bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting of peptide coupled dendrimers to human dendritic cells leads to autologous T cell activation (53.15)
Authors: Gert Philipp , Assenmacher Mario , Jähn Peter 
Published: January 2023

Abstract
Targeted delivery of vaccines to dendritic cells (DC) has been shown to be an effective approach to induce antigen-specific T cell immunity in vitro and in vivo. Peptides are used for ex vivo pulsing of DC, but not suitable to target dendritic cells in vivo. To overcome this limitation we have covalently attached 15 mers peptides covering the whole CMV pp65 amino acid sequence onto polyamidoamine (PAMAM) dendrimers and coupled them to an anti biotin antibody. Using this construct we were able to specifically target large amounts of peptides via CD36 biotin antibody to blood DC for effective stimulation of autologous CMV specific T cells analyzed by intracellular interferon gamma production. Appropriate activation of targeted DC with Toll like receptor ligands proved to be essential for effective T cell stimulation. Peptide pulsed DC were not sensitive to the antigen processing inhibitor chloroquine, whereas PAMAM-peptide targeted DC were and failed to stimulate T cells. Moreover T cell stimulation with PAMAM-peptide showed a substantial CD4 T cell response, but only weak CD8 response. Taken together this demonstrates that targeted PAMAM-peptides are internalized and processed before presentation via MHC class II molecules. In vivo targeting of PAMAM-peptides may represent a promising perspective for effective induction of DC derived immune responses against defined antigen epitopes.
Use of Ehrlichia Hsp60 and p28 in diagnostics and vaccines to protect against Ehrlichia infection (53.16)
Authors: Thomas Sunil , Valdes Patricia , Thirumalapura Nagaraja , Crossley Emily , Walker David 
Published: January 2023

Abstract
The obligately intracellular bacterium Ehrlichia chaffeensis that resides in mononuclear phagocytes is the etiologic agent of human monocytotropic ehrlichiosis (HME). HME is an emerging, highly prevalent, and often life-threatening tick-transmitted infectious disease in the United States. As yet there are no vaccines against ehrlichiosis. We had recently demonstrated that Ehrlichia Hsp60 and p28 are the major antigens of Ehrlichia, and both the proteins are post-translationally modified as determined by eastern blotting. Based on these observations we designed peptides specific to Ehrlichia Hsp60 and p28-19. The designed peptide sequences were highly conserved in Ehrlichia. In initial studies we tested the peptides as probes to detect antibodies to Ehrlichia. Both the Ehrlichia Hsp60 and p28 could detect antibodies stimulated by E. chaffeensis, E. canis, E. muris, and E. ewingii. However, the p28-19 peptide was more sensitive than Ehrlichia Hsp60 in diagnosis of ehrlichiosis. Both Ehrlichia peptides-Hsp60 and p28-19-could function as a vaccine. The bacteria were cleared more rapidly within 14 days in vaccinated mice. The p28-19 peptide elicited higher levels of IgG1, IgG2b, and IgG3 antibodies compared to Ehrlichia Hsp60. The experiments demonstrate that Ehrlichia antigenic peptides Hsp60 and p28-19 are good candidates to be used in diagnostics and also could function as vaccines to protect against ehrlichiosis.
Nano-antigen presenting cells for the development of therapeutic vaccines (53.2)
Authors: Liu Mengya , Miao Tizong , Li Su-ling , Wang Ping 
Published: January 2023

Abstract
Antigen presenting cells (APC) initiate immune responses against pathogens by presenting antigen and costimulatory signals to T lymphocytes. APCs loaded with antigens in vitro have been used as therapeutic vaccines to induce antiviral or tumour immune responses in chronic infectious diseases or cancer. However, the live APCs are unstable in vivo and cannot overcome the immune tolerance induced by persistent viral infection or tumour microenvironment. We have developed nano-sized APCs that are at the size of ~ 500nM and can present antigen, costimulatory molecules and bioengineered IL-2 to antigen specific T cells directly. The nano-APCs are prepared from isolated endoplasmic reticulum membranes of APCs engineered with an ER-retained IL-2. Assembled with specific antigenic peptides, the nano-APC effectively induce responses of CMV or HBV specific CD4 and/or CD8 T cells responses in peripheral blood lymphocytes (PBL) of CMV serum converted or chronic HBV infected patients. With selected antigens, the bio-engineered nano-APCs will be used as therapeutic vaccines for the treatment of chronic HBV, HCV or HIV infection and also cancer.
Dynamics of memory T cells clearing a persistent CNS infection in the absence of severe tissue injury (53.9)
Authors: Herz Jasmin , McGavern Dorian 
Published: January 2023

Abstract
Many viruses can infect the mammalian central nervous system (CNS), some with devastating consequences, and others with little or no overt pathology. Immunotherapy is a successful approach to treat persistent infections that has shown promise in humans. Our laboratory studies a murine model of persistent lymphocytic choriomeningitis virus (LCMV) infection to understand the mechanism(s) by which immunotherapy with virus-specific memory T cells cleanses the infected CNS with minimal cellular damage and blood brain barrier breakdown. Using two-photon microscopy, we observed that therapeutic memory T cells invade the meninges and brain parenchyma, scanning both areas systemically for viral antigen. Interestingly, T cell surveillance of the persistently infected brain was not associated with massive recruitment of peripheral myelomonocytic cells - innate cells known to cause severe vascular pathology during LCMV meningitis. Instead, we revealed using CD11c-YFP reporter mice that immunotherapeutic T cells transformed microglia into a DC phenotype, inducing CD11c expression on microglia throughout the brain parenchyma. Microglia also participated in immunotherapy by directly releasing chemokines such as CCL5. We propose that successful clearance of a persistently infected brain can be achieved without induction of severe tissue injury by tailoring chemokine release to limit myelomonocytic cell recruitment and by converting microglia into local antigen presenting cells.
Lung dysfunction in a mouse model of inflammation is dependent on T-cell-independent IL-13 expression (54.18)
Authors: Jacobsen Elizabeth , Sergei Ochkur , Wen Li , Zellner Katie , Colbert Dana , Protheroe Cheryl , Lee James , Lee Nancy 
Published: January 2023

Abstract
Chronic asthma is characterized by pulmonary remodeling and sustained lung dysfunction. The expression of IL-13 has been demonstrated as sufficient and necessary to induce these pathologies. Despite the common assumption that T cells are the primary source of IL-13 in the lung following allergen provocation, the mechanistic events leading to IL-13 expression are unclear, including the potential importance of other cells (i.e., non-T cells). Methods: Co-expression of IL-5 and eotaxin-2 induces pulmonary histopathologies and lung dysfunction that are eosinophil-dependent (i.e., they are absent in triple transgenic I5/hE2/PHIL) animals. IL-13 knockout and CD4 knockout mice were crossed with I5/hE2 mice to assess the effects of these deficiencies on the induced pathologies occurring in this double transgenic model. Conclusions: The Th2 pulmonary pathologies associated with I5/hE2 mice included recruitment of pulmonary effector T cells and increased brochoalveolar Th2 cytokine levels. Conversely, I5/hE2/CD4-/- had only a ~50% reduction in IL-13 levels as compared to I5/hE2 mice, suggesting that a significant portion of IL-13 is non-T cell derived in these mice. I5/hE2/IL-13-/- mice are improved in lung dysfunction and mucus production as compared to I5/hE2 mice. All mice had similar levels of eosinophil degranulation. These results demonstrate a role for non-T cell derived IL-13 that contributes to mucus production and lung dysfunction in a mouse model of chronic severe asthma.
Cholinergic activation by galantamine suppresses obesity-associated inflammation in mice (54.4)
Authors: Pavlov Valentin , Satapathy Sanjaya , Ochani Mahendar , Dancho Meghan , Hudson LaQueta , Rosas-Ballina Mauricio , Valdes-Ferrer Sergio , Olofsson Peder , Harris Yael , Chavan Sangeeta , Roth Jesse , Tracey Kevin 
Published: January 2023

Abstract
Low-grade systemic inflammation is a central event in obesity and mediates insulin resistance and other complications. Previously we discovered a role for neural cholinergic signaling in controlling inflammation (Nature, 2000, 405, 6785; Proc Natl Acad Sci USA, 2006, 5219) and demonstrated that the acetylcholinesterase inhibitor galantamine suppresses systemic lethal inflammation (Brain Behav Immun, 2009, 4; 1). Here we tested the efficacy of galantamine in alleviating obesity-associated inflammation. C57BL/6J mice with high fat-diet induced (for 8 weeks) obesity were treated with either galantamine (4 mg/kg daily, i.p.), or saline for 4 weeks while on the high-fat diet. Galantamine treatment of obese mice resulted in lower body weight and abdominal adiposity as compared to saline treatment. Galantamine significantly decreased systemic levels of characteristic pro-inflammatory cytokines/adipokines, including IL-6, MCP-1, resistin and leptin and increased adiponectin levels, accompanied by alleviated hyperglycemia, hyperinsulinemia, insulin resistance and hepatosteatosis. These results demonstrate that galantamine reduces obesity-associated inflammation and alleviates obesity-related complications and provide a rationale for further mechanistic studies and novel therapeutic implications. Translational aspects of these studies will be additionally facilitated by the fact that galantamine is a FDA approved (for the treatment of Alzheimer’s disease) cholinergic agent.
Aloe complex improves insulin sensitivity via inhibition of obesity induced inflammation in diet-induced obese type II diabetes mellitus (54.5)
Authors: Shin Seulmee , Shin Eunju , Do Seon-Gil , Park Yoonhee , Kim Seulah , Lee Chong-Kil , Cho Kyunghea , Kim Kyungjae 
Published: January 2023

Abstract
Aloe is known to have various medical effects. These include healing damaged skin, as well as anti-diabetic, anticancer, and anti-arthritis activity. This study was performed to investigate the therapeutic effect of Aloe complex on diabetic symptoms in die-induced obesity (DIO) C57BL/6N mice. Aloe complex was orally administrated to diabetic mice for 8 weeks and the diabetic clinical markers, including blood glucose level, body weight, and insulin level were measured. The oral administration of Aloe complex in DIO mice significantly decreased of blood glucose and body weight level including total WATs compared with diabetic control group. The levels of serum insulin, tissue insulin, GTT, and ITT were improved after Aloe complex treatment. Moreover, both serum and tissue adiponectin increased whereas serum leptin decreased by Aloe complex. Aloe exerted beneficial effects on lipogenesis related transcription factor genes, PPARγ and LXRα, and aP2 expression in WAT. The gene expression of pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α, and Th1 cytokines, IFN-γ, IL-12, protein levels were suppressed via inhibiting nuclear NF-κB by Aloe complex. In contrast, protein levels of Th2 cytokines, IL-4 and IL-10, in WAT and AMPK activity in muscles were increased. The results suggest that Aloe complex has hypoglycemic effects resulting the attenuation of glucose and lipogenesis and that Aloe-containing diet or drugs may give a benefit for controlling type II diabetes patients.
Cleavage of CD23 by ADAM proteins is regulated by beta-2 adrenergic receptor engagement on primed B cells (55.11)
Authors: Padro Caroline , Sanders Virginia 
Published: January 2023

Abstract
Allergic asthma severity may be associated with IgE levels. We have shown that beta-2 adrenergic receptor (β2AR) engagement on CD40L/IL-4-primed B cells increases the level of IgE produced per cell, without affecting class switch recombination. β2AR agonists alleviate bronchoconstriction by targeting the β2AR expressed on bronchiolar smooth muscle cells to trigger airway relaxation, but these drugs also target the β2AR on primed B cells, potentially producing an IgE effect that may be counterproductive to the drugs intended use. We reported that surface CD23 expression remained constant on primed B cells exposed to a β2AR agonist, while CD23 mRNA, total CD23 protein, and soluble CD23 (sCD23) increased. Thus, if sCD23 positively regulates IgE production, an increase due to β2AR engagement may worsen bronchoconstriction, albeit relieving it in the short term. We hypothesized that the primary sheddase of CD23, ADAM10, is regulated by β2AR engagement on a primed B cell. Although we found that β2AR engagement was unable to affect the level of ADAM10 protein or mRNA produced compared to primed cells alone, our recent data indicated that the β2AR-induced increase in CD23 shedding may be mediated by increased localization of mature ADAM10 with CD23. Thus, ADAM10 may be a molecular target that can be blocked during β2AR drug therapy to prevent increased sCD23 and IgE, which may counteract the therapeutic bronchorelaxation.
2-linoleoylglycerol inhibits allergic response and expression of inflammatory cytokines in mast cells (55.19)
Authors: Ahn Eun-Kyung , Lee Jae Yeon , Hong Seong Su , Oh Joa Sub 
Published: January 2023

Abstract
Mast cell-mediated allergic disorder is associated with many diseases such as allergic asthma, atopic dermatitis and allergic rhinitis. In this study, we investigated the effect of the 2-linoleoylglycerol isolated from Adenophora triphylla on the Immunoglobulin E (IgE)-mediated allergic response and expression of inflammatory cytokines in mast cells. We observed that 2-linoleoylglycerol significantly inhibited β-hexosaminidase release in a dose-dependent manner in antigen-stimulated RBL-2H3 mast cells. 2-linoleoylglycerol also suppressed the expression of TNF-α, IL-4, IL-10 and COX-2 mRNA in mast cells. In addition, we showed that 2-linoleoylglycerol attenuated the activating phosphorylation of AKT, p38MAPK, JNK and ERK1/2. Our findings suggest that 2-linoleoylglycerol inhibits mast cell-derived allergic response and expression of inflammatory cytokines and that this effect is related by inhibition of AKT, p38MAPK, JNK and ERK1/2 phosphorylations.
LPS-induced CD11b+Gr1intF4/80+ myeloid cells suppress allergic airway inflammation (55.3)
Authors: Arora Meenakshi , Poe Stephanie , Oriss Tim , Krishnamorthy Nandini , Yarlagadda Manohar , Ray Anuradha , Ray Prabir 
Published: January 2023

Abstract
The bacterial product lipopolysaccharide (LPS) has been associated with protection from allergic diseases such as asthma in humans. However, differential effects of LPS based on the dose have been noted in the mouse models of allergic asthma. Our recent work has described the ability of LPS to increase the frequency of CD11b+Gr1intF4/80+ cells in the lung tissue of mice in a dose-dependent fashion that is dependent on TLR4 and MyD88. Although the Gr1int cells are readily detectable in the lung tissue of LPS-treated mice, they are not detected in the lung-draining lymph nodes or in the airway lumen which causes selective enrichment of these cells over dendritic cells (DCs) in the tissue. The Gr1int cells were found to blunt the ability of lung DCs to upregulate GATA-3 or to promote STAT5 activation in primed Th2 cells, both transcription factors having critical roles in Th2 effector function. Suppression of Th2 effector function was reversed by anti-interleukin-10 or inhibition of arginase 1. Adoptive transfer of LPS-induced Gr1int cells suppressed allergen-induced airway inflammation suggesting that these myeloid cells may have regulatory functions in allergic asthma. Thus, a complete understanding of the generation and regulation of the Gr1int cells would provide new avenues to either promote or delete these cells for disease-specific immunoregulation.
Interleukin-3-deficient mice have increased susceptibility to Plasmodium berghei infection (56.2)
Authors: Saunders Bryan , Roth Kenneth , Howe Lauren , Lantz Chris 
Published: January 2023

Abstract
Interleukin-3 (IL-3), which can be derived from T cells and other sources, is well documented at promoting the in vitro differentiation and proliferation of murine hematopoietic progenitors, yielding multipotential blast cells, mast cells, and mature cells of the myeloid and erythroid lineages. Although IL-3-deficient (knockout [KO]) mice display intact steady-state hematopoiesis, administration of IL-3 to mice and humans can promote hematopoiesis and influence the effector functions of mature hematopoietic cells in vivo. Because of these biological activities of IL-3, the contribution of IL-3 to resistance to blood-stage malaria was investigated by infecting KO mice intraperitoneally with Plasmodium berghei-infected RBCs. We found that KO mice were more susceptible to infection than wild-type (WT) mice, as evidenced by markedly higher peak parasitemia. P. berghei-infected KO mice also had significantly greater anemia and splenomegaly compared to similarly infected WT mice. Our results indicate that IL-3 contributes to resistance to P. berghei infection.
The role of JAK/STAT pathway in the synthesis of prostaglandin E2 by macrophages infected with Francisella tularensis (56.24)
Authors: Studt Ashley , Bryan Joshua , Woolard Matthew 
Published: January 2023

Abstract
Francisella tularensis is the causative agent of the disease tularemia. Respiratory tularemia is the most serious form of the disease. F. tularensis induces the synthesis of prostaglandin E2 (PGE2) from infected bone marrow-derived macrophages. The synthesis of PGE2 inhibits the generation of beneficial adaptive immune responses during respiratory tularemia resulting in increased severity of disease. We lack knowledge of the signal transduction events that are required for F. tularensis to induce PGE2 synthesis from macrophages. The JAK/STAT pathway has been documented to be important in the macrophage response to F. tularensis. We wanted to determine if JAK/STAT pathways were involved in F. tularensis induced PGE2 synthesis. We demonstrated that STAT1-/- macrophages and macrophages treated with Ag490 (a JAK2 inhibitor) were unable to synthesize PGE2 in response to F. tularensis. These data suggest the involvement of the JAK/STAT pathway in the synthesis of PGE2.
Trypanosoma cruzi regulates the defensin alpha-1 interactome network and defensin alpha-1 causes trypanosome membrane pore formation to control the early process of infection. (56.30)
Authors: Johnson Candice , Kleshchenko Yulia , Furtak Vyachslav , Nde Pius , Pratap Siddharth , Madison Nia , Lima Maria , Villalta Fernando 
Published: January 2023

Abstract
The interactome networks of innate immune molecules operating in the early process of Trypanosoma cruzi infection of human cells are unknown. Here we show that T. cruzi regulates the defensin alpha-1 interactome network and that human defensin alpha-1 plays a fundamental role in the initiation of cellular responses to T. cruzi. We demonstrate that human epithelial cells respond to early infection by up regulating the expression and secretion of defensin alpha-1, which causes trypanosome membrane pore formation and depolarization to inhibit T. cruzi motility, which prevents cellular infection. The pores formed in the flagellar membrane of the invasive trypanosomes cause the detachment of the flagellum from the trypanosome body to abolish trypanosome motility, which is required for trypanosome cell entry. This is the first report elucidating the defensin alpha-1 interactome network and showing that defensin alpha-1 disrupts the T. cruzi flagellum to compromise trypanosome motility and prevent cellular infection. Thus, defensin alpha-1 possesses remarkably distinct modes of activity against protozoan parasites than bacteria and viruses, and its actions may provide insights for the development of new anti-trypanosomal strategies. This work was supported by NIH grants AI080580 and AI007281.
Ecto-5′-nucleotidase (CD73) decreases mortality and organ injury in sepsis (56.31)
Authors: Németh Zoltán , Csóka Balázs , Koscsó Balázs , Spolarics Zoltán , Rolandelli Rolando , Haskó György 
Published: January 2023

Abstract
The extracellular concentrations of adenosine are elevated during sepsis and adenosine receptors regulate the host’s response to sepsis. Here, we investigated the role of the adenosine generating ectoenzyme, ecto-5'-nucleotidase (CD73) in regulating immune and organ function during sepsis. Polymicrobial sepsis was induced by subjecting CD73 knockout (KO) and wild type (WT) mice to cecal ligation and puncture. CD73 KO mice showed increased mortality in comparison with WT mice, which was associated with increased bacterial counts and elevated inflammatory cytokine and chemokine concentrations in the blood and peritoneum. CD73 deficiency promoted lung injury as indicated by increased myeloperoxidase activity and neutrophil infiltration, and elevated pulmonary cytokine levels. CD73 KO mice had increased apoptosis in the thymus, as evidenced by increased activation of caspase-3, poly(ADP-ribose) polymerase and NF-κB. Septic CD73 KO mice had higher blood urea nitrogen levels and elevated cytokine levels in the kidney, indicating increased renal dysfunction. The increased kidney injury of CD73 KO mice was associated with augmented activation of p38 MAPK and decreased phosphorylation of Akt. Pharmacological inactivation of CD73 in WT mice using AMPCP augmented cytokine levels in the blood and peritoneal lavage fluid. These findings suggest that CD73-derived adenosine may be beneficial in sepsis.
SOCS molecules are upregulated during IL-4-induced inhibition of Type I interferon responses in murine myeloid dendritic cells. (57.23)
Authors: Sriram Uma , Xu Jun , Varghese Linda , Bennett Heather , Shivers Debra , Gallucci Stefania 
Published: January 2023

Abstract
We have previously reported that IL-4 suppresses the response of murine myeloid dendritic cells (mDCs) to Type I interferons (IFN). We are now investigating the molecular mechanisms of this inhibition in myeloid bone marrow-derived DCs (BMDCs). We have found that sub-optimal doses of IL-4 (down to 0.25ng/mL) can still suppress IFN-a induced gene expression and phosphorylation of STAT1 and STAT2, suggesting that IL-4 acts at the level or upstream of STAT molecules in the Type I IFN signaling pathway. IL-4 suppresses when administered before and also after Type I IFN stimulation and it inhibits the response of DCs to the autocrine IFN-b that is induced upon IFN-a stimulation, acting on its positive feedback loop. The inhibition of protein synthesis by Cyclohexamide (CHX) abrogated the suppressive effects of IL-4 indicating that IL-4 represses Type I IFN signaling through the upregulation of a protein. We then tested the expression of the SOCS molecules as immediate candidates that negatively regulate Type I IFN signaling and are regulated at the transcription level. The gene expression of SOCS-1was highly induced by IL-4 treatment and was synergistically upregulated in the presence of IL-4 and IFN-a; the levels drastically went down when DCs were pretreated with CHX, suggesting that SOCS-1 maybe one of the key players in suppressing the IFN responses. We are currently testing this hypothesis by silencing SOCS-1 expression in DCs.