bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-microbial immunity augmented by extracellular matrix adjuvant from porcine small intestinal submucosa (52.22)
Authors: Roy Chowdhury Roshni , Ghosh Swapan 
Published: January 2023

Abstract
Developing a long-lasting protective vaccine against Staphylococcus aureus has been a challenge, since S. aureus has several mechanisms to evade the immune system. The issue is whether appropriate adjuvant(s) could overcome this evasion and elicit a robust immune response. Porcine small Intestinal submucosa (SIS) exhibits adjuvanticity against pathogenic antigens and bacterial toxins (Suckow, USPA 20100136050). However, there is as yet no report on the adjuvanticity of SIS against the intracellular pathogen S. aureus. Hence, this study was designed to assess SIS as an adjuvant, relative to alum, in terms of specific antibody response, T-cell infiltration, inflammasome activation and TLR involvement, in BALB/c mice against heat-killed S. aureus. Our results showed that SIS helped evoke high-titer antibody, but alum was ineffective in augmenting antibody response. Both SIS and alum up-regulated the mRNA expression of GATA-3 and FOXP3. Our inflammasome microarray analysis showed that unlike alum, SIS did not involve any inflammasome pathway (Nlrp1a/Nlrp3/IPAF). In comparison with Staph alone, alum significantly upregulated the mRNA expression of chemokines Ccl12, Ccl7 and Cxcl3 but SIS did not. Alum although is TLR-independent, influenced the up-regulation of the mRNA expression of TLRs 2,3,5,7 and 8. SIS also showed a similar effect. In summary although SIS was more effective than alum in antibody production against S. aureus, its mode of action needs to be explored further.
Alternative mechanism for glycoconjugate vaccine activation of the adaptive immune system (52.25)
Authors: Avci Fikri , Li Xiangming , Tsuji Moriya , Kasper Dennis 
Published: January 2023

Abstract
Glycoconjugate vaccines, which are currently made by covalently coupling a bacterial capsular polysaccharide to a carrier protein, have been used to immunize many millions of people and have enormously reduced disease burden, particularly among children. However, the immunogenicity and efficacy of these vaccines have been relatively low and heterogeneous in some high-risk populations. The classic antigen presentation hypothesis for glycoconjugates proposes that helper CD4+ T cells recognize a peptide derived from the carrier protein. We investigated mechanisms of processing and presentation of a prototypic glycoconjugate vaccine in which group B streptococcal type III polysaccharide is coupled to a carrier. Upon uptake into the endosome of an antigen-presenting cell, the polysaccharide undergoes oxidative depolymerization, which, in conjunction with acidic protease-mediated digestion of the carrier protein, creates a carbohydrate T cell epitope conjugated to an MHCII binding peptide. These epitopes formed in the endosome bind to MHCII through the peptide and are subsequently presented on the APC surface, with the hydrophilic carbohydrate positioned for easy recognition by the T-cell receptor. Recognition of the carbohydrate in the presence of MHCII drives T-cell help for antibody-producing B cells. An enhanced understanding of immune mechanisms such as T-cell recognition of carbohydrates may lead to markedly improved vaccines against infectious diseases.
The inhibition of T cell proliferation in a mixed lymphocyte reaction by Itolizumab (T1h) is associated with reduction in pro inflammatory cytokines and CD6 internalization. (52.27)
Authors: Nair Pradip , Ghorai Abhijit , Adhikary Laxmi , Melarkode Ramakrishnan , Montero Enrique 
Published: January 2023

Abstract
We have shown previously that the CD6-ALCAM interaction in vitro induced a synergistic co-stimulation of normal human peripheral blood mononuclear cells (PBMCs), defined by Bliss analysis. The use of a CD6 membrane-distal domain (SRCR1)-specific non-depleting monoclonal antibody Itolizumab, inhibited the CD6-ALCAM induced proliferation of PBMCs. This is associated with reduction in pro inflammatory cytokines at the protein and mRNA level. In this study, we show that the antibody inhibits T cell proliferation in a typical mixed lymphocyte reaction wherein the matured dendritic cells over express ALCAM. The inhibition is associated with reduction in CD4 and CD25 surface expression in these T cells. A marked reduction in interferon-γ, tumour necrosis factor-α and IL-17 production is also observed. Using confocal microscopy we show that the receptor CD6 internalization occurs within minutes in T cells in the presence of Itolizumab and is not localized to the immunological synapse. Intriguingly, a deglycosylated antibody showed reduced inhibition of T cells in the mixed lymphocyte reaction. The deglycosylated antibody did not show any difference in binding to HuT 78 cell expressing CD6 as compared to the normal antibody. These results would suggest that the monoclonal antibody Itolizumab also prevents T cell proliferation induced in mixed lymphocyte reactions and there is a role for the Fc region glycosylation of the antibody to elucidate this function.
CD4 T-helper cell cytokine phenotypes following tetanus toxoid immunization (52.3)
Authors: Livingston Kimberly , Jiang Xiaowen , Stephensen Charles 
Published: January 2023

Abstract
Routine methods for enumerating antigen-specific T-helper cells may not identify low-frequency phenotypes such as Th2 cells. We compared methods of evaluating such responses to identify TT-specific Th1, Th2, Th17 and IL10+ cells. Eight healthy subjects were given a TT booster vaccination. Blood was drawn before, 3, 7, 14, and 28d after vaccination. PBMC cultures were stimulated with TT or PBS. Activation markers (CD25 and CD69) were measured after 44h (n=8), cytokines in supernatant after 3 and 7d of culture, and intracellular cytokine staining (ICS) was performed in proliferated cells (PKH67 dye dilution) after 7d of culture (n=6). Vaccination increased TT-specific expression of CD25 and CD69 on CD3+CD4+ lymphocytes, and TT-specific proliferation at 7, 14 and 28d post vaccination. Vaccination induced TT-specific Th1 (IFNγ, TNFα, and IL2) Th2 (IL13, IL5, and IL4), Th17 (IL17A) and IL10+ cells as measured by ICS. TT-specific Th1 cells were the most abundant (12-15% of all CD3+CD4+ T-cells) while IL10+ (1.8%) Th17 (1.1%) and Th2 cells (0.2-0.6%) were less abundant. TT-specific cytokine concentrations in PBMC supernatants followed the same pattern. A TT-specific IL-9 response was also seen in the supernatants. In conclusion, TT booster vaccination induced a broad T-helper cell response. This method of evaluating cytokine phenotypes may be useful in examining the impact of nutrition and environmental conditions on the plasticity of T-helper cell memory responses.
B cell depletion impairs both CD4+ and CD8+ T cell activation during acute viral infection in mice (52.33)
Authors: DiLillo David , Weimer Eric , Tedder Thomas 
Published: January 2023

Abstract
Therapeutic B cell depletion in mice using CD20 mAb significantly reduces CD4+ T cell activation in response to model and self-antigens, but not CD8+ T cell activation. However, the effects of B cell depletion on acute viral infections and the consequences of long-term B cell depletion on immune system function are unknown. To assess this, B cells were depleted in wild type mice using a potent CD20 mAb that depletes &gt;98% of tissue and circulating mature B cells. Short-term (2 week) B cell depletion did not affect tissue T cell numbers. However, when B cells were depleted 1 week before LCMV-Armstrong infection, splenic CD44hiCD62Llo CD4+ and CD8+ effector-memory T cell numbers were reduced by 51-57%. The numbers of LCMV-specific CD4+ T cells producing IFNγ and TNFα were reduced by 64% and 80%, respectively. Virus-specific CD8+ T cells producing IFNγ and TNFα were also reduced by &gt;56%. Even without pathogen challenge, similar changes were observed in mice treated chronically with CD20 mAb for 6 months, where CD4+ and CD8+ effector-memory T cell numbers were reduced by 76% and 39%, respectively. Chronic B cell depletion also reduced IFNγ- and TNFα-producing CD4+ T cell numbers by 76% and 35%. Nonetheless, naïve T cell numbers were not affected by either short-term or chronic B cell depletion. Thus, B cells are required for optimal CD4+ and CD8+ T cell activation, expansion, and function in vivo, particularly during cellular responses to pathogens.
Analysis of a live attenuated bacterial vaccine for tularemia in the MIMIC® (Modular Immune In vitro Construct) System (52.6)
Authors: Moser Janice , Sassano Emily , Muerrle Christopher , Waag David , Wittman Vaughan 
Published: January 2023

Abstract
Sanofi Pasteur has optimized a series of unique, sensitive, automatable, and cost-effective assay systems, termed the Modular IMmune In vitro Construct (MIMIC®), to permit the evaluation of human innate and adaptive immunity in a laboratory setting. The lymphoid tissue equivalent (LTE) module of the MIMIC® platform reproduces the correct cellular interactions and kinetics to initiate primary (naïve) human B and T cell responses in an in vitro setting. We are currently investigating LVS, a live attenuated bacterial vaccine strain of Francisella tularensis, in the MIMIC® System. LVS generates a strong, naïve, TH1-skewed CD4 T cell response demonstrated by the percentage of responding cells producing intracellular IFNγ and TNFα. This data is consistent with human in vivo data showing that protection elicited by LVS vaccine includes a strong cellular immunity component. Previous studies have also shown that LVS drives production of protective antibodies in humans. We have currently demonstrated that the MIMIC® System can drive the generation of LVS-specific antibody responses in vitro using a fully autologous system. These studies indicate that the in vitro MIMIC® system offers a platform in which to conduct experiments in a fully human system prior to the involvement of human subjects. Therefore, the MIMIC® system provides a platform for analysis of new vaccine candidates and can be utilized for greater understanding of how efficient vaccines function.
Innate immune responses to polyanhydride nanoparticles modified with a toll like receptor three ligand. (52.9)
Authors: Huntimer Lucas , Carrillo-Conde Brenda , Petersen Latrisha , Ross Kathleen , Ramer-Tait Amanda , Bellaire Bryan , Narasimhan Balaji , Wannemuehler Michael 
Published: January 2023

Abstract
Improving efficacy of subunit-based immunization protocols without eliciting adverse reactions continues to be a hurdle in vaccine design. Vaccination of mice in our laboratory with surface eroding polyanhydride nanoparticles (NPs) prepared from 1,6-bis(p-carboxyphenoxy)hexane (CPH) and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) administered as a single intranasal dose provided high-titer and high-avidity humoral responses and protection against a live Yersinia pestis challenge at 23 weeks post-vaccination. The goal of the current study was to elucidate the immune-enhancing properties of the NPs by functionalizing them with TLR3 ligands (i.e., poly I:C) via either surface modification or encapsulation into the particle in order to activate macrophages. We also tested the hypothesis that the protective responses observed following intranasal NP vaccinations was due to particles undergoing endocytic processing by targeting TLR3 located on the endosomal membrane. Our results demonstrated that stimulation of primary macrophages (bone marrow-derived) with poly I:C modified particles increased surface expression of MHC II and CD80/86 as well as enhanced secretion of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α as compared to stimulation with non-functionalized NPs. Encapsulation of TLR ligands in polyanhydride NPs enhanced the activation status of macrophages and targeted functionalization may improve the efficacy of this novel vaccine platform.
Enhanced transgene expression improves immune responses following DNA vaccination (53.1)
Authors: Skinner Nicole , Dietz Wynette , Jund Michelle , Hwu Patrick , Chen Zhi-Ying , Kay Mark , Blazar Bruce , Pennell Christopher , Osborn Mark 
Published: January 2023

Abstract
Plasmid DNA (pDNA)-based gene delivery has the potential to advance vaccine development due to advantages such as low cost, ease of production, safety (e.g. pDNA does not cause insertional mutagenesis), and the flexibility to introduce several genes at once. To date, there are more than 300 clinical trials involving pDNA-based gene transfer. Although promising, these trials have revealed that poor transfection efficiency, transient protein production, and low immunogenicity limit therapy efficacy. We are investigating the use of minicircle (MC) DNA as a means of circumventing these limitations. MC vectors contain the expression cassette of full-length plasmids, but lack the bacterial backbone sequences that are targeted for transcriptional repression in mammalian cells. Removal of these plasmid backbone sequences is achieved via site-specific recombination in Escherichia coli prior to episomal (i.e. MC) DNA isolation. The absence of these prokaryotic elements also reduces MC size relative to its parental pDNA, leading to enhanced transfection efficiencies. Data will be presented showing that vaccination with MC DNA results in significantly higher and more prolonged reporter transgene expression. Furthermore, we compare specific responses of adoptively transferred and endogenous CD8+ T cells following vaccination of mice with either parental pDNA or MC-encoded antigen.
B cell immunotherapy to resolve a persistent viral infection (53.10)
Authors: McGavern Dorian , Heydari Sara 
Published: January 2023

Abstract
Many viruses can establish persistence and cause disease in humans. Studies have established a role for T cells in resolving persistent viral infections; however, the importance of a humoral response is less clear. Emerging evidence suggests that a coordinated effort between T and B cells is required to resolve some persistent infections. In this study, we sought novel insights into the importance of humoral immunity in resolving a persistent infection by utilizing the lymphocytic choriomeningitis virus (LCMV) model. Infection with aggressive LCMV variants results in a chronic viral infection during which anti-viral T cells pass through a state of functional exhaustion, but the infection is nevertheless controlled over time. We postulated that humoral immunity was required for LCMV control and could be harnessed as an immunotherapy. We observed plasma B cells in the repertoire as early as one week following LCMV infection, which coincided with the emergence of anti-viral antibodies (non-neutralizing). Depletion of B cells with anti-CD79 antibodies starting at the peak of T cell exhaustion (day 15) resulted in a failure of mice to control virus. Moreover, B cells harvested from mice that had controlled infection and transferred into mice with active infection resulted in accelerated viral control. These data demonstrate that humoral immunity can contribute to the resolution of a persistent viral infection and that B cells can be harnessed for adoptive immunotherapy.
Driving HIV-1 specific responses in immune suppressed recipients: Listeria as a vaccine vector (53.20)
Authors: McEwen Lisa , Bui Cac , Paterson Yvonne , Harn Donald 
Published: January 2023

Abstract
Malaria, TB and HIV-1 remain tremendous disease burdens in much of the world’s population and functional vaccines are desperately needed. Although Sub-Saharan populations are those that will benefit most from these vaccines, they are also coincident with areas of endemic helminth infection. Infection with one or more species of parasitic helminths suppresses the immune system and has been shown, by our lab and others, to suppress vaccine-specific responses. One goal of our research is to find vaccines that drive significant vaccine-specific immune responses in helminth infected recipients, without the need to eliminate helminth infection prior to vaccination. In the current study, we demonstrate that administration of a Listeria vector HIV-1 gag vaccine to mice chronically infected with the helminth parasite Schistosoma mansoni drives significant immune responses to HIV-1 gag CTL and helper epitopes. This observation suggests that Listeria vector vaccines are capable of driving vaccine-specific responses in helminth-infected populations. Kinetic studies show the antigen-specific responses are both durable and capable of inducing CD8+ central memory. In addition to HIV-1, Listeria vectors should be considered in the development of new generation malaria and TB vaccines to be administered to sub-Saharan Africa populations where helminth infection is endemic. Studies are underway to determine if other vectors are also capable of overcoming helminth-induced immune suppression.
Enhanced HIV-1 Gag-specific immunity induced by a sPD-1-based vaccine directed to dendritic cells (53.23)
Authors: Zhou Jingying , Wang Haibo , Tan Zhiwu , Du Yanhua , Chen Zhiwei 
Published: January 2023

Abstract
HIV/AIDS is a serious disease worldwide. The development of a safe, effective and affordable HIV-1 vaccine remains the ultimate solution. This study is based on the discovery of a negative immune regulatory system, the PD-1/PD-L pathway, which exists on both human and other animals. The PD-1 ligands (PD-L1 and PD-L2) are expressed on DCs. So we hypothesize to utilize the soluble PD-1 parts to intervene in the negative signal transmission of the PD-1 pathway and to target the antigen to DCs as a mean to indentify vaccine strategy to enhance the virus specific immune responses. Here we constructed the novel vaccine and controls by inserting soluble PD-1 gene and/or HIV-1 p24 gene into the pVAX1 vector with fusing of rabbit Fc fragment named mspd1-p24-fc, and controls named mspd1-IgVΔ-p24-fc and p24-fc. When compared with control vaccines, we discovered that mspd1-p24fc can significantly enhance HIV-1 Gag-specific immune responses by measuring the number of IFN-γ expressed CD4 and CD8 T cells using Elispot assays and CD8 T cell tetramer staining. Furthermore, the mspd1-p24-fc can significantly enhance humoral immune responses by anti-Gag antibody titer analysis. Importantly, this novel vaccine protects mice against recombinant vaccinia virus-gagpol challenges. This novel vaccine design may be used as DNA vaccine model against other infectious disease and cancer which need eliciting significant antigen specific humoral and cellular immune responses.
Impact of pre-existing immunity on the selection of rare adenovirus vector candidates: implications for HIV vaccine development (53.27)
Authors: Perreau Matthieu , Welles Hugh , Hall Olivia , Harari Alexandre , Bibert Stephanie , Martin Ricardo , Roger Thierry , Calandra Thierry , Bett Andrew , Gall Jason , Kremer Eric , Pantaleo Giuseppe 
Published: January 2023

Abstract
Adenovirus serotype 5 (Ad5) phase IIb vaccine trial (STEP) was prematurely stopped due to a lack of efficacy and two-fold higher incidence of HIV infection among Ad5 seropositive vaccine recipients. We have recently demonstrated that Ad5 immune complexes (Ad5 ICs)-mediated activation of the dendritic cell (DC)-T cell axis was associated with the enhancement of HIV infection in vitro. Although the direct role of Ad5 neutralizing antibodies (NAbs) in the increase of HIV susceptibility during the STEP trial is still under debate, vector-specific NAbs remain a major hurdle for vector-based gene therapies or vaccine strategies. To surmount this obstacle, vectors based on “rare” Ad serotypes including Ad6, Ad26, Ad36 and Ad41 were engineered. The present study aimed to determine whether Ad IC-mediated DC maturation could be circumvented using these Ad-vector candidates. We found that all Ad vectors tested forming ICs with plasma containing serotype-specific NAbs had the capacity to 1) mature human DCs as monitored by the up-regulation of co-stimulatory molecules and the release of pro-inflammatory cytokines (TNF-α), via the stabilization of Ad capsid at endosomal but not lysosomal pH rendering Ad DNA/TLR9 interactions possible and 2) potentiate Ad-specific CD4 and CD8 T cell responses. In conclusion, despite a conserved DC maturation potential, the low prevalence of serotype-specific NAbs renders rare Ad vectors attractive for vaccine strategies.
Human immune responses to Burkholderia pseudomallei characterized by protein microarray analysis (53.3)
Authors: Suwannasaen Duangchan , Mahawantung Jirawan , Chaowagul Wipada , Limmathurotsakul Direk , Felgner Philip L , Davies Huw , Bancroft Gregory J , Titball Richard W , Letmemongkolchai Ganjana 
Published: January 2023

Abstract
This study aimed to determine the antibody and T cell responses to Burkholderia pseudomallei (B. pseudomallei) of healthy individuals in endemic areas, and recovered melioidosis patients in order to select candidate vaccine antigens. A protein microarray of 154 (B. pseudomallei) proteins was probed with plasma from healthy individuals (n=108) and recovered patients (n=72). The results showed that 27 proteins distinctively reacted with plasma from both groups suggesting that different responses occur following environmental exposure or clinical melioidosis. We also compared the responses according to their history of subsequent relapse and the average antibody response to BPSL2765 (putative OmpA family protein) was over 10 times higher in plasma from individuals who had only one episode of disease than those with recurrent melioidosis. A comparison of antibody and T-cell responses to five (B. pseudomallei) proteins revealed that BimA and flagellin induced responses which were similar between both groups but BPSS0530; a conserved hypothetical protein could induce T cell responses of healthy controls more than recovered melioidosis. By combining large scale antibody microarrays and assays of T cell mediated immunity, we have identified a panel of novel (B. pseudomallei) proteins which show distinct patterns of reactivity in different stages of human melioidosis. These proteins may be useful candidates for development of subunit based vaccines.
TSG-6, a new protein ligand for CXCL8, modulates the activity of this pro-inflammatory chemokine (54.12)
Authors: Dyer Douglas , Milner Caroline , Day Anthony 
Published: January 2023

Abstract
TSG-6, a 35 kDa secreted protein, is expressed during inflammation (e.g. in the cartilage/synovium of arthritis patients) and delays the onset/reduces the severity of joint damage in models of inflammatory arthritis. For example, TSG-6-/- mice with proteoglycan-induced arthritis exhibit elevated neutrophil invasion and protease activity in the paw joints compared to controls. The aim of this study is to investigate potential mechanisms for the anti-inflammatory and chondroprotective effects of TSG-6, focusing on its interaction with CXCL8. This chemokine is known to promote neutrophil migration and to induce matrix metalloproteinase (MMP) secretion by endothelial cells. Using plate-based assays and surface plasmon resonance we have demonstrated that TSG-6 binds to CXCL8 in a pH-dependent manner and that TSG-6 can inhibit the interaction of CXCL8 with heparin. Since the sequestration of CXCL8 by endothelial glycosaminoglycans (e.g. heparan sulphate) contributes to its pro-migratory activity, this might represent one mechanism through which TSG-6 limits neutrophil extravasation. We have also shown, using gelatin zymography, that TSG-6 can block the CXCL8-mediated production of active MMPs by endothelial cells. MMPs have been implicated in the destruction of articular cartilage in arthritis, where they occur at elevated levels (e.g. in RA synovial fluids). Inhibition of the expression and/or activation of MMPs could, therefore, contribute to TSG-6’s chondroprotective effect.