bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesenchymal stem cells inhibit RANK-RANKL interactions between osteoclasts and Th17 cells via osteoprotegerin activity.
Authors: Cho Kyung-Ah , Park Minhwa , Kim Yu-Hee , Ryu Kyung-Ha , Woo So-Youn 
Published: January 2023

Abstract
Th17 cells play a critical role in several autoimmune diseases, including psoriasis and psoriatic arthritis (PsA). Psoriasis is a chronic inflammatory skin disease associated with systemic inflammation and comorbidities, such as PsA. PsA develops in nearly 70% of patients with psoriasis, and bone erosion is a hallmark of the disease. Thus far, the effect of Th17 cells on osteoclastogenesis via direct cell-to-cell interactions is less understood. In this study, we observed that Th17 cells directly promote osteoclast differentiation and maturation via expression of receptor activator of nuclear factor-k β ligand (RANKL) in vitro. We investigated the impact of conditioned medium obtained from human palatine tonsil-derived mesenchymal stem cells (T-CM) on the interactions between osteoclasts and Th17 cells. T-CM effectively blunted the RANK-RANKL interaction between the osteoclast precursor cell line RAW 264.7 and Th17 cells via osteoprotegerin (OPG) activity. The frequency of tartrate-resistant acid phosphatase (TRAP)-positive cells in the bone marrow of an imiquimod (IMQ)-induced psoriasis mouse model was decreased following T-CM injection. Therefore, our data provide novel insight into the therapeutic potential of tonsil-derived mesenchymal stem cell-mediated therapy (via OPG production) for the treatment of pathophysiologic processes that occur in joints or bones under chronic inflammatory conditions such as psoriasis.
Key serum cytokine markers for evaluating the efficacy of vaccine therapy in autoimmune models of rheumatoid arthritis
Authors: Zimmerman Daniel H , Rosenthal Kenneth , Carambula Roy , Cress Steve , Markovics Adrienn , Glant Tibor , Mikecz Katalin 
Published: January 2023

Abstract

Background
Pro-inflammatory T helper (Th)17 or Th1 cell responses (IL17, IFNγ, TNFα) drive autoimmune pathology in rheumatoid arthritis (RA) at the expense of anti-inflammatory/regulatory (IL4, IL10, TGFβ) T cell responses. Ligand Epitope Antigen Presenting System (LEAPS) vaccines, composed of cell-binding and immunodominant peptides, can down-modulate Th17 or Th1 activity and thus have the potential to treat ongoing RA. Choice of appropriate treatment requires knowledge of key cytokines driving disease as well as responses to therapy.

Experimental design
Serum cytokines were assayed in mouse models of RA including proteoglycan-induced arthritis (PGIA) recombinant proteoglycan G1 domain-induced arthritis (GIA) and collagen-induced arthritis (CIA) after arthritic mice had been treated with LEAPS vaccines. Serum cytokine levels and ratios of anti-inflammatory to pro-inflammatory cytokines were correlated with visual and histopathologic scores of disease.

Results
Serum levels of pro-inflammatory cytokines were elevated in control mice with either PGIA, GIA, or CIA. Reduced disease progression in mice treated with LEAPS vaccines was accompanied by decreased pro-inflammatory cytokine levels and increased ratios of anti-inflammmatory/regulatory to pro-inflammatory cytokines.

Conclusion
Serum concentrations and ratios of key disease-related cytokines can predict therapeutic efficacy in different animal models of RA. Successful vaccine therapy is associated with ratios shifted in favor of anti-inflammatory/regulatory cytokines. The ability to predict cytokine responses to therapy will allow better design or choice of appropriate immunomodulatory LEAPS vaccines and other therapies in RA.
TAK-079 is a high affinity monoclonal antibody that effectively mediates CD38+ cell depletion
Authors: Smithson Glennda , Zalevsky Jonathan , Korver Wouter , Roepcke Stefan , Dahl Martin , Zhao Lin , Yuan Josh , McLean Lachy , Elias Kathleen 
Published: January 2023

Abstract
TAK-079 is a fully human, non-agonistic, IgG1 cell-depleting monoclonal antibody that binds human CD38 with high affinity (KD 1.2 nM, KinExA) and cross reacts with cynomolgus monkey CD38. CD38 is a cADPR hydrolase expressed on human plasmablasts, plasma cells, NK cells and activated T and B cells, but not on mature platelets or red blood cells, based on TAK-079 binding. In patients with rheumatoid arthritis (RA) and systemic lupus erythematousus (SLE), plasma cells, as well as activated B and T cells may be important contributors to disease. Unlike other B cell-selective therapies which target CD20 and do not directly deplete plasmablasts, which are CD20low/negative, CD38 is expressed at high levels on plasmablasts and plasma cells making these cells a direct target of TAK-079. In vitro studies with human blood cells and cell lines showed that binding of TAK-079 to CD38 did not result in PBMC cytokine activation demonstrating that TAK-079 is not an agonist. Rather, it mediated depletion of human B lineage cell lines by ADCC and CDC and in most cases cell lines with increased CD38 expression were more susceptible to cell lysis. This is consistent with findings in healthy cynomolgus monkeys where the efficiency of depletion correlated with level of CD38 expression and TAK-079 dose level. NK cells, which express high levels of CD38, were depleted to a greater extent than CD20+ B cells and CD3+ T cells, which express less CD38. In vivo, TAK-079 potently suppressed the human B cell recall responses to antigen in a mouse adoptive transfer model. Together these data support the further investigation of TAK-079 in autoimmune diseases.
Metformin attenuates the Type I Interferon response in human peripheral blood leukocytes.
Authors: Titov Anton A , Brusko Todd M. , Sobel Eric , Morel Laurence 
Published: January 2023

Abstract
Metformin (Dimethylbiguanide) is used for controlling blood sugar levels in patients with Type 2 Diabetes, primarily by suppression of hepatic gluconeogenesis. Recently, it has drawn attention in a clinical trial (ChiCTR-TRC-12002419) for its ability to reduce disease flares and lower effective prednisone dosage in Systemic Lupus Erythematosus (SLE) patients. We have previously demonstrated that a therapy combining metformin and a glucose inhibitor can reverse lupus in mouse models by normalizing CD4+ T cell metabolism. Studies in mouse and isolated ex vivo human CD4+ T cells have characterized metformin’s capacity to downregulate oxidative metabolism and skew differentiation away from Th1 and Th17 towards a Treg lineage. To investigate the mechanisms by which metformin modulates CD4+ T cells we performed a microarray study of CD4+ T cells from n=5 SLE patients and n = 5 healthy controls (HCs). CD4+ T cells were isolated from subjects and activated (anti-CD3, anti-CD28) in media or 1mM metformin for 24 hr. Multiple ANOVA analysis yielded 1,211 transcripts with a FDR &lt;0.05 between groups. Pathway analysis determined that type I interferon stimulated genes (ISG) were significantly downregulated in the CD4+ T cells of both cohorts, but to a greater extent in the HC cohort. Downregulation of ISGs by metformin was validated in primary PBMCs stimulated with IFNα ex vivo by qRT-PCR. Luciferase reporter assays suggest that metformin reduces IL-6-induced activation of STAT3. These experiments provide evidence that the therapeutic potential of metformin in SLE may be multifaceted, including the modulation of type I IFN stimulated genes, as well as STAT3 signaling. Studies are ongoing to characterize the key mediators involved in these pathways.
The therapeutic potential of natural killer cells in treating systemic lupus erythematosus.
Authors: Reighard Seth D , Brunner Hermine , Waggoner Stephen N 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a chronic disease defined by rampant autoantibody production and multi-organ pathology. Standard treatments for SLE are broadly immunosuppressive and often ineffective, as ~38% of patients develop lupus nephritis (LN) that can result in kidney failure and death. Current therapeutics may lack efficacy because they do not target the specific immune processes underlying SLE. For example, lupus autoantibodies can arise from aberrant germinal centers (GCs) driven by dysregulated follicular helper T cells (TFH). We have shown that natural killer (NK) cells suppress activated TFH during immunization, resulting in blunted GCs and antibody production. We hypothesize that an effective new strategy to treat SLE would involve harnessing of this NK cell-mediated humoral regulation. To assess whether therapeutic elevation of NK cell numbers can ameliorate disease, we used IL-2/αIL-2 complexes to expand endogenous populations of NK cells in the bm12 cGVHD mouse model of SLE-like disease. We also evaluated ex vivo activation, expansion, and infusion of NK cells as an immunotherapeutic means to ameliorate disease in mouse models of SLE. Finally, we are engineering human NK cells expressing a programmed death-ligand 1 (PD-L1)-based chimeric antigen receptor (CAR) that will facilitate cytolytic elimination of TFH and B cells that highly express programmed cell death protein 1 (PD-1). We plan to evaluate the capacity of these CAR NK cells to selectively kill PD-1+ targets and to reduce autoantibody-mediated LN in humanized mouse models of SLE. These CAR NK cells represent an innovative means to curtail autoantibody production, particularly during disease flares, and thereby promote disease remission in SLE.
Ebola virus: Development of Filovirus glycoprotein Fc fusion proteins as a vaccine candidate
Authors: Konduru Krishnamurthy 
Published: January 2023

Abstract
Krishnamurthy Konduru and Gerardo Kaplan
Laboratory of Emerging Pathogens, Division ofEmerging and Transfusion Transmitted Diseases, Center for Biologics Evaluationand Research, Food and Drug Administration, Silver Spring, MD 20993.
Recent Ebola virus(EBOV) epidemic in West Africa underscores the urgent need of vaccines ortherapeutics. Here we describe the development of EBOV and Marburg virus (MARV) subunit vaccines based on the extracellular domain of the viral glycoprotein (GP) fused to the Fc fragment of human IgG (EBOV gp-Fc or MARV gp-Fc) and expressed in mammalian cells. These GP fusion proteins undergo the complex post-translational processing observed in the membrane-bound GP. In vaccinated mice, EBOV gp-Fc induced high levels of total and neutralizing anti-GP antibodies and elicited T-cell immunity characterized by the production of IFNγ (Konduru et al. 2011). Vaccinated guinea pigs developed a strong humoral response as measured by total and neutralizing antibodies to GP, and were completely protected against EBOV lethal challenge (Konduru et al. 2016). We are currently extending our studies to the filo virus lethal challenge model in monkeys. Our preliminary data indicates that EBOV gp-Fc and MARV gp-Fc induces total and neutralizing antibodies as well as recall CD8+ T-cell immunity as assessed by the production of IFNγ and TNFα in PBMC. Further experiments, including protection against lethal challenge in monkeys, will be required to determine whether Filovirus GP-Fc fusion proteins could be developed as a candidate vaccine.
Modulation of epitope-specific antibody response by HIV Env immune-complex vaccines
Authors: Kumar Rajnish , Tuen Michael , Jiang Xunqing , Itri Vincenza , Pazner Susan Zolla , Kong Xiang-Peng , Hioe Catarina 
Published: January 2023

Abstract
HIV-1 envelope (Env) antigen is an important target for both neutralizing and non-neutralizing antibodies (Ab) against the virus. In the RV144 vaccine trial, correlate for reduced risk of HIV acquisition is the presence of binding but non-neutralizing Ab to V1V2 and V3 loops of HIV Env gp120. However, induction of high titer, durable, and cross-reactive Ab responses against these Env regions by vaccination is still an elusive goal.
Our past studies have shown that V3 immunogenicity can be significantly enhanced by vaccination with gp120/mAb immune complexes (IC) vs gp120 alone. Current study further examined parameters that confer enhanced immunogenicity to IC by testing in mice IC vaccines made with different HIV Env gp120 (clade B vs clade E) and mAb of different specificities (V3, V2, or CD4 binding site (CD4bs)). In addition, IC made of clade C gp140 and CD4bs mAb were also tested. The data showed that Greater titers of cross-reactive V3-binding Ab were induced by IC made of clade B gp120 and mAb to V2 or CD4bs as compare with gp120 alone, although the gp120/CD4bs IC was more potent in eliciting neutralizing V3 Ab. IC made with clade E gp120 or clade C gp140 did not show the same effects.Greater Ab responses to V1V2 were induced by IC made of clade E gp120 vs gp120 alone, regardless of the mAb used for IC, but the Ab were not neutralizing. IC made with clade B gp120 and clade C gp140 did not enhance V1V2 Ab titers.
These results demonstrate the capacity of Env/mAb IC vaccines to modulate induction of Ab responses to V1V2 and V3, and this activity is dependent on both Env proteins and mAb used to form IC. Further exploration using a cocktail of IC is proposed to improve Ab repertoires generated upon vaccination.
IL-33 enhances the induction, durability, and breadth of the antibody response to a DNA/protein-based HIV Env vaccine
Authors: Kobie James , Sarkar Sanghita , Piepenbrink Michael , Basu Madhubanti , Keefer Michael , Thakar Juilee , Hessell Ann Jones , Haigwood Nancy Logan 
Published: January 2023

Abstract
Induction of a sustained and broad antibody (Ab) response is a major goal in developing a protective HIV vaccine. DNA is an attractive priming strategy when combined with protein or viral vector boosting; however, DNA priming alone fails to induce a substantial Ab response, limiting its potential as a stand-alone immunogen. Using the VC10014 DNA/protein vaccine consisting of gp160 plasmids and gp140 proteins derived from an HIV clade B infected subject who developed broadly neutralizing serum Abs, and which has been previously shown to induce Tier 2 heterologous neutralizing Abs in rhesus macaques, we screened a panel of factors in C57BL/6 mice for their ability to enhance the Env-specific Ab response. IL-33, an alarmin, emerged as the lead candidate. The addition of recombinant IL-33 during the gp160 DNA priming phase dramatically changed the kinetics of the Ab response, inducing serum gp120-specific IgG (&gt;1:12,500 titer) after a single DNA immunization, which was not detectable in mice that did not receive IL-33 (p&lt;0.0001). Then following boosting with DNA/protein coimmunization in Alum, gp120-specific IgG levels were extraordinarily durable, remaining stable even at 6 weeks after final immunization compared to mice not receiving IL-33 (p&lt;0.0001), in which they rapidly declined. IL-33 also increased the cross-clade breadth and avidity of the serum gp120-specific IgG response. Analysis of the Env-specific B cell immunoglobulin repertoire and the IL-33 mechanism of action is ongoing. These results demonstrate the profound effect that priming conditions can have on the quality of the Env-specific antibody response.
Spike nanoparticle and recombinant adenovirus 5 vaccines induce specific antibodies against the Middle East respiratory syndrome coronavirus (MERS-CoV)
Authors: Park Hyo-Jung , Lee Eun-Young , Jung SeoYeon , Ko Hae Li , Lee Sang-Myeong , Nam Jae-Hwan 
Published: January 2023

Abstract
The Middle East respiratory syndrome coronavirus (MERS-CoV) is a single-strained RNA virus and is included in Betacoronavirus. While, in the Arabian Peninsula, it has shown an endemic pattern, a sporadic pattern was observed elsewhere. In 2015, there was big outbreak of the MERS-CoV in Korea. However, since we still have no clinically available vaccine to prevent the MERS-CoV infection, such a vaccine is urgently required. In the present study, we developed two types of MERS-CoV vaccines: a spike nanoparticle vaccine produced by an insect culture system and a recombinant adenovirus 5 vaccine expressing spike protein. Both vaccines induced total IgG, IgG1, and IgG2a against spike protein of the MERS-CoV. Thus, both vaccines can trigger Th1 and Th2 immune responses. Interestingly, as compared to spike nanoparticle formulation with Alum without RNA adjuvant, spike nanoparticle formulation with Alum and RNA adjuvant showed higher titers of IgG1 and IgG2a at 10 days after boosting immunization. Moreover, T cell proliferation in splenocytes of immunized mice was well induced after the spike nanoparticle treatment. Thus, RNA adjuvant may be effective to increase vaccine efficacy against the MERS-CoV. Taken together, the results of the present study suggest that the developed two type of MERS-CoV vaccines–the spike nanoparticle vaccine and the recombinant virus vaccine–may be helpful to prevent the spread of the MERS-CoV.
Immunomodulation by chicken NK-lysin-derived peptide, cNK-2 on chicken macrophages and monocytes.
Authors: Kim Woohyun , Lillehoj Hyun S. , Min Wongi 
Published: January 2023

Abstract
Chicken NK-lysin (cNK-lysin) is a homologue of human granulysin. Human granulysin is found in the cytolytic granules located in human natural killer and cytotoxic T lymphocytes. We previously demonstrated that cNK-lysin and cNK-2, a synthetic peptide incorporating the core α-helical region of cNK-lysin, have antimicrobial activity against apicomplexan parasites such as Eimeria spp., via membrane disruption. Besides of antimicrobial activity of AMPs, the immunomodulatory activity of AMPs mediated by their interactions with host cells is increasingly recognized. Thus, in this study, we investigated whether cNK-2 modulates the immune response in the chicken macrophages and monocytes by evaluating the induction of chemokines, anti-inflammatory properties, and activation of signalling pathways. cNK-2 induced the expression of CCL4, CCL5 and interleukin-1β (IL-1β) in HD11 cells, chicken macrophage cell line, and CCL4 and CCL5 in primary monocytes. We also determined that cNK-2 suppresses the lipopolysaccharide-induced inflammatory response by abrogating IL-1β expression. The immunomodulatory activity of cNK-2 involves the mitogen-activated protein kinases-mediated signalling pathway, including p38, extracellular signal-regulated kinase 1/2 and c-Jun N-terminal kinases, as well as the internalization of cNK-2 into the cells. These results indicate that cNK-2 is a potential novel immunomodulating agent rather than an antimicrobial agent.
A non-prototypic leukocyte immune-type receptor (LITR) is expressed in response to virus infection in the channel catfish, Ictalurus punctatus
Authors: Blackmon Laura Elizabeth , Wilson Melanie , Bengten Eva 
Published: January 2023

Abstract
The channel catfish, Ictalurus punctatus, is a well-defined comparative model used to study innate and adaptive immunity. Leukocyte immune-type receptors (LITRs) are unique to teleosts and represent a large polymorphic and polygenic family of immunoregulatory receptors phylogenetically related to mammalian LRC-encoded proteins. LITRs are currently classified as either type I or type II receptors with inhibitory or activating signaling capabilities, respectively. Notably, some LITRs, as defined by their reactivity with anti-LITR monoclonal antibody CC41, are distinct markers of a cytotoxic cell population which undergoes expansion during the antiviral response against Channel Catfish Virus (CCV). Recent genomic analyses have identified a new LITR subset, and in contrast to the previously described inhibitory type I and activating type II LITRs, members of this non-prototypic LITR subset lack typical D1-D2 immunoglobulin domains. In addition, members of this subset are not CC41-reactive. Interestingly, increased message expression of a member of this subset, termed LITR-NP, is observed in catfish clonal G14D T cells after infection with CCV. When G14D cells are treated with UV irradiation, heat shock or serum starvation, however, LITR-NP message expression is not induced. This expression pattern suggests that LITR-NP may serve as a target ligand for NK receptors in catfish.
Probing host immune response to porcine reproductive and respiratory syndrome virus (PRRSV) infection using 3′RNAseq and NanoString arrays
Authors: Walker Kristen , Hong Linjun , Reecy James M. , Fritz-Waters Elyn , Dong Qian , Rowland Robert R. R. , Ireland Derek D.C. , Verthelyi Daniela , Tuggle Christopher K. , Dekkers Jack C.M. , Lunney Joan K. 
Published: January 2023

Abstract
Porcine reproductive and respiratory syndrome (PRRS) is economically the most important disease of pigs worldwide and, when combined with porcine circovirus (PCV2) coinfection, increases severity of disease. Our goal is to assess the role of host genetics in determining efficacy of PRRS vaccine responses and on resistance/susceptibility to coinfection challenge. We performed 3′RNA-seq and NanoString analyses to explore the blood transcriptome and identify mechanisms and biomarkers involved. We used a nursery pig model in which 50% of 200 pigs received a PRRS vaccination (Vx); after 28 days all were challenged with PRRSV and PCV2. Each pig was genotyped (80K SNP chip) and deeply phenotyped, including repeated blood sampling for viremia level (VL), and immune proteins, and weight gain (WG). Blood RNA was analyzed to identify differentially expressed (DE) genes associated with anti-viral response phenotypes. Previous work identified a PRRS resistance marker on swine chromosome 4 (SSC4) so, for these studies, samples from 7 sib sets (AA or AB for SSC4 marker; with/without Vx; 28 pigs total) were used for RNA preparation from Tempus tube-preserved blood samples collected following vaccination (4, 7, 11, 14, 21 days) and challenge (0, 4, 7, 11, 14, 21, 28 days). Samples were subjected to 3′RNA-seq and swine immune-focused, 220 gene NanoString codeset analyses. Data will be presented on DE gene expression, and particularly on immune related genes, that may contribute to controlling PRRS vaccination and PRRSV and PCV2 challenge responses. Further studies are aimed at identifying genes and biomarkers that regulate anti-viral response phenotypes. Funding: USDA ARS, USDA NIFA grant # 2013-68004-20362.
A noninvasive cutaneous delayed type hypersensitivity test is effective for evaluating the effects of handling on immunological stress levels in rats
Authors: Redmond Sarah , Tingle April , Cooper Diamond , Ugarte Claudia Paniagua , Hayes Dayna 
Published: January 2023

Abstract
Rats are a common model for human physiology and psychology, yet routine handling associated with animal maintenance and treatment administration has been shown to impact behavioral and physiological measures in rats, which raises concerns about their use as a model. Adolescent and adult female rats (Sprague-Dawley, n=6 per group) were subjected to handling treatments (restraint, tickling, or playful handling) to evaluate the potential to minimize the physiological impacts of handling stress. Treatments were administered every other day for 21 days, and body weights, blood smears, and ultrasonic vocalizations were collected throughout this time and for 14 subsequent days without handling treatments. A noninvasive delayed type hypersensitivity test was performed by sensitizing rats to 2,4-Dinitrochlorobenzene on abdominal skin and later assessing the response to ear lobe exposure by measuring ear thickness. The greatest increase in lobe thickness was consistently observed at 48 hours post exposure, with few animals showing inflammation that persisted more than 72 hours. Assessments in the middle of the handling period (day 10) and at the end of the handling period (day 21) showed significantly less swelling for adolescent rats receiving the restraint treatment as compared to rats in the tickling or playful handling groups. This effect was observed in both adolescent and adult rats, however the adolescent rats showed more significant changes in circulating blood cell populations and body weight than did adults. No differences were detected outside of the handling treatment period. These results further establish that routine handling can impact immunological measures in rats and demonstrate efficacy of this noninvasive assay.