A Vaccine Based on Kunitz-Type Molecule Confers Protection Against Fasciola hepatica Challenge by Inducing IFN-γ and Antibody Immune Responses Through IL-17A Production

Dairy calves are unable to mount an effective immune response during their first weeks of life, which contributes to increased disease susceptibility during this period. Oxidative stress (OS) diminishes the immune cell capabilities of humans and adult cows, and dairy calves also experience OS during their first month of life. However, the impact that OS may have on neonatal calf immunity remains unexplored. Thus, we aimed to evaluate the impact of OS on newborn calf lymphocyte functions. For this, we conducted two experiments. First, we assessed the association of OS status throughout the first month of age and the circulating concentrations of the cytokines interferon-gamma (IFN-γ) and interleukin (IL) 4, as well as the expression of cytokine-encoding genes IFNG, IL2, IL4, and IL10 in peripheral mononuclear blood cells (PBMCs) of 12 calves. Subsequently, we isolated PBMCs from another 6 neonatal calves to investigate in vitro the effect of OS on immune responses in terms of activation of lymphocytes, cytokine expression, and antibody production following stimulation with phorbol 12-myristate 13-acetate or bovine herpesvirus-1. The results were compared statistically through mixed models. Calves exposed to high OS status in their first month of age showed higher concentrations of IL-4 and expression of IL4 and IL10 and lower concentrations of IFN-γ and expression of IFNG and IL2 than calves exposed to lower OS. In vitro, OS reduced lymphocyte activation, production of antibodies, and protein and gene expression of key cytokines. Collectively, our results demonstrate that OS can compromise some immune responses of newborn calves. Hence, further studies are needed to explore the mechanisms of how OS affects the different lymphocyte subsets and the potential of ameliorating OS in newborn calves as a strategy to augment the functional capacity of calf immune cells, as well as enhance calves’ resistance to infections.

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CKD-506: A novel HDAC6-selective inhibitor that exerts therapeutic effects in a rodent model of multiple sclerosis

Scientific Reports ◽

10.1038/s41598-021-93232-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daekwon Bae ◽

Ji-Young Lee ◽

Nina Ha ◽

Jinsol Park ◽

Jiyeon Baek ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Immune Responses ◽

Therapeutic Potential ◽

Autoimmune Encephalitis ◽

Selective Inhibitor ◽

Therapeutic Effects ◽

Treatment Regimens ◽

Ifn Γ ◽

Experimental Autoimmune

AbstractDespite advances in therapeutic strategies for multiple sclerosis (MS), the therapy options remain limited with various adverse effects. Here, the therapeutic potential of CKD-506, a novel HDAC6-selective inhibitor, against MS was evaluated in mice with myelin oligodendrocyte glycoprotein35–55 (MOG35–55)-induced experimental autoimmune encephalitis (EAE) under various treatment regimens. CKD-506 exerted prophylactic and therapeutic effects by regulating peripheral immune responses and maintaining blood–brain barrier (BBB) integrity. In MOG35–55-re-stimulated splenocytes, CKD-506 decreased proliferation and downregulated the expression of IFN-γ and IL-17A. CKD-506 downregulated the levels of pro-inflammatory cytokines in the blood of EAE mice. Additionally, CKD-506 decreased the leakage of intravenously administered Evans blue into the spinal cord; CD4+ T cells and CD4−CD11b+CD45+ macrophage/microglia in the spinal cord was also decreased. Moreover, CKD-506 exhibited therapeutic efficacy against MS, even when drug administration was discontinued from day 15 post-EAE induction. Disease exacerbation was not observed when fingolimod was changed to CKD-506 from day 15 post-EAE induction. CKD-506 alleviated depression-like behavior at the pre-symptomatic stage of EAE. In conclusion, CKD-506 exerts therapeutic effects by regulating T cell- and macrophage-mediated peripheral immune responses and strengthening BBB integrity. Our results suggest that CKD-506 is a potential therapeutic agent for MS.

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Evidence for Differential Roles for NKG2D Receptor Signaling in Innate Host Defense against Coronavirus-Induced Neurological and Liver Disease

Journal of Virology ◽

10.1128/jvi.02032-07 ◽

2007 ◽

Vol 82 (6) ◽

pp. 3021-3030 ◽

Cited By ~ 16

Author(s):

Kevin B. Walsh ◽

Melissa B. Lodoen ◽

Robert A. Edwards ◽

Lewis L. Lanier ◽

Thomas E. Lane

Keyword(s):

Liver Disease ◽

Immune Responses ◽

Host Defense ◽

Nk Cell ◽

Hepatitis Virus ◽

Innate Immune ◽

Liver Pathology ◽

Innate Immune Responses ◽

Ifn Γ ◽

The Brain

ABSTRACT Infection of SCID mice with a recombinant murine coronavirus (mouse hepatitis virus [MHV]) expressing the T-cell chemoattractant CXC chemokine ligand 10 (CXCL10) resulted in increased survival and reduced viral burden within the brain and liver compared to those of mice infected with an isogenic control virus (MHV), supporting an important role for CXCL10 in innate immune responses following viral infection. Enhanced protection in MHV-CXCL10-infected mice correlated with increased gamma interferon (IFN-γ) production by infiltrating natural killer (NK) cells within the brain and reduced liver pathology. To explore the underlying mechanisms associated with protection from disease in MHV-CXCL10-infected mice, the functional contributions of the NK cell-activating receptor NKG2D in host defense were examined. The administration of an NKG2D-blocking antibody to MHV-CXCL10-infected mice did not reduce survival, dampen IFN-γ production in the brain, or affect liver pathology. However, NKG2D neutralization increased viral titers within the liver, suggesting a protective role for NKG2D signaling in this organ. These data indicate that (i) CXCL10 enhances innate immune responses, resulting in protection from MHV-induced neurological and liver disease; (ii) elevated NK cell IFN-γ expression in the brain of MHV-CXCL10-infected mice occurs independently of NKG2D; and (iii) NKG2D signaling promotes antiviral activity within the livers of MHV-infected mice that is not dependent on IFN-γ and tumor necrosis factor alpha secretion.

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Inmunidad Celular en Ganado Vacuno Lechero Naturalmente Infectado con Fasciola hepatica en Cajamarca, Perú

Revista de Investigaciones Veterinarias del Perú ◽

10.15381/rivep.v26i4.11210 ◽

2015 ◽

Vol 26 (4) ◽

pp. 637

Author(s):

Heber Silva-Díaz ◽

Cristian Hobán-Vergara ◽

Rosmery Cruz-Cerna ◽

Hugo Solana ◽

Pedro Ortiz-Oblitas

Keyword(s):

Fasciola Hepatica ◽

Ifn Γ

La fasciolosis producida por Fasciola hepatica es una importante enfermedad parasitaria de la ganadería en muchos países. En Cajamarca, Perú, se reportan prevalencias superiores al 80% en el ganado lechero. El objetivo del estudio fue evaluar la capacidad de proliferación y la expresión de citoquinas (IFN-γ e IL-4) en células mononucleares de sangre periférica de terneras y vacas naturalmente infectadas, contra el antígeno no específico fitohemaglutinina y los antígenos específicos de excreción-secreción del estadio inmaduro y maduro de F. hepatica. La capacidad proliferativa fue determinada por linfoproliferación in vitro y la expresión de citoquinas se evaluó en sobrenadantes de cultivo celular por la técnica de ELISA. Las vacas infectadas con F. hepatica mostraron una disminución de la capacidad de respuesta frente a estímulos proliferativos inespecíficos y específicos. En el perfil de citoquinas contra el estímulo específico se encontró una baja expresión de IFN-γ, mientras que la respuesta de IL-4 fue alta, lo que indica que la respuesta permanece polarizada hacia una respuesta de tipo Th2. En el análisis comparativo, las terneras expresaron niveles de IFN-γ más altos que los valores obtenidos en las vacas, pero con una expresión similar de IL-4. No se observaron diferencias en la respuesta inmune a los antígenos del estadio inmaduro y maduro del parásito. Los resultados demuestran que a medida que la enfermedad progresa se expresa una respuesta inmunomoduladora en los animales adultos naturalmente infectados con F. hepatica.

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Abstract 116: Detrimental Role of Toll-Like Receptor 4 in Cardiovirus-Induced Myocarditis

Circulation Research ◽

10.1161/res.111.suppl_1.a116 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Fumitaka Sato ◽

Seiichi Omura ◽

Nicholas E Martinez ◽

Eiichiro Kawai ◽

Ganta V Chaitanya ◽

...

Keyword(s):

Immune Responses ◽

Acute Phase ◽

Viral Entry ◽

Viral Myocarditis ◽

Chronic Phase ◽

Enzyme Linked Immunosorbent Assay ◽

Tlr4 Ligand ◽

Ifn Γ ◽

Deficient Mice

Picornavirus infections have been known as a leading cause of viral myocarditis in humans. Theiler’s murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae and was reported to cause inflammation in the heart in one manuscript, while its pathomechanism is unclear. In viral myocarditis, viral replication in the heart and/or immune responses against virus as well as heart-antigen (autoimmunity) can contribute to the pathogenesis. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that are important for recognizing pathogens as well as triggering innate immunity. Among TLRs, TLR4 has been demonstrated to play important roles in virus-mediated pathology: 1) TLR4 can contribute to viral entry in some viruses, 2) TLR4 may mediate tissue damage by anti-virus immune responses (immunopathology), 3) high levels of TLR4 expression were observed in the heart of patients with dilated cardiomyopathy following acute viral myocarditis, and 4) some viruses can bind to lipopolysaccharide (LPS), which is a TLR4 ligand. To determine the role of TLR4 in TMEV-induced myocarditis, we infected male C3H/HeJ (TLR4-deficient) and C3H/HeNtac (control TLR4+) mice with the DA strain of TMEV. We harvested the hearts and spleens on days 6 and 7 (acute phase) or days 63 and 64 (chronic phase) post-infection. Cardiac pathology was evaluated by hematoxylin and eosin staining and production of pro-inflammatory cytokines, interleukin (IL)-17A and interferon (IFN)-γ, from spleen cells was measured by an enzyme-linked immunosorbent assay (ELISA). In both mice, mild myocarditis was observed during the acute phase of TMEV infection. During the chronic phase, both mice developed severe pathology in the heart, including basophilic degeneration and calcification. However, the incidence of myocarditis was higher in control mice than TLR4-deficient mice. IL-17A and IFN-γ production was higher in control mice than in TLR4-deficient mice (control vs. TLR4-deficient mice, acute phase: IL-17A, 196 vs. 146 pg/ml; IFN-γ, 72 vs. 39 ng/ml; chronic phase: IL-17A, 290 vs. 229 pg/ml; IFN- γ, 142 vs. 88 ng/ml). These results suggest that TLR4 may be detrimental in TMEV-induced myocarditis by increasing pro-inflammatory cytokine production.

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Gamma Interferon Produced by Antigen-Specific CD4+ T Cells Regulates the Mucosal Immune Responses to Citrobacter rodentium Infection

Infection and Immunity ◽

10.1128/iai.01343-09 ◽

2010 ◽

Vol 78 (6) ◽

pp. 2653-2666 ◽

Cited By ~ 45

Author(s):

Hideyuki Shiomi ◽

Atsuhiro Masuda ◽

Shin Nishiumi ◽

Masayuki Nishida ◽

Tetsuya Takagawa ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Gamma Interferon ◽

Immune Defense ◽

Interleukin 4 ◽

Mucosal Inflammation ◽

Citrobacter Rodentium ◽

Macrophage Phagocytosis ◽

Ifn Γ ◽

Deficient Mice

ABSTRACT Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the surface of intestinal epithelial cells and causes mucosal inflammation. This bacterium is an ideal model for investigating pathogen-host immune interactions in the gut. It is well known that gene transcripts for Th1 cytokines are highly induced in colonic tissue from mice infected with C. rodentium. However, it remains to be seen whether the Th1 or Th2 cytokines produced by antigen-specific CD4+ T cells provide effective regulation of the host immune defense against C. rodentium infection. To investigate the antigen-specific immune responses, C. rodentium expressing ovalbumin (OVA-C. rodentium), a model antigen, was generated and used to define antigen-specific responses under gamma interferon (IFN-γ)-deficient or interleukin-4 (IL-4)-deficient conditions in vivo. The activation of antigen-specific CD4+ T cells and macrophage phagocytosis were evaluated in the presence of IFN-γ or IL-4 in vitro. IFN-γ-deficient mice exhibited a loss of body weight and a higher bacterial concentration in feces during OVA-C. rodentium infection than C57BL/6 (wild type) or IL-4-deficient mice. This occurred through the decreased efficiency of macrophage phagocytosis and the activation of antigen-specific CD4+ T cells. Furthermore, a deficiency in antigen-specific CD4+ T-cell-expressed IFN-γ led to a higher susceptibility to mucosal and gut-derived systemic OVA-C. rodentium infection. These results show that the IFN-γ produced by antigen-specific CD4+ T cells plays an important role in the defense against C. rodentium.

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Construction and characterization of recombinant vaccinia viruses co-expressing a respiratory syncytial virus protein and a cytokine

Journal of General Virology ◽

10.1099/0022-1317-82-9-2107 ◽

2001 ◽

Vol 82 (9) ◽

pp. 2107-2116 ◽

Cited By ~ 20

Author(s):

Teresa R. Johnson ◽

Julie E. Fischer ◽

Barney S. Graham

Keyword(s):

Respiratory Syncytial Virus ◽

Immune Responses ◽

Vaccinia Virus ◽

Antigen Expression ◽

Virus Protein ◽

Recombinant Vaccinia ◽

Vaccinia Viruses ◽

Ifn Γ ◽

Syncytial Virus ◽

The Impact

Recombinant vaccinia viruses are well-characterized tools that can be used to define novel approaches to vaccine formulation and delivery. While vector co-expression of immune mediators has enormous potential for optimizing the composition of vaccine-induced immune responses, the impact on antigen expression and vector antigenicity must also be considered. Co-expression of IL-4 increased vaccinia virus vector titres, while IFN-γ co-expression reduced vaccinia virus replication in BALB/c mice and in C57BL/6 mice infected with some recombinant viruses. Protection against respiratory syncytial virus (RSV) challenge was similar in mice immunized with vaccinia virus expressing RSV G glycoprotein and IFN-γ, even though the replication efficiency of the vector was diminished. These data demonstrate the ability of vector-expressed cytokine to influence the virulence of the vector and to direct the development of selected immune responses. This suggests that the co-expression of cytokines and other immunomodulators has the potential to improve the safety of vaccine vectors while improving the immunogenicity of vaccine antigens.

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SLAMF7 engagement super-activates macrophages in acute and chronic inflammation

10.1101/2020.11.05.368647 ◽

2020 ◽

Author(s):

Daimon P. Simmons ◽

Hung N. Nguyen ◽

Emma Gomez-Rivas ◽

Yunju Jeong ◽

Antonia F. Chen ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Immune Responses ◽

Inflammatory Cytokine ◽

Macrophage Activation ◽

Rna Seq ◽

Autocrine Signaling ◽

Tnf Α ◽

Activated Macrophage ◽

Ifn Γ ◽

Acute And Chronic Inflammation

AbstractMacrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a super-activated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression. Engaging this receptor drove an exuberant wave of inflammatory cytokine expression, and induction of TNF-α following SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients, but in gut macrophages from active Crohn’s disease patients and lung macrophages from severe COVID-19 patients. This suggests a central role for SLAMF7 in macrophage super-activation with broad implications in pathology.

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