bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of anti-leukemic responses using cellular immunotherapy (TUM2P.921)
Authors: Fast Loren , Reagan John , Nevola Martha , Mulder Arend , Claas F. , Quesenberry Peter 
Published: January 2023

Abstract
Previous work has shown that blood cancers can be treated through stimulation of the cancer patient’s immune system. In initial studies, it was observed that 14/26 patients with refractory hematological malignancies responded (9 major) to the infusion of large numbers (1 -2 x 108 CD3+ cells/kg) of haploidentical white blood cells following low levels of total body irradiation (100cGy). A cytokine storm quickly developed with a median time of 14 hours and resulted in high fevers that were allowed to persist for 48 hours, if possible, and then controlled with corticosteroids if needed. However the potential role of anti-leukemic effector cells in these responses was not determined. Three patients have been enrolled into a re-opened cellular immunotherapy clinical trial in which haploidentical white blood cells are infused with no prior chemotherapy or radiation. Blood samples were obtained from the recipient approximately 1, 24, 48, 72 and 168 hours after infusion and analyzed for the persistence and activity of donor/recipient cells as well as levels of cytokines and other factors in the plasma. Thus far, the results demonstrate elimination of donor cells by day 7, rapid upregulation of PD-1 ligands on leukemic cells and prolonged plasma levels of IL-10. Evaluation of the trends obtained with increased number of patients enrolled in the clinical trials will provide insights into new approaches to enhance the anti-leukemic responses in these patients.
Design of T cell epitope-driven IAV vaccines for swine using immunoinformatics tools (VAC2P.929)
Authors: Liu Rui , Gutierrez Andres , Loving Crystal , Vincent Amy , Moise Leonard , Terry Frances , Martin Bill , Groot Annie 
Published: January 2023

Abstract
Immunoinformatics tools have accelerated human vaccine design, but have not been applied extensively to animal vaccines. iVAX is a comprehensive toolkit to design genome-derived epitope-driven vaccines (GD-EDV) that uses EpiMatrix for epitope-mapping, among other algorithms. EpiMatrix was designed for use with human HLA. Using the pocket profile method, we created new T cell epitope-prediction matrices (PigMatrix) for porcine MHC (SLA). Integration of PigMatrix into iVAX now makes it possible to design GD-EDV for swine pathogens. We analyzed proteins from five influenza A viruses (IAV) representative of those prevalent in North American swine for highly conserved T cell epitopes. IFN-γ ELISpot responses to eleven 9mer epitopes, predicted to bind to class I SLA-1*0401, were measured using samples from pigs vaccinated with adjuvanted, whole-inactivated IAV. Together, these epitopes represented more than 50% of the response observed for whole virus re-stimulation. In further studies, we developed matrices for class I and II SLA alleles and predicted 28 conserved class I and 20 class II T cell epitopes from seven common IAV genomes. These epitopes were concatenated into two multiepitope IAV DNA vaccines for efficacy testing. These early results demonstrate the potential for immunoinformatics tools to develop rapid responses to infections affecting animals used for food. The new enhanced tools will facilitate the design of GD-EDV for swine diseases lacking effective vaccines.
Epigenetic regulation in CD91+ cells following immunization with heat shock proteins (VAC3P.948)
Authors: Kinner Lauren , Binder Robert 
Published: January 2023

Abstract
The immunogenic HSPs are intracellular chaperones of peptides. When HSPs are released from cells they interact with the receptor CD91 on the surface of antigen presenting cells. This allows for cross-presentation of the chaperoned peptides and initiation of various signaling pathways. We have shown that low or high dose gp96 immunization of mice leads to priming of TH1 and Treg responses respectively. Although the mechanisms driving this switch remain largely unknown, these responses have been harnessed for immunotherapy of cancer and autoimmune disease. Our preliminary studies have indicated changes in accumulation and/or recruitment of multiple immune cell subsets in the draining lymph nodes and spleens of mice following immunization with gp96. We propose that such regulation is controlled by DNA methylation states in CD91+ cells. Using next generation sequencing, we have identified these modifications following gp96 immunization. Methyl-seq analysis of CD91+ cells derived from mice immunized with low or high doses of gp96 reveals differential methylation across at least 80 promoter regions, including genes involved in chemotaxis, signaling, and cytokine response. Further exploration will determine which, if any, of these regions are associated with gene silencing. Importantly, these studies show an early requirement for epigenetic changes in response to gp96 and will provide further understanding of the APC-T cell interaction following gp96 immunization and in general.
Genetic background influences the NK recruitment and Th1 polarization in response to TLR agonists (VAC3P.955)
Authors: Nouri-Shirazi Mahyar , Zeng Menghua , Bible Brittany , Tamjidi Saba 
Published: January 2023

Abstract
In response to vaccines, DCs do not act in isolation but potentiate their efficiency by interacting with NK cells. The recognition of PAMPs by TLRs triggers DC maturation which is essential for their migration and T-cell priming. Maturing DCs release IL-12 which regulates the function of NK cells and drives the Th1 cells differentiation. In turn, NK cells which are activated by IL-12 and PAMPs through their own TLRs, provide IFN-γ necessary for enhancing stable IL-12 production by DCs and maintaining Th1 cell polarization. Studies using Balb/c strain showed that TLR agonist R848 induces NK cell recruitment into lymph nodes and augments Th1 polarization through unknown mechanisms. In this study we tested whether the genetic background will influence the NK cell recruitment and subsequent Th1 polarization in response to vaccine formulated with a panel of TLR agonists and alhydrogel. We found that immunization with OVA protein mixed with TLR agonist R848 among adjuvants tested, increased up to 3-fold recruitment of IFN-γ producing CD27+CD11b+ NK cell expressing CXCR3 and CD62L in lymph nodes and spleen of Balb/c but to a much lesser extent in B6 mice. Interestingly, however, the increased in NK cell recruitment had limited impact on Th1 polarization in Balb/c as compared to Th1-prone B6 mice. These data suggest that for optimal Th1 polarization, adjuvant or adjuvant combination should be selected based on their ability to both recruit and maximize DC-NK bidirectional signaling.
Expression of triggering receptor expressed on myeloid cells-1 (TREM-1) is up-regulated following West Nile virus infection (WNV): implication for a role in innate immune responses (VIR1P.968)
Authors: Verma Saguna , Roe Kelsey , Orillo Beverly , Nelson Jacob , Gibot Sebastien 
Published: January 2023

Abstract
Activation of TREM-1 signaling via adaptor protein DAP12 is important for inflammation and activation of antigen presenting cells, however little is known about its role in viral infections. Innate immune responses are essential for the control of Flaviviruses including WNV, which has emerged as a significant cause of viral encephalitis in humans. Here, we investigated the effect of Flavivirus infection on the expression of TREMs and its potential role in production of cytokines. We show that expression of TREM-1 was markedly increased in dengue virus-infected THP-1 cells, which correlated with peak viral titers. Similarly, WNV infection significantly increased the mRNA levels of TREM-1 in mouse embryonic fibroblasts (MEFs), BMDM and BMDC. In vivo characterization of TREMs in mice demonstrated significant up-regulation in the transcripts of TREM-1, -3 and -4 in the peritoneal cavity cells and brain at day 3 and 8 after WNV infection respectively. Interestingly, serum levels of soluble-TREM-1 also increased significantly at days 2-3 after infection. Further, activation of TREM-1 using an agonist antibody increased mRNA of WNV-induced cytokines such as IFN-α, TNF-α and IL-6 in MEFs, which decreased following blocking of TREM-1. Collectively, our results for the first time document response of TREMs to Flavivirus infection and indicate a novel role of TREM-1 in modulating inflammatory response to WNV. Further studies are ongoing to define role of TREM-1 in WNV disease outcome.
STAT1 -/- mice are protected against exacerbation of MRSA pneumonia during influenza co-infection (VIR2P.1021)
Authors: Lee Benjamin , Robinson Keven , McHugh Kevin , Mandalapu Sivanarayana , Manni Michelle , Alcorn John 
Published: January 2023

Abstract
In mice, bacterial lung defense requires Th17 activation, which is attenuated by preceding influenza, resulting in exacerbation of pneumonia. Influenza induced-type I IFN requires STAT1 signaling and inhibits dendritic cell production of Th17-activating IL-23. We explored the need for STAT1 signaling in influenza-associated Th17 suppression in a mouse model of influenza and MRSA co-infection using STAT1 -/- mice. WT and STAT1 -/- mice were infected with influenza A PR/8/34/H1N1 or PBS. Mice were challenged with PBS or MRSA on day 6 and sacrificed on day 7; BAL and lungs were harvested for cell count, flow cytometry, bacterial burden, cytokine levels, and gene expression. Compared to WT, influenza-infected STAT1 -/- mice had increased day 6 weight loss (82.3% vs 88.5% of baseline) and higher BAL neutrophil count (2.85 x104 vs 4.15 x105). Co-infected STAT1 -/- mice had higher total cell count (1.04 x106 vs 1.61 x106 cells), but did not show increased bacterial burden compared to WT mice. IL-17 and IL-22 producing CD4+ and γδ T cells were reduced in co-infected WT mice versus MRSA alone but were increased overall in STAT1 -/- mice. No differences in Th17 cytokines (IL-17, IL-22, IL-23) or in IFN-β gene expression were detected in whole lung. These data suggest that STAT1 -/- mice are protected from exacerbation of MRSA pneumonia during influenza co-infection despite increased influenza severity and lung inflammation, but the mechanism of these findings remains unclear.
Viral neuraminidase and the biphasic immune regulation by host cytokine interleukin-10 in influenza (VIR2P.1030)
Authors: Dutta Avijit , Chen Tse-Ching , Lin Chun-Yen , Chiu Cheng-Hsun , Lin Yung-Chang , Chang Chia-Shiang , He Yueh-Chia , Huang Ching-Tai 
Published: January 2023

Abstract
Influenza virus invades the host while the host immune response defends to clear the virus. These responses may result in excessive inflammation with tissue injury, which is as detrimental as the invasiveness of the virus. Here we demonstrate a biphasic immune regulation by the host T cell cytokine interleukin-10. During the early phase of infection, viral neuraminidase increases with multiplication of the virus. The abundance of neuraminidase mediates a robust release of the suppressive cytokine TGF-β. Host interleukin-10 interacts with neuraminidase, counteracts the release of TGF-β, and supports the antiviral immunity. Neuraminidase activity wanes with eradication of the virus. In the late phase of the infection, interleukin-10 preferentially binds to up-regulated interleukin-10 receptors and attenuates the immune responses to avoid immune-mediated damage to the host.
A role for MHC-mediated signalling in the functional and phenotypic heterogeneity of naive T cells (IRC8P.454)
Authors: Rath Satyajit , Rane Sanket , Das Rituparna , Gund Rupali , Balyan Renu , Das Arundhoti , Khalsa Jasneet , Ranganathan Vidya , Prabhu Savit , Mattoo Hamid , Durdik Jeannine , George Anna , Bal Vineeta 
Published: January 2023

Abstract
Variability in cellular activation in the immune system can have diverse consequences, resulting in heterogeneity in effector programming and function as well as in cell survival. While examining relationships between lymphocyte heterogeneity and functionality, we find that apparently unimodally distributed coreceptor heterogeneity among naive T cells, simplistically expected to be due to intrinsic noise, is not only correlated with major functional variation but is modulated by extrinsic microenvironmental cues in vivo. Thus, when naive T cells from young mice are separated into coreceptor-hi and coreceptor-lo subsets, we find that coreceptor-lo cells are smaller, have higher CD5 levels, respond poorly, are more susceptible to death, and show altered effector differentiation. Human coreceptor-lo and coreceptor-hi naive T cells show similar differences. Coreceptor-lo and coreceptor-hi subsets of 'single-positive' (SP) thymocytes do not show these differences, whereas peripheral coreceptor-lo and coreceptor-hi subsets of naive T cells from TCR-transgenic mice do. Adoptive transfer-mediated parking in vivo in MHC-sufficient but not in MHC-deficient mice causes reduction in coreceptor levels, increase in CD5 levels and hyporesponsiveness in naive T cells. Naive T cells from aged mice show similar phenotypic and functional differences. Thus, our data show complex roles for tonic signaling in the functional heterogeneity of naive T cell populations.
LRBA deficiency in in Mexican patients with common variable immunodeficiency (IRM10P.616)
Authors: Moreno Corona Nidia , Berron Ruiz Laura , Mogica Martinez Dolores , Nakashimada Yamazaki , Segura Mendez Nora , Santos-Argumedo Leopoldo , López-Herrera Gabriela 
Published: January 2023

Abstract
CVID is one of the most common primary immunodeficiency diseases and is a diagnosis of exclusion. CVID is characterized by hypogammaglobulinemia and recurrent bacterial infections. About two third of CVID subjects have an autoimmune condition. The etiology of about 80% of CVID remains unknown. Genetic linkage studies in such families have found distinct homozygous mutations in the gene encoding LRBA. Since then, all 11 LRBA deficient CVID subjects identified to date have autoimmune diseases, all patients, except one presented hypogammaglobulinemia. All mutations reported caused the loss or LRBA expression in PBMCs. In this work, we explore the frequency of LRBA deficiency in a cohort of 40 patients with clinical diagnosis of CVID diagnosis, most of which, consanguinity is unknown. Two patients with LRBA deficiency were identified in this cohort. All of the forty patients showed hypogammaglobulinemia. We also correlate the deficiency of LRBA with Freiburg classification from which patients with mutations in LRBA were from group Ia an Ib.
Ikaros tumor suppressor function in pre-B ALL: potential role of Ikaros target gene Ctnnd1 (IRM10P.621)
Authors: Schjerven Hilde , Eggesbo Linn , Lindeman Ida , Muschen Markus 
Published: January 2023

Abstract
Ikaros is a zinc finger transcription factor required for B-cell development and proper hematopoiesis, and an important tumor suppressor in developing lymphocytes. To understand the mechanism of Ikaros tumor suppressor function and potentially develop new and improved targeted therapies, it is important to elucidate the downstream target genes involved. With this aim, we combine mouse models of pre-B ALL and in vitro culture of human patient-derived pre-B ALL cells. A mouse model with targeted deletion of the fourth DNA-binding zinc finger of Ikaros resulted in loss of tumor suppressor function, with a limited set of deregulated genes useful to narrow down the list of putative relevant Ikaros target genes (Schjerven et al., 2013). To specifically address the role of Ikaros as a tumor suppressor in human pre-B ALL, we developed TET-regulated Ikaros expression in human pre-B ALL cells. This enables us to test specific Ikaros target genes from the mouse model, and allows for genome-wide expression analysis by RNA-seq to elucidate all genes downstream of Ikaros in human pre-B ALL cells. To help distinguish direct from indirect target genes, we have mapped the genome-wide binding sites of Ikaros in these human pre-B ALL cells by ChIP-Seq. This approach has identified the Ikaros target gene Ctnnd1. Ongoing experiments explore the potential role of Ctnnd1 and test the current hypothesis that Ikaros-mediated repression of Ctnnd1 limits CyclinD levels and leukemic growth in pre-B ALL.
Analysis of germinal centers in mice with Chagas’ disease treated with NIPOx-B
Authors: Mora Albany Reséndiz , Baeza Carlos Wong , Marin Daniela Cruz , Flores Elizabeth Celso , Ramírez Isabel Baeza , Ramírez Carlos Wong 
Published: January 2023

Abstract
Chagas’ disease is caused by the parasite Trypanosome cruzi; it affects 10 million people in Latin America and it remains incurable: the only drugs available for its treatment, Benznidazole (Bz) and Nifurtimox (Nx), are inefficient to cure patients. The chronic phase of the disease is characterized by megacolon and megaesophagus; this phase is established by parasite evasion of the host adaptive immunity, a process that is facilitated by the free radicals generated by Bz and Nx, which affect lymphocytes and other immune cells. We designed and synthesized the benzyl ester of N-isopropyl oxamic acid (NIPOx-B) and determined that it is an effective inhibitor of alpha-hydroxy acid dehydrogenase II enzyme, a key enzyme in the parasite metabolism. NIPOx-B is more efficient than Bz and Nx in decreasing mice parasitemia. In this work, we studied by flow cytometry the cell populations in germinal centers in mice with Chagas’ disease, untreated or treated with Bz or with NIPOx-B. The percentage and the activation of B cells, macrophages, CD4 lymphocytes, dendritic and follicular dendritic cells in germinal centers were higher in mice treated with NIPOx-B than in mice treated with Bz. The IgG and IgE antibodies titers were also higher in mice treated with NIPOx-B. Untreated mice had the lowest cell percentages and antibody titers. Mice treated with NIPOx-B did not develop megasyndromes, while untreated mice or mice treated with Bz developed them. Because NIPOx-B has trypanomicidal activity and did not affect the percentage of cells involved in the immune response it can be proposed as a drug for the treatment of Chagas’ disease.
Immune triage: prioritization of host immune responses.
Authors: Jamieson Amanda Mercedes , Crane Meredith , Xu Yun , Lee Kayla 
Published: January 2023

Abstract
The immune response is important in many functions, including host defense against pathogens, wound healing, development, response to cancer, and maintenance of homeostatic physiological responses. We are interested in the concept of immune triage, in that a given host must be able to deal effectively with multiple insults, and at times prioritize immune responses. It is important for the overall health status of the host that the immune system responds effectively to protect essential organs. We have developed several mouse models, focusing on the lung immune response, that allow us to examine different aspects of immune triage. The lung is an essential and delicate organ and thus pulmonary immune responses must be tightly regulated. We have determined that lung infection with influenza A virus (IAV) alters the response to bacterial lung infections. Depending on the bacterial infection, previous infection with IAV can suppress or augment the immune response to bacteria. We have also determined that pulmonary infection with IAV alters many aspects of the systemic immune response. There is a global suppression to systemic bacterial infection, and a decrease in the wound healing response. Our data indicate that the immune system prioritizes lung infections over many other responses. This is most likely due to the importance of the lung in host survival. We have established several regulatory mechanisms by which this immune triage occurs. By understanding how the immune system responds to multiple insults we can improve our understanding of the immune network on a global level.
Investigating mechanisms of sex bias in lung fibrosis using mice with sex chromosome complement
Authors: Valera Isela C , Kafaja Suzanne , Pham Brandon , Fishbein Michael , Singh Ram R 
Published: January 2023

Abstract
Men with systemic sclerosis (SSc) have more end organ damage, an accelerated course, and lower survival than women. Mechanism underlying such sexual dimorphism is unclear. Here, we investigated the role of sex chromosomes in the development of SSc using the four-core genotype (FCG) mouse model that was created to identify effects of the sex chromosome complement without the confounding effects of differences in sex hormones. In this model, findings in the XX females (XXF) can be compared with XY females [XYF = XY−(Sry)], and in XX males [XXM = XX.SryTg] with XY males [XYM = XY−Sry.SryTg]. The FCG C57Bl/6 mice were administered with bleomycin to induce SSc and euthanized 2 weeks later. We found that regardless of the gender, mice with XY sex chromosome complement had more severe disease than mice with XX complement (p = 0.04, n= 37 and 48, respectively). When we compared the groups based on gender, XYF mice had higher fibrosis scores than XXF (p = 0.01). The differences between XY and XX were even more significant in males: XYM animals had much more severe fibrosis than XXM (p &lt; 0.0001). Furthermore, the levels of soluble collagen in bronchoalveolar lavage fluid and of Col1a1 mRNA in lung tissue correlated with the extent of lung fibrosis. Animals with more fibrosis (i.e., XYM) had higher proportions and numbers of myeloid and plasmacytoid dendritic cells in the lungs. XYM mice also had more natural killer T cells, B cells, and T cells in the lungs than XXM mice at 2 weeks post-instillation. Thus, the presence of a Y chromosome, and not the male sex itself, predisposes to lung fibrosis; androgen may play an additive role in causing increased lung fibrosis, whereas the presence of the second X chromosome and/or estrogen might be protective.
Air Pollution Particulate Matter Exposure Modulates Human Peripheral Blood Mononuclear Cell Host Immunity to Mycobacterium tuberculosis (M.tb)
Authors: Sarkar Srijata , Rivas-Santiago Cesar , Munoz Felipe , Ohman-Strickland Pamela , Torres Martha , Schwander Stephan 
Published: January 2023

Abstract
Epidemiological studies indicate that indoor air pollution exposure increases susceptibility to M.tb infection and Tuberculosis (TB) development. Recently, we demonstrated that diesel exhaust particles and urban air pollution particulate matter (PM) impair human peripheral blood mononuclear cell (PBMC) and respiratory epithelial cell (A549) innate immune responses to M.tb via downregulation of TLR-dependent cytokines (IFN-γ, IL-1β IL-6, TNF-α), and antimicrobial peptides, respectively. Here we examined effects of real-world-derived air pollution PM from Iztapalapa, a municipality with high prevalence of air pollution and TB in Mexico City on innate and adaptive human immune responses to M.tb. Cytotoxic and inflammatory PBMC responses were examined upon exposure to PM2.5 (&lt;2.5μm diameter) and PM10 (&lt;10μm) from rainy, cold-dry and warm-dry weather seasons. PBMC from IGRA+ (immunodiagnostic evidence of M.tb exposure) and IGRA- donors were exposed for 20 hours to PM at 0.1, 1 and 10 mg/mL followed by additional 20-hour M.tb exposure. A PM dose-dependent inhibition of IFN-γ production was observed in M.tb-infected PBMC from IGRA+ but not IGRA- donors. Furthermore, the size range of PM, but not their seasonal source, affected the M.tb-induced IFN-γ production. No PM dose-dependent inhibition of IL-1β production was observed in M.tb-infected PBMC from either IGRA+ or IGRA− donors. PM10 from cold-dry and warm-dry seasons at high concentration caused cytotoxicity. This data suggests that urban ambient air pollution PM exposure (1) modulates M.tb-induced adaptive immune responses (suppression of IFN-γ but not IL-1β production in IGRA+ donors) and (2) potentially alters M.tb infection outcomes.
Funding NIEHS 5R01ES020382-05