka , Miyazawa Teruo , Kinjyo Yuki , Kronenberg Mitchell , Kaku Mitsuo , Kawakami Kazuyoshi 
Published: January 2023

Abstract
Previously, we reported that NKT cells play an important role in the development of Th1 responses and host resistance to Cryptococcus neoformans, an opportunistic fungal pathogen in AIDS. In the present study, we addressed the role of dendritic cells (DCs) to activate mouse liver mononuclear cells (LMNCs), known as a rich source of NKT cells. LMNC were activated in response to C. neoformans-pulsed mouse bone marrow-derived dendritic cells (BMDCs) and produced IFN-γ, which was significantly suppressed by anti-CD1d antibody. This response was abrogated or reduced when BMDCs from CD1dKO or LMNCs from Jα18KO mice were used. In addition, NKT hybridoma cells were cultured on recombinant CD1d protein-coated plates with lipid from this fungal pathogen and IL-2 synthesis was measured. The total lipid led to their activation, although not profound in magnitude. These results suggest that DCs present some lipid antigen from C. neoformans in a CD1d-dependent manner for the activation of NKT cells.
Suppression of Toll-like receptor-mediated signaling by Cryptococcus neoformans (B177)
Authors: Inden Ken , Xiao Gang , Miyazato Akiko , Nakamura Kiwamu , Kaku Mitsuo , Kawakami Kazuyoshi 
Published: January 2023

Abstract
Cryptococcus neoformans is an intracellular fungal pathogen, host defense to which is mediated by cellular immunity and Th1 immune responses. This microorganism is eliminated by nitric oxide (NO) produced from activated macrophages. In the current study, we elucidate the influence of C. neoformans on NO synthesis by macrophages activated via Toll-like receptors (TLR).
A mouse alveolar macrophage cell line, MH-S, was activated by TLR ligands such as peptidoglycan (PGN), lipopolysaccharide (LPS) and CpG-oligo DNA (ODN) in the presence of IFN-ƒ×. These treatments caused NO synthesis measured by Griess method and expression of iNOS mRNA detected by RT-PCR. C. neoformans encapsulated strains, YC-11 and B3501, and an acapsular strain, Cap67, strongly inhibited these activities. For this suppression, physical interaction between MH-S and C. neoformans was requied, and heat-killed organism was not effective. Lipid fractions derived from C. neoformans did not show such inhibitory activity. This fungal microorganism inhibited the activation of NFƒÛB in TLR-transfected HEK293 cells using a luciferase reporter assay. These results suggest that C. neoformans may suppress the NO-mediated killing by alveolar macrophages activated via a TLR pathway.