bluuebunny/crossref_metadata_2025_split huggingface dataset:
A unique adjuvant combination modulates immune responses preventing vaccine-enhanced pulmonary histopathology after vaccination with fusion protein and challenge with respiratory syncytial virus
Authors: Lee Youri , Ko Eun-Ju , Lee Young-Tae , Kim Ki-Hye , Kwon Young-Man , Kang Sang-Moo 
Published: January 2023

Abstract
Vaccination of young children with alum-adjuvanted formalin-inactivated respiratory syncytial virus (FI-RSV) induced vaccine-enhanced disease (VED) after natural infection during epidemic season, resulting in hospitalizations and two deaths. There is no licensed RSV vaccine. VED was also observed in previous reports with fusion (F) protein RSV vaccines and adjuvants including oil-in-water emulsion, delta-inulin, and natural killer T cell agonist α-GalCer. In this study to search for adjuvants preventing RSV VED, we investigated a novel combination of monophosphoryl lipid A (MPL TLR4 agonist) and oligodeoxynucleotide CpG (CpG TLR9 agonist) in the RSV F protein vaccination. RSV specific IgG antibodies and neutralizing titers, and controlling RSV lung viral loads after challenge were similarly observed in the alum and MPL+CpG adjuvant groups of mice that received a single dose prime immunization with RSV F protein vaccine. Analysis of IgG isotypes and cytokines suggested the induction of T helper type 1 (Th1) immune responses by inclusion of MPL+CpG adjuvant in contrast to alum adjuvant biasing Th2 type immune responses. Most importantly, lung histopathology and infiltration of inflammatory innate immune cells (eosinophils, neutrophils) were not observed after F protein vaccination with MPL+CpG adjuvant whereas severe lung histopathology was induced after alum adjuvanted F protein vaccination and RSV challenge. The results in this study suggest a novel adjuvant approach to improve efficacy and safety of RSV subunit vaccines.
Reversing T cell Exhaustion Through Discovery of Small Molecules
Authors: Marro Brett S. , Zavareh Reza Beheshti , Teijaro John R. , Lairson Luke L. , Oldstone Michael B.A. 
Published: January 2023

Abstract
Inhibitory receptors (IR) function as critical regulators of immunity by tempering T cell responses to microbial infections. In humans, persistent viruses such as HIV, HCV and HBV as well as several types of cancer have adapted to exploit IR signaling by upregulating IR ligands, resulting in the suppression of T cell function (exhaustion) and escape from immunity. T cell exhaustion and T cell recovery, by blocking IR signaling, was first defined in C57BL/6 mice following infection with the Clone 13 variant of LCMV that results in varying degrees of suboptimal CD4 and CD8 T cell polyfunctionality, ranging from reduced to absent cytotoxic capacity of CD8 T cells to decreased production of anti-viral effector molecules such as IFN-γ and TNF-α. Chronicling the resurrection of anti-viral T cell effector function using antibodies that target IRs suggests that an in vitro phenotypic assay using the LCMV system could be an effective screening platform to identify small molecule(s) that disrupt pathways regulating T cell dysfunction. To this end, we developed a screening strategy that utilizes transgenic mice (IFN-γ-YFP) combined with high-throughput (HTS) flow cytometry to examine compounds that potentiate IFN-γ expression in exhausted T cells isolated from LCMV infected animals. Using this approach, we have screened a library of 10,000 investigational new drugs (IND). We have identified several unique hits among the INDs that encompass a broad range of known targets. Thus, this novel screening strategy offers an unprecedented opportunity to identify potent small molecules that influence T cell function in the context of persistent infection and cancer.
Hematopoietic stem/progenitor cells engineered with T cell receptors for immunotherapy for HIV infection
Authors: Joglekar Alok , Sandoval Salemiz , Jeppson John , Liu Zhe , Leonard Michael Troy , Swift Margaret , Baltimore David 
Published: January 2023

Abstract
HIV infection causes progressive depletion of CD4+ T cells and leads to severe immunodeficiency if left untreated. Current antiretroviral therapy can control infection, but does not cure it. The goal of this study was to develop a “functional cure” for HIV infection by providing a long-term, self-renewing source of antiviral immunity. To that end, we hypothesized that immunotherapy using engineered hematopoietic stem/progenitor cells (HSPCs) to express HIV-specific T cell receptors (TCRs) will be effective at controlling HIV. We first isolated six TCRs specific to the KK10 epitope from HLA-B27+ individuals and compared their function in vitro. Two TCRs, EC27 and EC5.5, were chosen for immunotherapy studies based on their superior function. To test HSPC-based immunotherapy, we transduced mobilized peripheral blood CD34+ HSPCs from HLA-B27+ healthy donors to express these TCRs and engrafted them in immunocompromised NOD/SCID/IL2Rγc−/− (NSG) mice. Transduced HSPCs were able to engraft mice and differentiate into T cells expressing the TCRs in peripheral blood and lymphoid tissues. Furthermore, engineered T cells isolated from engrafted mice showed KK10-driven expansion, cytotoxicity, and cytokine secretion. Expanded T cells were able to inhibit HIV-infection in vitro. Moreover, the functional activity of engineered T cells isolated from mice was comparable to modified primary T cells, highlighting their therapeutic potential. We are currently testing whether mice engrafted with transduced HSPCs can suppress HIV infection in vivo. If successful, these studies would demonstrate a “functional cure” of HIV infection, warranting further testing in clinical trials.
Co-delivery of mucosa-associated epithelial chemokine (MEC/CCL28) enhances anti-HIV-1 mucosal responses through CCR10 in the context of DNA vaccination
Authors: Gary Ebony Nicole , Kathuria Noshin , Bernui Mariana Estrella , Humeau Laurent , Weiner David B. , Kutzler Michele A. 
Published: January 2023

Abstract
Mucosal antibody plays a vital role in protection against HIV transmission. Mucosa-associated epithelial chemokine (CCL28) is secreted by mucosal epithelial cells following commensal colonization, and binds CC-chemokine receptor 10 (CCR10), expressed on IgA+ plasma cells. Deletion of CCR10 impairs mucosal IgA production and memory responses. Thus, the CCL28/CCR10 axis is critical for regulating mucosal IgA production and memory immunity. Mice were vaccinated twice with consensus HIV-1 gp160 DNA alone (antigen-only), or antigen and plasmid-encoded CCL28 (pCCL28) via intramuscular injection and in vivo electroporation (EP). pCCL28 increased antigen-specific IgA in fecal extracts (average 36.7ng/ml IgA in the antigen only group compared with 90.9ng/ml in the pCCL28 group). The intestinal compartment from animals co-immunized with pCCL28 harbored a higher frequency of HIV-specific, IgA+ B cells compared to the antigen-alone group (13.1% compared to 5.7%, respectively), and these cells expressed significantly-higher levels of CCR10 than those from mice in the non-adjuvanted group (MFI 413 compared to 181, respectively). Colonization with commensals induces CCL28 secretion by intestinal epithelial cells. Indeed, In vitro experiments with human colonic epithelial cell lines indicate that these organisms increased expression of CCL28 at the transcript and protein level. These studies suggest that electroporated delivery of the mucosal chemokine CCL28, can enhance antigen-specific anti-HIV immunity in the mucosa. Ongoing studies will determine if supplementation of commensal flora during vaccination can enhance CCL28 secretion in vivo and promote retention of vaccine-induced IgA+ B cells at mucosal surfaces.
Overcoming obesity-induced immunotherapeutic failure
Authors: Boi Shannon Kathryn , Orlandella Rachael , Gibson Justin Tyler , Starenki Dmytro , Makkouk Amani , Joshi Vijaya , Gross Brett , Salem Aliasger , Weiner George , Norian Lyse A. 
Published: January 2023

Abstract
Obesity is a leading public health concern that affects &gt;37% of US adults and increases the risk of developing 13 types of cancer, including renal cancer. Renal cancer is treated by immunotherapy, but the impact of obesity on immunotherapy efficacy remains unclear. We addressed this issue by evaluating treatment efficacy in lean or diet-induced obese (DIO) mice with orthotopic renal tumors. Endogenous T cell priming with adenovirus-encoded TRAIL + CpG (AdTR/CpG) significantly reduced renal tumors in lean mice, but failed in ~80% of DIO mice. We then asked: 1) if failure were specific to this model and 2) if it could be reversed by reinvigoration of T cells with checkpoint blockade. Here, we report that obesity-induced impairment occurs across multiple immunotherapies and tumor types, and is independent of diet alone. Combining AdTR/CpG with checkpoint blockade (either anti-PD-1 or anti-CTLA-4) improved response rates in DIO mice with renal tumors to 44% and 67%, respectively. nanoString immunogenetic profiling of responder versus non-responder tumors revealed increases in T cell-related genes with concomitant decreases in myeloid/dendritic cell genes in responder mice (coined a ‘T cell-myeloid-inversion (TMI) signature’). These results were supported by flow cytometric data, which revealed increased intratumoral CD8+ T cell : Treg ratios and decreased myeloid-derived suppressor cells and tolerogenic dendritic cells in responders. Our results identify obesity as a confounder of immunotherapeutic efficacy that can be partially overcome by combining upstream T cell priming agents with checkpoint blockade. Further investigations will be aimed at targeting immunosuppressive populations to further boost therapeutic efficacy.
Characterization of a Single Nucleotide Variant of Ccdc85c as a Tumor Rejection-Mediating Neoepitope of Meth A Fibrosarcoma
Authors: Ebrahimi-Nik Hakimeh , Corwin William L. , Mandoiu Ion I. , Srivastava Pramod K. 
Published: January 2023

Abstract
An 18-mer peptide (named Neo1) containing a single amino acid variation (deduced from comparison of Meth A transcriptome with normal mouse genome) is capable of eliciting complete protection of BALB/c mice against a lethal challenge with Meth A fibrosarcoma cells. A similar peptide containing an un-mutated sequence does not elicit tumor rejection. In an attempt to identify the exact MHC-binding epitope within Neo1, nineteen smaller and distinct peptide constructs derived from Neo1 were tested in a prophylactic tumor rejection assay. The exact epitope was observed to be a 9-mer. This 9-mer neoepitope was not predicted to bind MHC I by NetMHC; NetMHC did predict four other peptides within Neo1 to bind Kd and Ld. None of these four predicted peptides elicited tumor rejection. Of note, even seemingly minor changes in the flanking regions of the precise neoepitope on either side of the peptide had a dramatic influence on anti-tumor immunogenicity of the peptide.
Roles of nitric oxide in hematopoietic differentiation induced by the vaccine adjuvant
Authors: Yang Ya-Wun , Liu Yen-Chi , Gupta Amit 
Published: January 2023

Abstract
N(ω)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), is involved in the pathogenesis of inflammatory disorders. The roles of nitric oxide (NO) in myeloid differentiation induced by the cancer vaccine adjuvant is unknown. The objective this study was to examine the effect of NOS inhibitor in the hematopoietic differentiation induced by the L121-adjuvant, an emulsion vaccine adjuvant containing Pluronic L121 previously shown to exhibit potent immune responses when combined with soluble protein antigens. C57BL/6J mice were vaccinated by subcutaneous injection on days 0 and 7 with 100 μl L121-adjuvant, containing 50 μg ovalbumin (OVA), followed by daily treatment with L-NAME (10 mg/kg). The animals were sacrificed on day 10, and bone marrow cells and splenocytes were isolated, lysed with the ammonium-chloride-potassium (ACK) lysing buffer, followed by flow cytometric analysis. Our results showed that vaccination of mice with the L121-adjuvant stimulated a considerable generation of CD11b+Gr-1+ myeloid populations in the bone marrow and spleens. Treatment of animals with L-NAME significantly upregulated the lineage−Sca-1+c-kit+ (LSK) frequency, but down-regulated the lineage− Sca-1− c-kit+CD16/CD32+ granulocytic/monocytic progenitor (GMP) populations in the bone marrow. These data demonstrated the involvement of NO in the modulation of granulocytic/monocytic differentiation and generation of inflammatory response in cancer vaccine adjuvant-mediate hematopoietic differentiation.
Immunologic synergy between intermittent NSAID administration and antigen specific vaccination in inhibiting the development of intestinal polyps in the APC(Min/+)
Authors: Gad Ekram , Corulli Lauren , Cowan Paul , Sei Shizuko , Grubbs Clinton , Disis Mary L. 
Published: January 2023

Abstract

Introduction
Studies from our group have shown that administration of NSAIDs in mouse models of Familial Adenomatous Polyposis results in a decrease in polyp formation and a significant increase in CD8 tumor infiltrating lymphocytes with downregulation of PD-L1 expression in tumors. We questioned whether a short course of NSAID could be used in combination with vaccination to even further reduce the development of intestinal polyps.

Methods
At 4–6 weeks of age, APC(Min/+) male/female mice were given CFA/IFA adjuvant with or without a multi-antigen (EGFR, COX2, CDC25B) peptide vaccine. Upon start of vaccinations, normal food or 400ppm naproxen mixed with food was provided either continuously (CON; 18w on) or intermittently (INT; 3w on + 3w off for 3 cycles). Animals were euthanized at 22±1 weeks and tumors quantified. Systemic and tissue specific immunity was measured by ELISPOT, FACS, and direct tumor staining.

Results
Tumor development was significantly inhibited both by vaccine alone and naproxen alone (p&lt;0.0001). Combining naproxen (INT or CON) with vaccine was additive compared to vaccine alone (p&lt;0.0001) and naproxen alone (INT+Vaccine p&lt;0.0007; CON+Vaccine p&lt;0.0003). INT naproxen was as effective as CON, with or without vaccine (p&gt;0.999). Mice with greater tumor inhibition demonstrated higher magnitude antigen specific T-cell responses (p=0.0441, r=−0.423) and CD8+ T-cell infiltration (p&lt;0.0001, r=−0.506) than those with less protection.

Conclusions
Data demonstrates that short-term administration of NSAIDs may be as effective as the more toxic long-duration alternative. Further, a short course of NSAID significantly synergizes with antigen specific vaccination to inhibit the development of polyps.
Role of glucose metabolism in herpes simplex encephalitis
Authors: Rajasagi Naveen K. , Rouse Barry T. 
Published: January 2023

Abstract
Herpes simplex virus-1 (HSV-1) is an important human pathogen without an effective vaccine. Following ocular infection the virus replicates in the epithelial tissues and is transported to the trigeminal ganglia (TG) where it establishes latency. Upon periodic reactivation, the virus multiplies in the TG and the replicating virus can reenter the cornea which could result in clinical consequences in many cases. Frequent recurrences can result in chronic inflammatory reactions in the corneal stroma which impairs vision and such recurrences can ultimately result in blindness. Although rare, the virus can spread to the brain and can cause serious complications such as encephalitis especially in immunocompromised individuals. The host immune responses, especially CD8 T cells play a crucial role in controlling virus replication in the TG and prevent spread to the brain. In mouse model of ocular infection, we found that blocking glucose metabolism using 2-deoxy glucose (2DG) resulted in increased virus spread to the brain. The majority of animals treated with 2DG succumbed to herpes simplex encephalitis (HSE). Our results demonstrated that 2DG treatment impacted on both the magnitude and function of the CD8 T cells in the draining lymph nodes and TG. These data show that glucose uptake is essential for HSV specific CD8 T cell responses to be appropriately induced and function and suggest that manipulation of glucose metabolism may serve to enhance anti-viral CD8 T cell responses acting to more effectively control infection.
Inhibitory receptor signatures on gamma delta T cells predict ART-suppressed HIV infection, are synergistically altered by HIV and aging, and co-vary with inflammatory plasma analytes.
Authors: Snyder-Cappione Jennifer E. , Belkina Anna C. , Starchenko Alina , Drake Katherine , Proctor Elizabeth , Lauffenburger Douglas A. , Browning Jeffrey L. , Olson Alex , Lin Nina H. 
Published: January 2023

Abstract
Virologically suppressed HIV+ individuals have an increased risk and earlier onset of age-associated diseases such as cardiovascular atherosclerosis, cancer, and osteoporosis, referred to as HIV-Associated Non-AIDS conditions (HANAs). Whether HIV drives HANAs via same mechanisms as normal aging or other processes is unclear. We analyzed PBMC from 45 ART-suppressed HIV+ subjects (20 ≤35yo ‘younger’, 25 ≥50yo ‘older’) and 39 uninfected controls (20 younger, 19 older) with a 16-color flow cytometry panel that measures the inhibitory receptors (IRs) PD-1, TIGIT, CD160, TIM-3, and LAG-3 on CD4+ T cells, CD8+ T cells, NK cells, iNKT cells, and gd T cells. Bioinformatic (CITRUS) analysis revealed that gd T cell IR expression exclusively differentiated HIV+ subjects from controls. Also, a synergistic effect of HIV and aging on TIGIT+ and ≥ 2 IR gd T cell percentages was found. gd T cell functional profiling revealed a positive association between TIGIT expression and spontaneous release of granzymes A and B from HIV+ subjects but not controls. Using supervised multivariate modeling (Partial Least Squares discriminant analysis, PLS) of gd T IR signatures, gd T cell cytokine secretion, and inflammatory plasma analytes, all four subject groups (HIV+ and uninfected, ≤35 and ≥50yo) were effectively distinguished. Also, a statistically significant covariance between gd T cell IR signatures and levels of inflammatory plasma analytes, including IL-6, IL-1b and fibrinogen was found. Our data implicate gd T cells as a key inflammatory driver in ART-suppressed HIV infection and our PLS results suggest a divergence of ART-suppressed HIV inflammation and healthy aging processes, revealing differential “inflammaging” with and without HIV infection.
5-Fluorouracil depletion of Myeloid Derived Suppressor Cells in mice infected with LP-BM5 retrovirus.
Authors: Green Kathy A. , Green William R. 
Published: January 2023

Abstract
Tumor associated MDSC inhibit tumor-directed T-cell responses. We have shown the induction of monocytic MDSCs (M-MDSC) during infection of B6 mice by LP-BM5 immunodeficiency inducing retrovirus. These M-MDSCs suppressed proliferation and function of T cells, ~100% via iNOS/NO; and that of B cells, ~50% via iNOS/NO along with the negative checkpoint regulator VISTA, NOS, ROS, and other soluble mediators. Because of overlapping cell-surface phenotypes, our attempts to selectively deplete M-MDSCs in vivo have been challenging. However, 5-Fluorouracil (5-FU), a pyrimidine analog widely used in tumor chemotherapy, has recently been reported to selectively eliminate MDSCs by apoptosis (Biomed. J. 2015:38:111–116). Here, we treated LP-BM5 infected mice with an extended course of 5-FU: at 6–7 weeks post infection achieving ~50% depletion of splenic M-MDSCs, and spleen cells from depleted mice exhibited greatly decreased suppression in ex vivo assays. LP-BM5 infected mice with this level of M-MDSC depletion, had significantly less disease, including: splenomegaly and immunodeficiency – i.e. impaired B and T-cell ex vivo polyclonal responses. Also, regarding other disease parameters, the loss of LP-BM5 induced splenic: CD4 Thy1.2 and B-cell CD23 expression was greatly reduced in M-MDSC depleted mice. As compared to sham treated mice, via flow cytometry, the splenic CD8+ T cell subset from LP-BM5 infected/M-MDSC depleted mice was greatly increased in cell number and MFI. Future directions include extending these initial experiments to further characterize the effects on B and T-cells resulting from in-vivo 5-FU-mediated M-MDSC depletion during LP-BM5 retrovirus-induced immunodeficiency.
The human B cell response to infection with dengue virus serotype 2 broadly engages the plasmablast repertoire and maintains a high degree of type-specificity in memory.
Authors: Diehl Sean A. , Tu Huy , Nivarthi Usha K. , McElvany Benjamin D. , Emerling Daniel E. , de Silva Aravinda M. 
Published: January 2023

Abstract
The complexity of the serological response to the four serotypes of the dengue virus (DENV1-4) is a key factor confounding rational vaccine development for dengue. To refine our understanding of the basis of the humoral response to DENV, we used high-coverage approaches to unravel the early and late B cell response at the clonal level to a single controlled infection with DENV2 in humans. In peripheral blood specimens we identified the peak DENV2-induced early plasmablast response. By analyzing paired immunoglobulin heavy (IGH) and light (IGL) chains derived from peak plasmablasts we found broad evidence of lineage expansion, somatic hypermutation, and variable gene usage. We selected 92 IGH/IGL pairs from expanded lineages and found that 54 (59%) of these monoclonal antibodies (mAb) bound DENV2, five of which also neutralized virus. In these same subjects we assessed the memory B cell (MBC) repertoire at six months post infection by screening IgG from MBCs immortalized by genetic reprogramming to a germinal center-like state. Compared to the early plasmablast response, we found a drastic reduction in the DENV-specific population in the memory phase of the B cell response. There was a unexpectedly high degree of DENV2 type-specificity in the convalescent MBC pool, though heterotypic clones were also observed. MBC-derived mAbs mainly reacted to epitopes present on whole virions. Our results suggest that controlled DENV2 infection elicits a broad and complex early B cell response to DENV that contracts to yield a DENV-specific MBC compartment. These results provide insights into the basis for long-term serotype-specific humoral immunity and provide additional metrics by which to assess DENV vaccines.
Targeting TNF-α against dengue virus-induced neurotoxicity and acute viral encephalitis-like symptoms
Authors: Lin Chiou-Feng 
Published: January 2023

Abstract
Pro-inflammatory tumor necrosis factor α (TNF-α) facilitates dengue virus (DENV) infection in endovascular dysfunction and neurotoxicity. The introduction of TNF-α blocking therapy with antibodies and antagonists is performed for testing its therapeutic effects in this study. In DENV-infected mice, TNF-α was produced in the brains accompanied by the progression of neurotoxicity and encephalitis. DENV infection caused loss in hippocampal neurons with TNF-α expression around the damaged regions. Additionally, immunostaining showed the induction of apoptosis in hippocampal neurons. TNF-α was expressed in active microglia as well as astrocytes of DENV-infected mice. TNF-α facilitated DENV-induced neurotoxicity in vitro in murine Neuro-2a cells. By using a currently established encephalitic mice model that DENV infection caused progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality 7 days post-infection, TNF-α transgenic mice represented the progressive disease development while administration of neutralizing TNF-α antibody reduced dengue encephalitis and mortality. These results demonstrate an immunopathogenesis of TNF-α for mediating DENV-induced encephalitis-associated neurotoxicity and targeting TNF-α can be used as a strategy against dengue encephalitis.