bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of the kinetics and magnitude of the immune response to rhesus rhadinovirus in immune competent and immune deficient macaques (45.14)
Authors: Messaoudi Ilhem , Powers Michael F. , Wong Scott W 
Published: January 2023

Abstract
Rhesus Rhadinovirus (RRV) is closely related to human herpesvirus 8 (HHV-8) or Kaposi’s sarcoma-associated herpesvirus (KSHV). In rhesus macaques (RM) previously inoculated with simian immunodeficiency virus (SIV), RRV infection results in the development of several B cell lymphoproliferative disorders similar to those seen in AIDS patients infected with KSHV. In this study we compared the adaptive immune response to RRV infection generated in both immune deficient (SIV+) and immune competent (SIV-) RM. We evaluated the kinetics and size of the proliferative burst to RRV infection by determining the prevalence of Ki-67+ cells within CD4, CD8b, and CD20 positive subsets. Furthermore, we measured the prevalence of antigen specific T cells in peripheral blood as well as bronchial alveolar lavage. Our data indicates that immune competent animals generate substantially larger CD8 and CD20 responses, albeit with similar kinetics, than immune deficient animals. Furthermore, immune deficient animals show higher viral loads and sustained viremia, suggesting that CD8 and CD20 responses are critical in the initial control of RRV viral growth and spread. Interestingly, antigen specific responses are more easily detected in peripheral blood of immune deficient animals.
Stress-Induced Changes In Immune Cell Populations In Mice Exposed To Hindlimb Unloading Restraint (45.19)
Authors: O’Donnell Phyllis M , Aviles Hernan O , Orshal Julia M , Sonnenfeld Gerald 
Published: January 2023

Abstract
Hindlimb unloading (HU) is a rodent model that has been successfully used to simulate some of the aspects of space flight including alterations of the immune system. We have shown in previous studies that exposure of mice to HU results in significantly increased plasma norepinephrine levels, decreased IL-6 and TNF-α from LPS stimulated spleen cell supernatants, and increased susceptibility to bacterial infection compared to control mice. The purpose of this study was to examine the populations of immune cells affected by HU to better understand the mechanisms by which HU induced changes in susceptibility to infection. Spleens from HU or control normally caged mice were asceptically removed after 18 or 48 hours of HU exposure, weighed, and analyzed for cell antigen marker expression. Spleen weights were significantly reduced in the HU group with no significant changes in body weights. Flow cytometric analyses revealed that the percentage of splenic CD19+ B cells in mice exposed to HU was significantly reduced at both 18 and 48 hr following HU commencement compared to controls. CD4:CD8 ratios declined from control 2.3 to 2.2 with 18 hr HU and to 1.9 with 48 hr HU. These results suggest that lymphocyte sub-population changes may contribute to the dysregulation of immunity in mice exposed to HU and the subsequent reduced ability of these mice to resist infections.
Funded in part by a grant from the Amino Up Chemical Company (Sapporo, Japan).
MECHANISMS OF NEUTROPHIL DEATH IN HIV INFECTED PATIENTS: ROLE OF ROS, CASPASES AND MAP KINASES PATHWAYS (46.14)
Authors: Salmen Siham , Montes Henry , Soyano Andres , Hernandez Dimas , Berrueta Lisbeth 
Published: January 2023

Abstract
Neutrophils from HIV+ patients have an increased susceptibility to undergo programmed cell death (PCD), which could explain neutropenia during advanced disease. In this work, key steps of PCD have been evaluated in neutrophils from HIV+ patients. The role of caspase-3, caspase-8, MAPK and ROS, were analyzed. Spontaneous neutrophil death is caspase-3 but no caspase-8 dependent, suggesting that the intrinsic pathway is involved as a pathogenic mechanism of PCD. Inhibition of ROS decreased spontaneous PCD and caspase-3 hydrolysis, connecting oxidative stress and Caspase-3 within neutrophils PCD in HIV infected patients. An increased constitutive phosphorylation of p38 MAPK, associated to increased neutrophils death in HIV+ patients, following inhibition of this kinase, was observed, suggesting a role for p38 MAPK in cell survival during the disease. We conclude that oxidative stress secondary to HIV infection can accelerate neutrophil death.
CD103-expressing CD4+Foxp3+ regulatory T cells are critical for the survival of mice infected with the helminth parasite Schistosoma mansoni. (46.17)
Authors: Hesse Matthias , Wilson Mark S. , Cheever Allen W. , Wynn Thomas A. , Bajracharya Siddhartha 
Published: January 2023

Abstract
The complicated life cycle of helminths requires a lasting infection of their hosts. The parasites must avoid destruction by the host’s immune response but also prevent exacerbated immunopathology. Activation of immunoregulatory mechanisms during helminth infection establishes a protective homeostatic immune response. We reported the presence of CD4+Foxp3+regulatory T cells (naTreg) in S. mansoni-egg-induced hepatic granulomas. In immunizations they controlled egg-induced cytokine production. Strikingly, with disease progression the frequency of CD103+naTregs significantly increased. CD103 (the αE chain of αEβ7 integrin) is an activation marker for naTregs with potential roles for migration/maintenance of naTregs at inflammatory sites. Using CD103-deficient mice we investigated the role of CD103 in schistosomiasis. Most infected CD103-KO mice succumbed during transition from acute to chronic inflammation. They developed lower Th-2 responses, reduced Th-2-pathology but exacerbated liver damage. The frequency of naTregs in granulomas was not changed. Importantly, transfer of CD103-competent naTregs rescued infected CD103-KO mice. We demonstrate for the first time the essential protective role of naTregs in schistosome-infected immunocompetent hosts. Although CD103 is not necessary for the presence of naTregs in granulomas, it seems to be pivotal for their function in schistosomiasis.
IL-10 blockade resurrects T cell activity and eliminates a persistent viral infection (46.3)
Authors: Brooks David G , McGavern Dorian B , Oldstone Michael B 
Published: January 2023

Abstract
By definition persistent viral infections are accompanied by immune evasion, and most notably the failure to sustain robust T cell responses, responses that are essential to control of these infections. Identifying and understanding the immunoregulatory mechanisms that direct productive versus abortive T cell responses to viral infections is critical, but currently unclear. Using the model of persistent lymphocytic choriomeningitis virus (LCMV) infection, we found that upregulation of interleukin (IL)-10 early during infection induces T cell exhaustion and directly leads to viral persistence. Blockade of IL-10 activity induced sustained T cell function, the rapid elimination of an otherwise persistent virus infection and development of functional memory T cells capable of preventing re-infection. Antibody blockade of the IL-10 receptor during the chronic phase of infection restored T cell activity and eliminated an established persistent viral infection. Further, by manipulating this immunoregulatory molecule we significantly enhance immune responses to vaccination, indicating a potential “adjuvant” role to anti-IL10 immunotherapy. Thus, we propose a novel therapy to treat persistent viral infection by targeting host immunoregulatory molecules and reactivating antiviral T cells.
Murine AIDS requires CD154/CD40L expression by the CD4 T cells that mediate retrovirus-induced disease: Is CD4 T cell receptor ligation needed? (46.9)
Authors: Li Wen , Green William R 
Published: January 2023

Abstract
LP-BM5, a retroviral isolate, induces a disease featuring an acquired immunodeficiency syndrome termed murine AIDS (MAIDS). Many of the features of the LP-BM5-initiated disease are shared with HIV/AIDS. Our lab has shown that the interaction of B and CD4 T cells that is central to MAIDS pathogenesis requires ligation of CD40 on B cells by CD154 on CD4 T cells. Despite this strict requirement for CD154 expression, whether CD4 T cell receptor (TCR) occupancy, and the generation of TCR-associated “Signal 1”, are essential for the induction of MAIDS is unknown. To functionally block TCR engagement, transgenic (Tg) mouse strains with monoclonal TCR of irrelevant peptide/MHC specificities, all on MAIDS-susceptible genetic backgrounds, were tested: the study of a panel of TCR Tg CD4 T cells controlled for the possibility of serendipitous crossreactive recognition of virus-associated or induced-self peptide, or superantigen, MHC complexes by a given TCR. The data indicate that CD4 T-cell TCR ligation is not a necessity for these CD4 T cells to mediate MAIDS initiation and progression, and thus the induction of CD154 expression that is required of the “pathogenic” CD4 T cells must be occurring in the absence of TCR occupancy and classic generation on Signal 1.
This work was supported by National Institutes of Health Grants CA50157 and AI059580 (to W.R.G.).
DEC-205 antigen targeting at a dendritic cell-enriched site and CD40L-directed dendritic cell activation enhances CD4+ T cell priming. (47.12)
Authors: Mwangi Waithaka , Brown Wendy C. , Hope Jayne C. , Palmer Guy H. 
Published: January 2023

Abstract
To enhance DNA vaccine efficacy, we tested the hypothesis that inoculation of calves with a single dose of a DNA vaccine capable of DC recruitment, DC antigen-targeting and activation will prime significant CD4+ T cell responses. To test this hypothesis, we developed a DNA construct, pCC98MSP1, in which a DEC-205-specific single chain antibody was used for DC-targeting of an Anaplasma marginale MSP1a DR-restricted CD4+ T cell antigen. A DNA construct, pCD40L-ED, encoding CD40 ligand was used for DC activation and DNA-encoded Flt3L/GM-CSF were used for DC recruitment. Recombinant CC98MSP1 binds to DEC-205 in vitro and to skin DCs in situ. In a dose-escalation experiment, DR-matched calves were immunized with a single dose of pCC98MSP1 (0.25–3mg) mixed with pCD40L-ED, pFlt-3L and pGM-CSF (0.5mg each). Immunization with 0.25mg pCC98MSP1 primed CD4+ T cell responses detectable in fresh PBMC 1wk post-immunization (PI). A dose dependent CD4+ T cell response was detected and surprisingly, at 2wks PI, the response induced by 0.25mg was not statistically different from the responses induced by 0.5–3mg pCC98MSP1. The responses were maintained for &gt;9wks PI and underwent rapid recall 4 days post-boost with 0.25mg pCC98MSP1. This data supports the hypothesis that immunization with a single dose of a DNA vaccine capable of DC recruitment, DC-antigen targeting and activation enhances vaccine efficacy.
Funding: USDA-CSREES 2005-01693
Novel vaccination (HVJ-liposome/HSP65 DNA+ IL-12 DNA against Tuberculosis) (47.15)
Authors: Okada Masaji , Kita Yoko , Nakajima Toshihiro , Kanamaru Noriko , Hashimoto Satomi , Nagasawa Tetsuji , Kaneda Yasufumi , Nishida Yasuko , Fukamizu Reiko , Tsunai Yoshie , Inoue Ruriko , Nakatani Hitoshi , Namie Yumi , Yamada Junko , Takao Kyoko , Asai Ritsuko , Asaki Ryoko , Tan Esterlina Babie , Sakatani Mitsunori 
Published: January 2023

Abstract
We have developed a novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-liposome (HSP65+IL-12/HVJ). This vaccine provided remarkable protective efficacy in BALB/C mouse and guinea pig models compared to the BCG vaccine, on the basis of an induction of the CTL activity and improvement of the histopathological tuberculosis lesions, respetively. This vaccine strongly induced CTL against HSP antigen and M.tuberculosis antigens
Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This novel vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR and immune responses. The combination of HSP65 + IL-12/HVJ and BCG by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). In contrast, the survival of the BCG Tokyo group was 33%. These data indicate that our novel DNA vaccine might be useful against M.tuberculosis for human clinical trials. [H-17-Shinko-5] of Research on Emerging and Re-emerging Infectious Diseases in Health Sciences Research grants from Japan.
Co-delivery of lymphopoietic cytokines in live Salmonella vaccines enhances the T cell response (47.17)
Authors: Feng Chiguang , Rodriquez Liliana , Davis Katherine , Pasetti Marcela 
Published: January 2023

Abstract
Live bacteria vaccine S. Typhi elicits strong mucosal and systemic immune responses. It is useful as a live vector to deliver heterologous antigens. Additionally, delivery of a eukaryotic expression vector by attenuated Salmonella leads to temporary expression of the coded gene in host cells after invasion. Because Salmonella invades preferentially macrophages and dendritic cells, the live bacteria could also be used to deliver immunomodulatory molecules to antigen-presenting cells. We hypothesize that co-delivery of lymphopoietic cytokine such as IL-2, IL-7 and IL-15, which has potential in promoting immune memory, enhances the efficacy of vaccination.
Murine IL-2, IL-7 and IL-15 were cloned into eukaryotic expression vector pCMS-EGFP, and introduced into S. Typhi(F1), which carries Y. pestis protective antigen F1. Mice were immunized intranasally with above derivative strains, and boosted with purified antigen F1 in alum adjuvant Alhydrogel.
This prime-boost strategy elicited strong mucosal and systemic antibody responses, as well as cell-mediated responses, e.g. antigen-specific proliferation and IFN-γ production of splenocytes. Inclusion of cytokine, however, further enhanced the cell-mediated responses. Antibody responses were not affected.
Our data strongly support our hypothesis that production of lymphopoietic cytokine during priming vaccination promotes memory T cell responses.
Immunogenicity of co-administered recombinant VSV vectors expressing GM-CSF and HIV-1 Gag in mice (47.25)
Authors: Wright Kevin James , Calderon Priscilla C , Guo Min , Natuk Robert J , Nasar Farooq , Johnson J Erik , Witko Susan , Clarke David K , Hendry R Michael , Parks Christopher , Eldridge John , Cooper David 
Published: January 2023

Abstract
Highly attenuated recombinant vesicular stomatitis virus (rVSV) vectors expressing HIV-1 Gag have been shown to be immunogenic in preclinical animal models. Here we explored the potential to enhance immunogenicity through co-delivery of either replication-competent (rVSV-N3CT9) or non-propagating (rVSV-Gstem) vectors expressing GM-CSF. A construct expressing both antigen and cytokine, Gstem-Gag1-GMCSF6, was also generated. BALB/c mice were injected i.m. with Indiana rVSV vectors and boosted 8 weeks later with New Jersey glycoprotein-exchange vectors. Co-delivery of 105pfu of N3CT9-GMCSF5 and 105 pfu of N4CT9-Gag1 resulted in Gag specific IFN-g responses that were approximately two-fold higher than responses elicited by 105pfu of N4CT9-Gag1 alone. These results were confirmed by CBA analysis of supernatants from peptide-restimulated cells. Interestingly, MHC-pentamer staining revealed no significant difference in the frequency of Gag specific CD8+ cells between the two immunization groups. Similar observations were made in tests of the Gstem vector, where 106pfu of Gstem-Gag1-GMCSF6 elicited a more robust IFN-g response after boost than 106pfu of Gstem-Gag1, while the percentage of Gag specific CD8+ cells remained equivalent. In conclusion, GM-CSF exerted immunomodulatory effects in vivo, distinguished here by the enhanced functional differentiation of vaccine elicited effector cells.
This work was supported by NIH contract NO1-AI-25458
Timing, dose and combination impact immune memory recall with TLR ligands (47.30)
Authors: Kumaraguru Uday , Woolard Stacie N , Nandakumar Subhadra 
Published: January 2023

Abstract
The hygiene hypothesis and the study of probiotic and prebiotic effects have emphasized the need to understand, and ultimately to manipulate, our physiological interactions with commensal flora, and with other transient but harmless organisms from the environment that affect immunoregulatory circuits. A long-term memory response is established following primary antigen exposure that stays more or less constant. It appears to adopt a set-point in magnitude but upon re-exposure the response is quicker and better and there is an upward shift in memory frequency. This new set-point is likely higher than the primary set-point and varies with individuals based on the exposure pattern to other microbes or its components.
Our investigations have been designed to test such differences of non-specific stimulation by PAMPs in lowering the threshold of activation. Accordingly, young mice were pre-exposed to TLR stimulation intermittently and later analyzed for its resilience to challenge with virus during later part of their life. Secondly, adult mice with pre-existing memory to virus were exposed to various TLR ligands in the presence and absence of cognate antigen and analyzed for their quality and frequency of the memory response.
Animals that are constantly reminded of the danger in a subtle way are better responders to a new agent exposure compared to the animals kept in sterile surroundings. However, immune memory recall with TLR ligands differed based on the dose, timing and combination of ligands used. Taken together, results provide insights into the role of hyper-sanitized environment versus PAMP mediated signaling in adaptive immune response and long term memory.
Active Hexose Correlated Compound (AHCC) Activates Immune Function to Decrease Bacteria Load in a Murine Model of Surgical Wound Infection (47.34)
Authors: Aviles Hernan O , O’Donnell Phyllis M , Orshal Julia M , Sonnenfeld Gerald 
Published: January 2023

Abstract
In spite of the use of modern techniques, infection continues to be a leading cause of death in patients subjected to severe trauma and surgical wounds. Previous studies have shown that AHCC, a natural compound, increases survival and prolongs the time to death in a murine model of surgical wound infection. This model simulates some of the conditions that occur after trauma or surgical procedures including systemic infection and food deprivation. To better understand the mechanisms involved in this model, food-deprived mice receiving either AHCC or the excipient were infected with sub-lethal doses of Klebsiella pneumoniae. Organ bacterial load, plasma levels of cytokines, and differential white blood cell counts were determined at different time points after infection. In contrast to control mice, which did not clear bacteria from organs, mice receiving AHCC had significantly reduced numbers of bacteria at day 5 and cleared bacteria entirely from the system at day 6. Levels of IL-12, TNF-α, and IL-6 peaked earlier in this group (day 3) compared with controls (day 5). AHCC also induced a significant increase of numbers of macrophages at day 2 and lymphocytes at day 3. Additional studies indicated that AHCC improved the function of peritoneal cells as measured by nitric oxide production and spleen cell proliferation affected by food deprivation in this model. Taken together, these results suggest that AHCC protects mice restoring the immune system and promoting effective clearance of bacteria and, consequently, a rapid recovery.
Funded in part by a grant from the Amino Up Chemical Company, Sapporo, Japan.
Blockade of PD-1/B7-H1 interaction restores antigen-specific CD8+ T cell responses in HCV core transgenic mice (47.8)
Authors: Lukens John R , Hahn Young S. 
Published: January 2023

Abstract
Impaired CD8+ T cells have been implicated to play a role in the establishment of HCV persistent infection. HCV has evolved multiple strategies to avoid T cell responses. HCV core protein has been shown to contain immunomodulatory functions. To determine HCV core-mediated regulation of antigen-specific CD8+ T cell responses in vivo, a transgenic mouse where the expression of core protein is directed to the liver using the albumin (Alb) promoter was generated. Using this HCV core transgenic murine model system, we demonstrated that core-expressing mice failed to clear adenovirus-LacZ (Ad-LacZ) infection in the liver. Particularly, the generation of Ad-LacZ specific CD8+ T cells was impaired in the liver of HCV core transgenic mice having suppression of the production of IFN-gamma and TNF-alpha by CD8+ T cells and alteration of the production of the cytolytic protease, granzyme-B. Interestingly, HCV core transgenic mice exhibited enhanced expression of the inhibitory receptor PD-1 by Ad-LacZ specific CD8+ T cells and its ligand B7-H1 following Ad-LacZ infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway using a B7-H1 blocking antibody in core transgenic mice enhances effector function of CD8+ T cells and clearance of Ad-LacZ-infected cells. It suggests that the regulation of the PD-1/B7-H1 inhibitory pathway is crucial for HCV core-mediated impaired T cell responses and viral persistence/maintenance. Also, these findings implicate that manipulation of PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent infection.
RTK-based vaccines elicit specific CD8+ T cell responses in HLA-A2 transgenic mice (48.1)
Authors: Komita Hideo , Mandic Maja , Kawabe Mayumi , Storkus Walter J 
Published: January 2023

Abstract
Many receptor tyrosine kinases (RTK) are overexpressed/dysregulated in advanced cancers, serving as negative prognostic indicators. We evaluated the immunogenicity of dendritic cell (DC)/RTK(EphA2, EGFR, Her2/neu)-based vaccines in HLA-A2 (HHD) Tg mice. To enhance the stimulatory capacity of BM-derived DCs, these cells were infected with a recombinant adenovirus encoding mIL-12p70 (Ad.IL12), prior to being pulsed with RTK-derived peptides. We also evaluated a cohort of DC co-infected with both Ad.IL12 and Ad.EphA2. Each of these DC preparations (vs. control DCs) were injected three times s.c. into HHD mice on a weekly schedule. DTH reactions were monitored 48–72h after each vaccination and splenocytes were harvested on d28 and d60 to assess specific CD8+ T cell reactivity (IFN-γ ELISA). Autoimmunity pathology in RTK+ normal tissues (i.e. kidney, liver, lung) were also evaluated for immune infiltration and tissue destruction by (immuno)histochemistry. Vaccines induced specific DTH responses and Tc1 responses in HHD mice, in association with an increased accumulation of CD8+ T cells around proximal endothelial cells (PEC) in the kidney and in the interstitial lung at d28, in the absence of tissue pathology. DC/RTK-based vaccines may promote specific Type-1 immunity that has the potential to eradicate RTK+ tumors, while sparing normal RTK+ tissues.
This work was supported by NIH R01 grant CA114071 (W.J.S.)