bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of the CD8+ T cell response to subdominant epitopes of respiratory syncytial virus by deletion of an immunodominant epitope (43.9)
Authors: Lee Sujin , Mok Hoyin , Wright Daivd , Crowe James E 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTLs) are critical for control of respiratory syncytial virus (RSV) infection in humans and mice. Recently, we identified a new H-2Kd- restricted subdominant epitope in the RSV M2 protein. This finding allowed us to study the frequency of T lymphocytes responding two H-2Kd-restricted epitopes, M282–90 and M2127–135, following RSV infection in both lymphoid and non-lymphoid tissues. The ratio of T lymphocytes during the peak CTL response to RSV infection that were specific for immunodominant or subdominant was approximately 3:1 in the spleen and 10:1 in the lung. This ratio was observed consistently in primary or secondary infection. In addition, we showed that the kinetics of response against the two epitopes was regulated differently; the response to the subdominant epitope was delayed compared to the dominant epitope. In further studies, we demonstrated that modification of residues at positions 2 and 9 in the dominant M282–90 epitope altered the CTL epitope dominance hierarchy following immunization with plasmid DNA encoding M2 or mutant M2 proteins. Immunogenicity of the subdominant epitope M2127–135 was enhanced when the anchor residues of the dominant epitope were mutated, suggesting that the immunodominant epitope induces a suppression of response to subdominant epitopes. Taken together, our findings have implications for understanding the immune response to RSV infection or vaccination and provide insight into methods for the rational design of vaccines that induce CD8+ T cells.
Cholesterol-dependent cytolysins elicit adenosine triphosphate from dendritic cells that acts through the P2X7 purinergic receptor (44.12)
Authors: Chu Jessica , Thomas Louis Michael , Watkins Simon C. , Salter Russell D. 
Published: January 2023

Abstract
Cholesterol-dependent cytolysins (CDCs), a class of gram-positive bacterial exotoxins, bind cholesterol in cell membranes and oligomerize to form pores. We observe that CDCs induce pores in dendritic cells (DC) as well as other cell types in a dose dependent manner, which allows the subsequent release of adenosine triphosphate (ATP). Extracellular ATP can exert stimulatory effects on cells through engagement of surface purinergic receptors, several of which are expressed on DC, including P2X7, which upon ATP binding forms a pore in the plasma membrane. We show here that a mutant DC line selected for resistance to lytic CDC doses loses expression of the P2X7 receptor and also becomes insensitive to ATP-induced pore formation compared to wild type cells. A model is suggested where CDCs form pores in DC membranes, allowing the release of ATP that signals through P2X7 on DC. Chronic ATP stimulation of DC results in skewed DC maturation that favors type 2 immune responses. Thus, CDC-induced ATP release from DC could represent a novel evasion mechanism for gram-positive bacteria.
Mice lacking TLR4 function exhibit enhanced susceptibility to Rickettsia conorii, correlated with decreased NK cell activity (44.14)
Authors: Jordan Jeffrey M. , Woods Michael E. , Walker David 
Published: January 2023

Abstract
Toll-like receptors (TLR) are critical in the initiation and polarization of protective immune responses to a wide variety of pathogens. However, the importance of TLRs in immunity to rickettsial diseases has been poorly defined. We demonstrated in a model of human rickettsiosis that mice lacking TLR4 function exhibited enhanced susceptibility to R. conorii infection compared to mice having functional TLR4 responses. Lack of TLR4 signaling resulted in overwhelming rickettsial growth in the brain and lung—the major pathologic organs. Infected mice lacking TLR4 function had decreased splenic NK cells and an increase in regulatory T-cells in peripheral lymph nodes. Further, splenocytes obtained from infected mice lacking TLR4 activity had decreased NK cell cytotoxicity activity. The lack of TLR4 signaling resulted in significantly reduced serum IL-12, IL-23, and IL-17. Thus, TLR4 is important in initiating early rickettsial immunity, possibly because of enhanced Th1 proinflammatory cytokines and increased NK cell activity.
Notch ligand Delta-like 4 regulates disease pathogenesis during viral infections by modulating Th2 cytokines (44.21)
Authors: Schaller Matthew , Rudd Brian D , Kunkel Steven L , Kelley Lara K , Neupane Rupak , Lukacs Nicholas W 
Published: January 2023

Abstract
Notch has recently been implicated in skewing T cell phenotype during immune responses. It has previously been reported that DCs from MyD88 deficient mice do not express the notch ligand delta-like 4. Our recent data has shown that CD4+ T cells from MyD88 deficient mice are skewed toward a Th2 phenotype during RSV infection. Here we demonstrate that the addition of recombinant dll4 to a dendritic cell/T cell co-culture reduced the amount of Th2 cytokines produced upon restimulation of MyD88 deficient T cells with RSV. In this system there was no change in the amount of IFNγ produced. To further investigate the role of dll4 in viral infection, we developed a polyclonal antibody to dll4 and blocked the protein in vivo during the RSV response. We found that mice receiving anti-dll4 had significantly higher airway hyperreactivity, an increase in the number of CD69+ CD4+ T cells in the lung, and a lower number of CD69+CD8+ T cells. CD4+ T cells isolated from lung draining lymph nodes during RSV infection and restimulated with RSV pulsed DCs produced significantly more IL-4, IL-5 and IL-13, however no change was observed in IFNγ. To investigate the role of dll4 during primary T cell responses, recombinant dll4 was used in co-cultures of DCs and DO11 ova-specific transgenic T cells. The presence of dll4 during a primary ova response decreased IL-4 and IL-13 production and increased IFNγ.
Mast cells play a critical role in host defenses against Yersinia pestis (44.8)
Authors: O’Bryant Deanna M , Nilles Mathew L , Bradley David S 
Published: January 2023

Abstract
There is increasing evidence that mast cells play a role in host defenses, both via an IgE-FcεR mediated, allergy-like, response, as well as an IgG-FcγR mediated response. We provide evidence here that the inhibition of mast cell degranulation greatly enhances susceptibility of HLA-DQ8αβ transgenic (tg) mice to the plague. DQ8 tg mice are significantly more resistant to Yersinia pestis infection compared to out bred Swiss Webster mice, LD50 of &gt;104 and 20 CFUs respectively. The magnitude of the resistance observed in DQ8 tg mice allowed us to examine the contribution of various immunological components during Y. pestis infection. To assess the role of mast cells, DQ8 tg mice were treated with cromolyn, a specific inhibitor of mast cell degranulation, prior to infection with Y. pestis. The enhanced resistance observed in DQ8 tg mice was completely eliminated with cromolyn treatment, suggesting an important role for mast cells in the host response of DQ8 tg mice to Y. pestis. We have previously reported that Y. pestis infected DQ8 tg mice develop a strong total IgG response, while infected Swiss Webster mice do not have any elevation in total IgG levels. The presence of elevated IgG levels may trigger the mast cell response in the DQ8 tg mice. These findings provide further evidence for a role of mast cells in host defenses and provide a model in which the molecular mechanisms of this interaction may be better understood.
Characterization of CCR5 chemokine receptor gene polymorphisms in Japanese and Thai populations (45.11)
Authors: Liu Huanliang , Nakayama Emi E , Theodorou Ioannis , Nagai Yoshiyuki , Likanonsakul Sirirat , Wasi Chantapong , Debre Patrice , Iwamoto Aikichi , Shioda Tatsuo 
Published: January 2023

Abstract
Variations in the human CCR5 gene may alter the expression and/or function of the protein product, thereby altering chemokine binding/signaling or HIV infection of the cells that normally express CCR5 protein. We performed a systematic survey of genetic variations in the entire CCR5 gene as well as CCR2V64I in 50 Japanese subjects and evaluated the effects of those variations on CCR5 promoter activity. We also analyzed CCR5 promoter and CCR2V64I genotypes in 80 more Japanese and 186 Thais. Two types of non-synonymous substitutions in Japanese CCR5 gene were found. Our results showed several novel characteristics of the CCR2-CCR5 haplotype structure that were not reported from studies on Caucasians and African-Americans. Specifically, we were able to show that the G allele at position -2852 from the CCR5 translational start codon in Japanese and Thais is the representative of the CCR5 promoter haplotype that was reported to be associated with rapid progression to AIDS in HIV-infected individuals. Furthermore, nearly all non-synonymous polymorphisms in Japanese CCR5 gene occurred in haplotypes with elevated promoter activity. We thus hypothesized that there was certain selective pressure favoring low levels of CCR5 expression during human evolution.
Increased arthritis and carditis severity in mice coinfected with Borrelia burgdorferi and Babesia microti (46.24)
Authors: Moro Manuel H , Braga Walter U , Zegarra-Moro Ofelia L , Vinasco Javier , Narayanan Sanjeev , Kuroki Keichi 
Published: January 2023

Abstract
The most commonly recognized tick-borne coinfection in most of the eastern USA is Lyme borreliosis and babesiosis, caused by the spirochete Borrelia burgdorferi and the erythrocytic parasite Babesia microti respectively, accounting for ~80% of coinfections. Studies of clinical outcomes indicate that coinfected patients have more severe symptoms and longer duration of illness than patients with Lyme borreliosis alone. Little is known about the immune related mechanisms during tick-borne coinfections. This study used a murine model to examine whether defined disease conditions differed in severity in mice infected solely with B. burgdorferi and in mice coinfected with B. microti and B. burgdorferi. C3H.HeN and BALB/c mice cohorts were coinfected or singly infected and then monitored experimentally for 1, 7, 10, 14, 21 and 60 days after inoculation. Carditis and arthritis was determined by blinded histopathological evaluation of myocardium and tibiotarsal joints. Cytokine measurements were made on lymph node and spleen supernatants for IFN-γ, interleukin (IL-4), IL-10 and TNF-α. Coinfected C3H and BALB/c mice had a significant increase in carditis severity at day 7. In addition, a significant increase in arthritis severity was observed at day 21 and 60 for BALB/c mice. This clinical observation was correlated with a significant increase in the expression of IFN-γ and TNF-α and with a significant reduction of IL-4 and IL-10.
NIH P20RR016443-04
Application of adjuvant therapy for increased innate resistance against Phase II Coxiella burnetii (47.14)
Authors: Lubick Kirk James , Radke Miranda , Wilson Suzanne , Jutila Mark 
Published: January 2023

Abstract
Coxiella burnetii, the causative agent of Q fever, is an obligate intracellular bacterial parasite of macrophages, is classified as a select agent and can be readily weaponized. To date, there is no approved vaccine for C. burnetti in the U.S. and antibiotic therapy is only effective if given very early following initial infection. Infected macrophages can be induced to kill the bacterium, suggesting that “adjuvant therapy” may be an alternative approach to countering infection. As a first test of this approach, the capacity of TLR2 and TLR4 agonists to activate and induce increased killing of Phase II C. burnetii was tested in vitro and in vivo. TLR agonists induced activation and increased killing in vitro, yet showed minimal activity in vivo. In a concurrent drug discovery effort we screened 2,000 natural compounds on macrophage cells as well as on other innate cells for their potential use in “adjuvant therapy”. These novel activating agents identified in the drug screens induced IL-8 release and upregulation of cathepsin D and reproducibly increased clearance of C. burnetii both in vitro and in vivo. These results show that Phase II C. burnetii is susceptible to adjuvant therapy, but TLR agonists are not consistent in inducing protection. Novel agonists from a screen of a natural product library hold promise as potential therapeutic adjuvants for Q-fever.
Funded by: NIH AI-04018 and DoD W91 13M-04-1-0001.
A New Human Adenoviral Type 4 viral vector system displays highly enhanced immunogenicity that is complement-dependent and correlates with altered adaptive responses (47.24)
Authors: Hartman Zachary , Appledorn Daniel , Mendelson Todd , Lyerly Herbert Kim , Clay Tim , Amalfitano Andrea 
Published: January 2023

Abstract
Human Adenovirus Type 4 is widely known as the responsible agent for epidemic outbreaks of Acute Respiratory Disease in military recruits. Although studied for over 50 years, we still have precious little insight into the epidemiology and high viral morbidity surrounding HAdV-4 infections. To address these issues we developed an attenuated HAdV-4 vector system as a basic tool for viral and immunologic research. Our plasmid-based system allows for the manipulation of the HAdV-4 genome, which we used to produce replication attenuated [E1−,E3−] LacZ+ 1st generation Ad4 vectors. Using these vectors, we found that Ad4 elicits an enhanced immunogenic response (comprised of significantly greater IL-6, MCP-1, RANTES, and G-CSF) in murine macrophages in vitro and upon intravenous injection in C57/BL6 mice in vivo. The enhanced immunogenicity is capsid-dependant and is partially complement-dependent in vivo for certain cytokines, related to a more pronounced thrombocytopenia upon i.v. administration. Surprisingly, our studies demonstrate that the HAdV-4 early immunogenicity correlates with suppressed IgG responses, despite different routes of administration for the vector encoded LacZ transgene. These results demonstrate that capsid specific recognition is of paramount importance to both innate and adaptive immune responses and should be an important consideration in vaccine development.
Derivation of synergistically acting, neutralizing, chimeric human-mouse anti-SEB monoclonal antibodies (47.35)
Authors: Tilahun Mulualem E. , Rajagopalan Govindarajan , Osborne Barbara A. , Goldsby Richard A. 
Published: January 2023

Abstract
Staphylococcal Enterotoxin B (SEB) is a superantigen made by S. aureus. SEB can cause food poisoning and shock and its stability and ease of preparation make it a potential agent of bioterrorism. SEB-mediated activation induces T cell proliferation and secretion of cytokines. Antibodies that block the interaction between SEB and MHC or SEB and TCR, can neutralize the activating effects of SEB and provide protection against its debilitating effects. Human IVIG, a therapy for SEB intoxication is of low potency and sometimes, short supply. To surmount we have derived of mouse monoclonal antibodies that block the binding of SEB to MHC at separate and distinct sites. Combinations of these antibodies synergistically neutralize SEB mediated T cell activation. Genes encoding the VL and VH genes of synergistically neutralizing pairs of cell lines were cloned and grafted onto genes encoding either the constant region of human IgH or Igκ and transfected into SP2/0 cells. Chimeric human-mouse antibodies expressed by the transfectants were purified. Tests of these chimeric antibodies demonstrated that they were neutralizing and in combination with each other, still capable of synergistic neutralization of SEB.
Supported by NIH grant # AI057652
Interferon mimetic as a therapeutic for lethal vaccinia virus infection (47.6)
Authors: Ahmed Chulbul M , Martin James P , Johnson Howard M 
Published: January 2023

Abstract
We have developed small peptide mimetics of gamma interferon (IFNγ) that can bypass the poxvirus virulence factor B8R protein and can inhibit vaccinia virus replication in cell culture where intact IFNγ is ineffective. We demonstrate here that the mouse IFNγ mimetic peptide, IFNγ(95–132) with an attached lipophilic group for cell penetration, protects C57BL/6 mice against overwhelming lethal vaccinia virus infection. Intraperitoneal (IP) injection of mimetic before and at the time of intranasal (106 pfu) or IP (107 pfu) challenge with virus resulted in complete protection at 200 ug mimetic and 40 to 60 percent protection at 5 ug mimetic. Initiation of treatment of mice with IFNγ mimetic up to two days post infection resulted in complete protection against death, while initiation of treatment at six days post infection resulted in 40 percent protection. Administration of mimetic by the oral route also completely protected mice against the intranasal route of a lethal dose of vaccinia virus challenge. The mimetic also possessed adjuvant effects in boosting humoral and cellular immunity to vaccinia virus. The combination of antiviral and adjuvant effects by the IFN mimetic probably plays a role in its potent anti-vaccinia virus properties. These results suggest an effective therapeutic against ongoing, lethal poxvirus infections that taps into innate and adaptive host defenses.
Supported by NIH grant AI 056152 and DoD grant W911NF-05-1-0170, both to HMJ.
Tumor cell lysate and adjuvant B7DC-XAb confers effective protection from two antigenically distinct melanomas (48.15)
Authors: Pavelko Kevin D. , Hanson Michael J. , Pease Larry R. 
Published: January 2023

Abstract
Immunotherapeutic approaches to the treatment of melanoma have been hindered by the emergence of melanoma variants and relapsing tumors that are antigenically distinct and hence not recognized by memory cells. We have identified an antibody that has proven effective for the treatment of a mouse model of melanoma, B16. B7DC-XAb is an antibody that specifically binds to dendritic cells and increases their antigen uptake capabilities and their ability to activate T-cells and generates strong cytotoxic lymphocyte responses. We are using B16 tumor cell lysates along with this antibody as an adjuvant for the generation of robust and rapid CTL responses to B16 melanoma. Treatment of B16 tumor challenged mice with B7DC-XAb leads to a CTL response that recognizes an epitope from tyrosinase related protein-1. Subsequent B16-OVA tumor challenge results in a lack of protection, against this related but antigenically unique tumor. Therefore we have used tumor cell lysates in conjunction with antibody treatment in an attempt to broaden the specificity against the melanoma lines. Therapeutic treatment with B16 tumor cell lysate and B7DC-XAb leads to clearance of a 6 day established B16 tumor. Further, re-challenge 30 days later with B16-OVA is also cleared demonstrating an enhanced memory response, to this antigenically distinct tumor. Further studies will determine which antigens are responsible for initiating this response as well as those that are important for tumor clearance.
Conditional triggering of EphA2 epitope presentation results in the enhanced tumor cell recognition by specific CTL. (48.25)
Authors: Mandic Maja , Kawabe Mayumi , Vasquez Anna-Cecilia , Storkus Walter J 
Published: January 2023

Abstract
The receptor tyrosine kinase EphA2 is over-expressed in numerous carcinomas in association with poor clinical prognosis. While pharmacologic agents that antagonize EphA2-mediated signaling could be contemplated as a therapy, a more preferred result would be to decrease tumor cell EphA2 expression while coordinately enhancing specific immune reactivity to tumor cells. We show that specific mAb triggers the internalization of EphA2, resulting in increased processing of EphA2 protein and presentation of EphA2-derived epitopes in tumor cell HLA class I complexes to CD8+ T cells (detected by IFN-γ production and CD107b translocation). Ab-enhanced CTL recognition is blocked by tumor cell co-treatment with Pseudomonas Exotoxin-A and proteasome inhibitors, but not by chloroquine, suggesting that internalized EphA2 complexes are rapidly translocated into the cytoplasm for delivery of peptides into the class I biosynthetic route. When combined with vaccines designed to augment the frequency of circulating anti-EphA2 CD8+ T cells, this agonist strategy may define an effective therapy for patients harboring EphA2+ cancers.
Anti tumor immunity of cyclophosphamide(CY) mediated by homeostatic proliferation of memory type T cells and reduction of regulatory T cells. (48.29)
Authors: Hong Sohee , Yun Il Hee , Lim Jong Hyung , Park Chung Gyu 
Published: January 2023

Abstract
In addition to its cytotoxic effect, CY has been known to have a certain type of immune modulation effects. In this study, we investigated the modulation effect of high dose CY on anti-tumor immunity of tumor bearing mouse under a tumor-mediated immune suppression status. In murine melanoma tumor model, a single injection of CY(200mg/kg) to tumor bearing mouse delayed the tumor progression and increased the mean survival days by 2fold. The phenotypic analysis by FACS revealed CY caused significant increase of both percentage and absolute number of CD4+and CD8+ T cells in draining LNs on 10 days post injection (DPI). Of note, the proportion of CD4+CD25+Foxp3+ T cell was significantly decreased whereas that of CD4+CD44hi and CD8+CD44hiT cell was increased. Caspase-3 staining of CD44hiT cells on 3 DPI indicated the increase was preceded by the early-phase apoptosis. In vitro functional analysis by ELISPOT revealed the number of IFN-γproducing cells stimulated by ConA was increased to the level comparable to tumor non-bearing mouse. We could not find any significant changes in the percentage of monocyte and NK cells with CY treatment. In conclusion, the enhancement of anti-tumor immunity by CY may be due to the increase of the ratio of CD44himemory type T cells to regulatory T cells, which would be induced by early phase depletion followed by preferential homeostatic proliferation of memory type T cells over regulatory T cells.
Phase I clinical and U.S. regulatory experience with designer T cells in cancer (48.33)
Authors: Junghans Richard Paul 
Published: January 2023

Abstract
The process of bringing any product from the bench to the bedside is complex, and particularly so for gene therapy applications. Yet these are some of the most promising agents for the future treatment of cancer and infectious diseases. Designer T cells are autologous T cells retrovirally-modified to express chimeric immune receptors (CIR) against tumor or viral antigens. In this is described our Phase I clinical trial experience with 1st generation anti-carcinoembryonic antigen (CEA) designer T cells in adenocarcinoma and the regulatory processes and timeline for product introduction into the clinic. Further, the regulatory and clinical aspects are summarized for two additional, more advanced designer T cell applications in gastric cancer and prostate cancer that are slated to enter patient trials early in 2007. This information may be of value to investigators who are interested in the translation of laboratory discoveries to human use.
National Cancer Institute, FDA Orphan Product Development Program, Department of Defence, Prostate Cancer Foundation, American Cancer Society