Increased Cell-Free DNA Plasma Concentration Following Liver Transplantation Is Linked to Portal Hepatitis and Inferior Survival

Donor organ quality is crucial for transplant survival and long-term survival of patients after liver transplantation. Besides bacterial and viral infections, endogenous damage-associated molecular patterns (DAMPs) can stimulate immune responses. Cell-free DNA (cfDNA) is one such DAMP that exhibits highly proinflammatory effects via DNA sensors. Herein, we measured cfDNA after liver transplantation and found elevated levels when organs from resuscitated donors were transplanted. High levels of cfDNA were associated with high C-reactive protein, leukocytosis as well as granulocytosis in the recipient. In addition to increased systemic immune responses, portal hepatitis was observed, which was associated with increased interface activity and a higher numbers of infiltrating neutrophils and eosinophils in the graft. In fact, the cfDNA was an independent significant factor in multivariate analysis and increased concentration of cfDNA was associated with inferior 1-year survival. Moreover, cfDNA levels were found to be decreased significantly during the postoperative course when patients underwent continuous veno-venous haemofiltration. In conclusion, patients receiving livers from resuscitated donors were characterised by high postoperative cfDNA levels. Those patients showed pronounced portal hepatitis and systemic inflammatory responses in the short term leading to a high mortality. Further studies are needed to evaluate the clinical relevance of cfDNA clearance by haemoadsorption and haemofiltration in vitro and in vivo.

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Anti-viral properties of interferon beta treatment in patients with multiple sclerosis

Multiple Sclerosis Journal ◽

10.1191/1352458502ms794oa ◽

2002 ◽

Vol 8 (3) ◽

pp. 237-242 ◽

Cited By ~ 29

Author(s):

J Hong ◽

M V Tejada-Simon ◽

V M Rivera ◽

Y CQ Zang ◽

J Z Zhang

Keyword(s):

Multiple Sclerosis ◽

Treatment Efficacy ◽

Interferon Beta ◽

Viral Infections ◽

Human Herpesvirus ◽

Virion Protein ◽

Cell Free Dna ◽

Free Dna

Viral infections are potentially associated with the etiology and pathogenesis of multiple sclerosis (MS). It has been speculated that the treatment efficacy of interferon beta (IFN beta) in MS may relate to its anti-viral properties. The study was undertaken to evaluate the in vivo anti-viral effects of IFN beta-1a in patients with MS. Human herpesvirus-6 (HHV-6) was studied as an example for being a latent neurotropic virus. IFN beta used at concentrations of approximately 0.5 mg/ml was shown to significantly reduce in vitro HHV-6 replication in a susceptible T-cell line. Sera derived from 23 MS patients treated with IFN beta-1a were examined for serum cell-free DNA of HHV-6 as an indicator for viral replication and the reactivity of IgM antibodies to a recombinant HHV-6 virion protein containing a known immunoreactive region. The results were compared with those of control sera obtained from untreated MS (n=29) and healthy individuals (n=21). The findings indicated that IFN beta treatment significantly reduced HHV-6 replication as evident by decreased cell-free DNA in treated MS specimens. The results correlated with decreased IgM reactivity to the HHV-6 antigen in treated MS patients compared to untreated controls, suggesting reduced exposure to HHV-6. The findings were confirmed in paired sera obtained from seven MS patients before and after the treatment. The study provides new evidence indicating that IFN beta has potent in vivo anti-viral effects that may contribute to the treatment efficacy in MS.

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Positive regulation of plasmacytoid dendritic cell function via Ly49Q recognition of class I MHC

Journal of Experimental Medicine ◽

10.1084/jem.20080718 ◽

2008 ◽

Vol 205 (13) ◽

pp. 3187-3199 ◽

Cited By ~ 43

Author(s):

Lee-Hwa Tai ◽

Marie-Line Goulet ◽

Simon Belanger ◽

Noriko Toyama-Sorimachi ◽

Nassima Fodil-Cornu ◽

...

Keyword(s):

Immune Responses ◽

Cell Function ◽

Viral Infections ◽

Plasmacytoid Dendritic Cell ◽

Class I ◽

Type I ◽

Class I Mhc ◽

Mhc Molecules

Plasmacytoid dendritic cells (pDCs) are an important source of type I interferon (IFN) during initial immune responses to viral infections. In mice, pDCs are uniquely characterized by high-level expression of Ly49Q, a C-type lectin-like receptor specific for class I major histocompatibility complex (MHC) molecules. Despite having a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, Ly49Q was found to enhance pDC function in vitro, as pDC cytokine production in response to the Toll-like receptor (TLR) 9 agonist CpG-oligonucleotide (ODN) could be blocked using soluble monoclonal antibody (mAb) to Ly49Q or H-2Kb. Conversely, CpG-ODN–dependent IFN-α production by pDCs was greatly augmented upon receptor cross-linking using immobilized anti-Ly49Q mAb or recombinant H-2Kb ligand. Accordingly, Ly49Q-deficient pDCs displayed a severely reduced capacity to produce cytokines in response to TLR7 and TLR9 stimulation both in vitro and in vivo. Finally, TLR9-dependent antiviral responses were compromised in Ly49Q-null mice infected with mouse cytomegalovirus. Thus, class I MHC recognition by Ly49Q on pDCs is necessary for optimal activation of innate immune responses in vivo.

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Natural Killer Cells and Mast Cells from gp49B Null Mutant Mice Are Functional

Molecular and Cellular Biology ◽

10.1128/mcb.20.19.7178-7182.2000 ◽

2000 ◽

Vol 20 (19) ◽

pp. 7178-7182 ◽

Cited By ~ 14

Author(s):

Susana Rojo ◽

Christopher C. Stebbins ◽

Mary E. Peterson ◽

David Dombrowicz ◽

Nicolai Wagtmann ◽

...

Keyword(s):

Mast Cells ◽

Immune Responses ◽

Nk Cells ◽

Natural Killer ◽

Survival Rates ◽

Term Survival ◽

Effector Cells ◽

Null Mutant Mice

ABSTRACT Immune responses are controlled by a combination of positive and negative cellular signals. Effector cells in the immune system express inhibitory receptors that serve to limit effector cell expansion and to protect the host from autoreactivity. gp49B is a receptor of unknown function that is expressed on activated mast cells and natural killer (NK) cells and whose cytoplasmic tail endows it with inhibitory potential. To gain insight into the function of gp49B in mice, we disrupted the gp49B gene by homologous recombination. gp49B0 mice were born at expected ratios, were healthy and fertile, and displayed normal long-term survival rates. gp49B0 mice showed no defect in NK or mast cell development. Furthermore, NK and mast cells from the gp49B0mice showed activation properties in vitro similar to those of cells isolated from wild-type mice. Therefore, gp49B is not critical for the development, expansion, and maturation of mast cells and NK cells in vivo. The healthy status of gp49B0 mice makes them suitable for testing the role of gp49B in immune responses to infectious agents.

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MicroRNA-141-3p Attenuates Oxidative Stress-induced Hepatic Ischemia Reperfusion Injury via Keap1/Nrf2 Pathway

10.21203/rs.3.rs-1107846/v1 ◽

2021 ◽

Author(s):

Tingting Li ◽

Qingsong Chen ◽

Jiangwen Dai ◽

Zuotian Huang ◽

Yunhai Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Transplantation ◽

Reperfusion Injury ◽

Inflammatory Responses ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Hepatic Ischemia ◽

Hepatic Ischemia Reperfusion

Abstract Hepatic ischemia reperfusion injury (IRI) is a major factor affecting the prognosis of liver transplantation through a series of severe cell death and inflammatory responses. MicroRNA-141-3p (miR-141-3p) has been reported to be associated with hepatic steatosis and other liver diseases. However, the potential role of miR-141-3p in hepatic IRI is currently unknown. In the present study, we found that miR-141-3p levels were negatively correlated with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) in liver transplantation patients. The results demonstrated that miR-141-3p was decreased in mouse liver tissue after hepatic IRI in mice and in hepatocytes after hypoxia/reoxygenation (H/R). Overexpression of miR-141-3p directly decreased Kelch-like ECH-associated protein 1 (Keap1) levels and attenuated cell apoptosis in vivo and in vitro, while inhibition of miR-141-3p facilitated apoptosis. Further experiments revealed that overexpression of miR-141-3p also attenuated oxidative stress-induced damage in hepatocytes under H/R conditions. Taken together, our results indicate that miR-141-3p plays a major role in hepatic IRI through the Keap1 signaling pathway, and the present study suggests that miR-141-3p might have a protective effect on hepatic IRI to some extent.

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A novel recombinant protein vaccine containing the different E7 proteins of the HPV16, 18, 6, 11 E7 linked to the HIV-1 Tat (47-57) improve cytotoxic immune responses

10.21203/rs.3.rs-195613/v1 ◽

2021 ◽

Author(s):

Tahoora Mousavi ◽

Reza Valadan ◽

Alireza Rafiei ◽

Ali Abbasi ◽

Mohammad Reza Haghshenas

Keyword(s):

T Cell ◽

Immune Responses ◽

Fusion Protein ◽

Protein Vaccine ◽

Term Survival ◽

Ifn Γ ◽

E7 Proteins ◽

Hiv 1

Abstract Objectives Human papillomavirus infection (HPV) is the most common viral infection which is causes of cervical, penal, vulvar, anal and, oropharyngeal cancer. E7 protein of HPV is a suitable target for induction of T cell responses and controlling HPV-related cancer. The aim of the current study was to designed and evaluated a novel fusion protein containing the different E7 proteins of the HPV 16, 18, 6 and 11, linked to the cell-penetrating peptide HIV-1 Tat 49-57, in order to improve cytotoxic immune responses in in-vitro and in-vivo. Results In this study whole sequence of HPV16,18,6,11 E7-Tat (47-57) and HPV16,18,6,11 E7 cloned into the vector and expressed in E.coli (BL21). The purified protein was confirmed by SDS page and western blotting and then injected into the C57BL/6 mice. The efficiency of the fusion protein vaccine was assessed by antibody response assay, cytokine assay (IL-4 and IFN-γ), CD+8 cytotoxicity assay and tumor challenge experiment. Result showed that fusion proteins containing Adjuvant (IFA,CFA) could express higher titer of antibody. Also, we showed that vaccination with E7-Tat and, E7-Tat-ADJ induced high frequencies of E7-specific CD8+ T cells and CD107a expression as well as IFN-γ level and enhanced long-term survival in the therapeutic animal models. Conclusion Our finding suggested that this novel fusion protein vaccine was able to induce therapeutic efficacy and immunogenicity by improving CD8+ T cell in TC-1 tumor bearing mice; so this vaccine may be appreciated for research against HPV and tumor immunotherapies.

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A Novel Recombinant Protein Vaccine Containing the Different E7 Proteins of the HPV16, 18, 6, 11 E7 Linked to the HIV-1 Tat (47-57) Improve Cytotoxic Immune Responses

10.21203/rs.3.rs-106264/v1 ◽

2020 ◽

Author(s):

Tahoora Mousavi ◽

Reza Valadan ◽

Alireza Rafiei ◽

Ali Abbasi ◽

Mohammad Reza Haghshenas

Keyword(s):

T Cell ◽

Immune Responses ◽

Fusion Protein ◽

Protein Vaccine ◽

Term Survival ◽

Ifn Γ ◽

E7 Proteins ◽

Hiv 1

Abstract Objective: Human papillomavirus infection (HPV) is the most common viral infection which is causes of cervical, penal, vulvar, anal and, oropharyngeal cancer. E7 protein of HPV is a suitable target for induction of T cell responses and controlling HPV-related cancer. The aim of the current study was to designed and evaluated a novel fusion protein containing the different E7 proteins of the HPV 16, 18, 6 and 11, linked to the cell-penetrating peptide HIV-1 Tat 49-57, in order to improve cytotoxic immune responses in in-vitro and in-vivo. Methods: In this study whole sequence of HPV16,18,6,11 E7-Tat (47-57) and HPV16,18,6,11 E7 cloned into the vector and expressed in E.coli (BL21). The purified protein was confirmed by SDS page and western blotting and then injected into the C57BL/6 mice. The efficiency of the fusion protein vaccine was assessed by antibody response assay, cytokine assay (IL-4 and IFN-γ), CD+8 cytotoxicity assay and tumor challenge experiment. Results: Result showed that fusion proteins containing Adjuvant (IFA,CFA) could express higher titer of antibody. Also, we showed that vaccination with E7-Tat and, E7-Tat-ADJ induced high frequencies of E7-specific CD8+ T cells and CD107a expression as well as IFN-γ level and enhanced long-term survival in the therapeutic animal models. Conclusion: Our finding suggested that this novel fusion protein vaccine was able to induce therapeutic efficacy and immunogenicity by improving CD8+ T cell in TC-1 tumor bearing mice; so this vaccine may be appreciated for research against HPV and tumor immunotherapies.

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Inhibition of Type 1 Cytokine–mediated Inflammation by a Soluble CD30 Homologue Encoded by Ectromelia (Mousepox) Virus

Journal of Experimental Medicine ◽

10.1084/jem.20020319 ◽

2002 ◽

Vol 196 (6) ◽

pp. 829-839 ◽

Cited By ~ 73

Author(s):

Margarida Saraiva ◽

Philip Smith ◽

Padraic G. Fallon ◽

Antonio Alcami

Keyword(s):

Viral Infections ◽

Inflammatory Responses ◽

Severe Disease ◽

Interferon Γ ◽

Reverse Signaling ◽

Soluble Cd30

CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon γ–producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30–CD30L interactions in the generation of inflammatory responses.

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Positive and Negative Regulation of Cellular Immune Responses in Physiologic Conditions and Diseases

Clinical and Developmental Immunology ◽

10.1155/2012/485781 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 27

Author(s):

S. Viganò ◽

M. Perreau ◽

G. Pantaleo ◽

A. Harari

Keyword(s):

Immune Response ◽

T Cells ◽

Immune System ◽

T Cell ◽

Immune Responses ◽

Viral Infections ◽

Therapeutic Interventions ◽

Cellular Immune

The immune system has evolved to allow robust responses against pathogens while avoiding autoimmunity. This is notably enabled by stimulatory and inhibitory signals which contribute to the regulation of immune responses. In the presence of a pathogen, a specific and effective immune response must be induced and this leads to antigen-specific T-cell proliferation, cytokines production, and induction of T-cell differentiation toward an effector phenotype. After clearance or control of the pathogen, the effector immune response must be terminated in order to avoid tissue damage and chronic inflammation and this process involves coinhibitory molecules. When the immune system fails to eliminate or control the pathogen, continuous stimulation of T cells prevents the full contraction and leads to the functional exhaustion of effector T cells. Several evidences bothin vitroandin vivosuggest that this anergic state can be reverted by blocking the interactions between coinhibitory molecules and their ligands. The potential to revert exhausted or inactivated T-cell responses following selective blocking of their function made these markers interesting targets for therapeutic interventions in patients with persistent viral infections or cancer.

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Real-Time In Vivo Biodistribution of Multipotent Adult Progenitor Cells (MAPC): Role of the Immune System in MAPC Resistance in Non-Transplanted and Bone Marrow Transplanted Mice.

Blood ◽

10.1182/blood.v104.11.507.507 ◽

2004 ◽

Vol 104 (11) ◽

pp. 507-507

Author(s):

Jakub Tolar ◽

Scott Bell ◽

Ron McElmurry ◽

Lily Xia ◽

R. Scott McIvor ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Nk Cells ◽

Nk Cell ◽

Sleeping Beauty ◽

Whole Body ◽

Term Survival ◽

Hematopoietic Stem

Abstract MAPC are non-hematopoietic stem cells derived from adult BM with the potential for a wide differentiation pattern in vitro and in vivo. MAPCs are MHC class I and thus may be a target of natural killer (NK) cell mediated elimination in the syngeneic setting. To determine whether MAPC are susceptible targets for NK mediated killing, splenocytes from poly I:C (an inducer of NK activity) treated C57BL/6 mice were mixed with Yac-1 (H2a; a NK sensitive target) or MAPC (from C57BL/6J-rosa26) in a chromium release assay. Effector:target ratios indicated that MAPC were susceptible to NK lysis albeit less so than Yac-1 cells. To assess in vivo immune responses to MAPC, we infused MAPC into mice with various degrees of T-, B-, and NK- cell immune competence. To follow biodistribution of MAPC in live animals with whole body imaging (WBI), we labeled MAPC with red fluorescent protein DsRed2 and luciferase, using Sleeping Beauty transposons. MAPC (106) were co-nucleofected (Amaxa) with 5mcg of each pT/CAGGS-DsRed2 and pT/CAGGS-Luciferase and an SB transposase-encoding plasmid (p/CMV-HSB2) at a 1:50 ratio. Selected double transgenic MAPC (MAPC DL) clones were euploid, and maintained their characteristic trilineage differentiation. MAPC DL (106) were injected IV into cohorts (n=5–6) of adult C57BL/6 (B6), Rag2−/− (T- and B-cell deficient) and B6 Rag2/IL-2Rgc (T-, B- and NK deficient mice). Additional cohorts of B6 and Rag2−/− were given anti-NK1.1 mAb 2x/wk to deplete NK cells. In B6 mice, MAPC DL were detected on d4 but not d14 or d30. In Rag2−/− mice, MAPC DL were detected throughout the 30d period. NK depletion did not substantially increase MAPC DL number in B6 mice. However, in Rag2/IL-2Rgc mice MAPC DL were persistent and in 50% of mice they increased in number from d4‡d30. Post-mortem analysis revealed MAPC DL cells in all but B6 wild type mice: Rag2/IL-2Rgc ≥ Rag2−/− with NK depletion>> Rag2−/−. These data suggest that endogenous NK cells and T cells resist MAPC DL. Interestingly, in vitro studies indicate that MAPCs suppress an allogeneic mixed lymphocyte reaction (MLR) culture. Therefore, the T cell resistance to MAPC may be due to an immune response generated to the multiple foreign reporter proteins expressed by these cells. Since MAPCs may be useful as cellular therapies for the treatment of regimen-related toxicity, studies were performed in which B10.BR mice were lethally irradiated (TBI) and given B6 BM ± MAPC DL (106). MAPC DL were seen in the chest, abdomen, face, and paws on d4, d7, d10 and d28 at high numbers suggesting that TBI conditioning overcomes both NK and T cell mediated resistance resuting in a widespread homing/migration of MAPC. These data are the first to illustrate the immune responses to MAPCs and indicate that TBI conditioning may be advantageous in the long-term survival and widespread homing of MAPCs.

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Chrysophyllum cainito: A Tropical Fruit with Multiple Health Benefits

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7259267 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Hau V. Doan ◽

Thao P. Le

Keyword(s):

Human Health ◽

Leaf Extract ◽

Viral Infections ◽

Inflammatory Responses ◽

Biological Effects ◽

Antioxidant Properties ◽

Tropical Fruit ◽

Chrysophyllum Cainito

Chrysophyllum cainito is a tropical fruit tree with multiple benefits to human health. C. cainito possesses strong antioxidant properties either in vitro or in vivo. Extracts from the leaves, stem bark, fruits, peel, pulp, or seed of C. cainito are promising candidates in traditional medicine for curing diabetes and fighting against bacterial, fungal, and viral infections. C. cainito leaf extract alone or in a complex formula exhibits anti-inflammatory responses by reducing hypersensitivity, acts as inflammatory markers, and has antinociceptive effects. The leaf extract also increases wound healing speed and assists in regulating fat uptake. In addition, the C. cainito fruit shows anticancer activity against osteosarcoma. In conclusion, the aerial parts of C. cainito have strong beneficial biological effects on human health.

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