scholarly journals Helper-Dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses In Vivo

2004 ◽  
Vol 78 (11) ◽  
pp. 5966-5972 ◽  
Author(s):  
Daniel A. Muruve ◽  
Matthew J. Cotter ◽  
Anne K. Zaiss ◽  
Lindsay R. White ◽  
Qiang Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Second Phase ◽  
Liver Inflammation ◽  
Adaptive Immune Responses ◽  
Necrosis Factor Alpha ◽  
Host Immune Responses ◽  
Animal Models Of Disease ◽  
Adaptive Immune

ABSTRACT Helper-dependent adenovirus (HD-Ad) vectors with all adenoviral genes deleted mediate very long-term expression of therapeutic transgenes in a variety of animal models of disease. These vectors are associated with reduced toxicity and improved safety relative to traditional early region 1 deletion first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad vectors induce innate and adaptive immune responses in vivo; however, a comprehensive analysis of host immune responses to HD-Ad vectors has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad vectors encoding LacZ (HD-AdLacZ) or a murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including interferon-inducible protein 10, macrophage inflammatory protein 2, and tumor necrosis factor alpha, and were expressed in a pattern similar to that induced by FG-Ad vectors encoding AdSEAP. Like AdSEAP, and consistent with the pattern of cellular gene expression, HD-AdLacZ and HD-AdSEAP induced the recruitment of CD11b-positive leukocytes to the transduced liver within hours of administration. AdSEAP also induced a second phase of liver inflammation, consisting of inflammatory gene expression and CD3-positive lymphocytic infiltrates 7 days posttransduction. In contrast, beyond 24 h no infiltrates or expression of inflammatory genes was detected in the livers of mice receiving HD-AdSEAP. Despite the lack of liver inflammation at 7 days, Ad-specific cytotoxic T lymphocytes could be detected in mice receiving HD-AdSEAP. This lack of liver inflammation was not due to reduced transduction since levels of transgene expression and the amounts of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad vectors induce intact innate but attenuated adaptive immune responses in vivo.

scholarly journals Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions

2009 ◽  
Vol 206 (13) ◽  
pp. 3101-3114 ◽  
Author(s):  
Olga Schulz ◽  
Elin Jaensson ◽  
Emma K. Persson ◽  
Xiaosun Liu ◽  
Tim Worbs ◽  
...  
Keyword(s):  
Immune Responses ◽  
Direct Injection ◽  
Turnover Rates ◽  
Mesenteric Lymph Nodes ◽  
Adaptive Immune Responses ◽  
Cell Functions ◽  
Adaptive Immune ◽  
Inflammatory Conditions

Chemokine receptor CX3CR1+ dendritic cells (DCs) have been suggested to sample intestinal antigens by extending transepithelial dendrites into the gut lumen. Other studies identified CD103+ DCs in the mucosa, which, through their ability to synthesize retinoic acid (RA), appear to be capable of generating typical signatures of intestinal adaptive immune responses. We report that CD103 and CX3CR1 phenotypically and functionally characterize distinct subsets of lamina propria cells. In contrast to CD103+ DC, CX3CR1+ cells represent a nonmigratory gut-resident population with slow turnover rates and poor responses to FLT-3L and granulocyte/macrophage colony-stimulating factor. Direct visualization of cells in lymph vessels and flow cytometry of mouse intestinal lymph revealed that CD103+ DCs, but not CX3CR1-expressing cells, migrate into the gut draining mesenteric lymph nodes (LNs) under steady-state and inflammatory conditions. Moreover, CX3CR1+ cells displayed poor T cell stimulatory capacity in vitro and in vivo after direct injection of cells into intestinal lymphatics and appeared to be less efficient at generating RA compared with CD103+ DC. These findings indicate that selectively CD103+ DCs serve classical DC functions and initiate adaptive immune responses in local LNs, whereas CX3CR1+ populations might modulate immune responses directly in the mucosa and serve as first line barrier against invading enteropathogens.

scholarly journals Severe Symptomatic Primary Human Cytomegalovirus Infection despite Effective Innate and Adaptive Immune Responses

2016 ◽  
Vol 91 (5) ◽  
Author(s):  
Raphaëlle Riou ◽  
Céline Bressollette-Bodin ◽  
David Boutoille ◽  
Katia Gagne ◽  
Audrey Rodallec ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Human Cytomegalovirus ◽  
Hcmv Infection ◽  
Cytokine Production ◽  
Lymphocyte Activation ◽  
Adaptive Immune Responses ◽  
Host Immune Responses ◽  
Adaptive Immune ◽  
Cell Compartments

ABSTRACT Primary human cytomegalovirus (HCMV) infection usually goes unnoticed, causing mild or no symptoms in immunocompetent individuals. However, some rare severe clinical cases have been reported without investigation of host immune responses or viral virulence. In the present study, we investigate for the first time phenotypic and functional features, together with gene expression profiles in immunocompetent adults experiencing a severe primary HCMV infection. Twenty primary HCMV-infected patients (PHIP) were enrolled, as well as 26 HCMV-seronegative and 39 HCMV-seropositive healthy controls. PHIP had extensive lymphocytosis marked by massive expansion of natural killer (NK) and T cell compartments. Interestingly, PHIP mounted efficient innate and adaptive immune responses with a deep HCMV imprint, revealed mainly by the expansion of NKG2C+ NK cells, CD16+ Vδ2(−) γδ T cells, and conventional HCMV-specific CD8+ T cells. The main effector lymphocytes were activated and displayed an early immune phenotype that developed toward a more mature differentiated status. We suggest that both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage observed in PHIP. Taken together, these findings bring new insights into the comprehensive understanding of immune mechanisms involved during primary HCMV infection in immunocompetent individuals. IMPORTANCE HCMV-specific immune responses have been extensively documented in immunocompromised patients and during in utero acquisition. While it usually goes unnoticed, some rare severe clinical cases of primary HCMV infection have been reported in immunocompetent patients. However, host immune responses or HCMV virulence in these patients has not so far been investigated. In the present study, we show massive expansion of NK and T cell compartments during the symptomatic stage of acute HCMV infection. The patients mounted efficient innate and adaptive immune responses with a deep HCMV imprint. The massive lymphocytosis could be the result of nonadapted or uncontrolled immune responses limiting the effectiveness of the specific responses mounted. Both massive lymphocytosis and excessive lymphocyte activation could contribute to massive cytokine production, known to mediate tissue damage. Furthermore, we cannot exclude a delayed immune response caused by immune escape established by HCMV strains.

scholarly journals Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5

2018 ◽  
Vol 215 (11) ◽  
pp. 2901-2918 ◽  
Author(s):  
Maria Buxadé ◽  
Hector Huerga Encabo ◽  
Marta Riera-Borrull ◽  
Lucía Quintana-Gallardo ◽  
Pilar López-Cotarelo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Cell Type ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Cell Type Specific ◽  
Antigen Presenting ◽  
Mhcii Expression

MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type–specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita. This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.

scholarly journals Undaria pinnatifida Fucoidan-Rich Extract Induces Both Innate and Adaptive Immune Responses

2019 ◽  
Vol 14 (8) ◽  
pp. 1934578X1987372
Author(s):  
Hwan H. Lee ◽  
Yoo J. Cho ◽  
Daeung Yu ◽  
Donghwa Chung ◽  
Gun-Hee Kim ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cd8 T Cells ◽  
Undaria Pinnatifida ◽  
Plasma Concentrations ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Ifn Γ

Fucoidans are widely used as an ingredient of dietary supplements. We investigated the immune stimulatory activities of Undaria pinnatifida ( Alariaceae) fucoidan-rich extract (UPF-RE) in vitro as well as in vivo . In vitro, the extract stimulated Raw 264.7 cells to produce significant nitric oxide (NO) metabolites and cytokines (TNF-α, IL-1α, IL-1β, and IL-6). It also induced the proliferation of primary mouse splenocytes and the secretion of IL-4, which correlated with the phosphorylation of Extracellular-signal-regulated kinase (ERK) protein. In in vivo experiments, first, 50 mg/kg of 3 different types of UPF-RE, DSU02, DSU02L (low molecular weight, <3 kDa), and DSU02H (high molecular weight, >10 kDa), were orally administered to C57BL/6 mice. After 14 days, the frequencies of CD3+, CD4+, and CD8+ T cells and NK cells from each group were analyzed. Plasma concentrations of TNF-α and IFN-γ were determined. The frequencies of CD3+ and CD4+ showed a statistically significant increase in splenocytes isolated from the DSU02 and DSU02H groups. Also, there was significant production of TNF-α and IFN-γ from the DSU02 group. Second, 3 different concentrations of DSU02 (50, 100, and 150 mg/kg) were orally administered. After 14 days, the proliferative capacity of CD3+, CD4+, and CD8+ T cells was investigated, and the plasma concentrations of IgM and total IgG were determined. Plasma concentration of IgM from the DSU02 150 mg/kg group was statistically significantly higher compared with that from the other groups. We suggest that UPF-RE could be a good candidate for a natural immune stimulator to induce innate as well as adaptive immune responses.

Differential Expression of Cow Innate and Adaptive Responses Genes in Response to Eugenol

2021 ◽  
Vol 99 (Supplement_2) ◽  
pp. 31-32
Author(s):  
Mulumebet worku ◽  
Bahrath Kumar ◽  
Hamid Ismail
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Regulation Of Gene Expression ◽  
Interferon Regulatory Factor ◽  
Farm Animals ◽  
Type I ◽  
Regulatory Factor ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Interferon Regulatory Factor 7

Abstract Dietary phytochemicals have both nutritional and health benefits for farm animals. Research on the immunomodulatory effects of phytochemicals may aid in developing novel therapeutic agents and provide insights into the regulation of gene expression. Eugenol (4-allyl-2-methoxyphenyl) is the active ingredient in clove oil that has been studied for its immunomodulatory/anti-inflammatory effects. The objective of this study was to evaluate the effect of eugenol on the expression of genes associated with the cow’s innate and adaptive immune responses. Blood was collected from (n = 3) clinically healthy Holstein-Friesian cows from the North Carolina A&T State University Dairy Unit. One milliliter of whole blood from three cows was treated individually with 10 ng/mL of Eugenol (Sigma-Aldrich St. Louis, MO), or maintained in PBS, incubated at 37ºC for 30 minutes. Total RNA was extracted, reverse transcribed, and real-time PCR was carried out using the RT2 Profiler™ human Innate & Adaptive Immune Responses PCR Array containing 84 genes, as recommended by the manufacturer (Qiagen). The Livak method was used to calculate fold change (FC &gt;2 considered significant). The analysis showed that 25 genes out of 84 genes were affected by treatment with eugenol. Among 25 genes, 19 were upregulated, and 2 genes were downregulated. The highest up-regulated and down-regulated genes following exposure to eugenol was IL23A and Interferon Regulatory Factor 7 (IRF7), respectively. The upregulation of the IL-23A gene expression by exogenous eugenol may be important in the production of pro-inflammatory cytokines and warrants further studies to investigate the mechanism involved. Interferon Regulatory Factor 7 is a critical regulator of type I interferon production and plays an important role in innate immune responses. The observed transcriptional expression of IL23A and IRF7 by eugenol provides an insight into immune modulation in cow blood.

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