scholarly journals Interferon γ Regulates Acute and Latent Murine Cytomegalovirus Infection and Chronic Disease of the Great Vessels

1998 ◽  
Vol 188 (3) ◽  
pp. 577-588 ◽  
Author(s):  
Rachel M. Presti ◽  
Jessica L. Pollock ◽  
Albert J. Dal Canto ◽  
Andrew K. O'Guin ◽  
Herbert W. Virgin
Keyword(s):  
Immune System ◽  
Chronic Disease ◽  
Interferon Γ ◽  
Murine Cytomegalovirus ◽  
Mcmv Infection ◽  
Great Vessels ◽  
Ifn Γ

To define immune mechanisms that regulate chronic and latent herpesvirus infection, we analyzed the role of interferon γ (IFN-γ) during murine cytomegalovirus (MCMV) infection. Lethality studies demonstrated a net protective role for IFN-γ, independent of IFN-α/β, during acute MCMV infection. Mice lacking the IFN-γ receptor (IFN-γR−/−) developed and maintained striking chronic aortic inflammation. Arteritis was associated with inclusion bodies and MCMV antigen in the aortic media. To understand how lack of IFN-γ responses could lead to chronic vascular disease, we evaluated the role of IFN-γ in MCMV latency. MCMV-infected IFN-γR−/− mice shed preformed infectious MCMV in spleen, peritoneal exudate cells, and salivary gland for up to 6 mo after infection, whereas the majority of congenic control animals cleared chronic productive infection. However, the IFN-γR was not required for establishment of latency. Using an in vitro explant reactivation model, we showed that IFN-γ reversibly inhibited MCMV reactivation from latency. This was at least partly explained by IFN-γ– mediated blockade of growth of low levels of MCMV in tissue explants. These in vivo and in vitro data suggest that IFN-γ regulation of reactivation from latency contributes to control of chronic vascular disease caused by MCMV. These studies are the first to demonstrate that a component of the immune system (IFN-γ) is necessary to regulate MCMV-associated elastic arteritis and latency in vivo and reactivation of a herpesvirus from latency in vitro. This provides a new model for analysis of the interrelationships among herpesvirus latency, the immune system, and chronic disease of the great vessels.

scholarly journals Immunity to pathogenic free-living amoebae: role of cell-mediated immunity

1980 ◽  
Vol 29 (2) ◽  
pp. 408-410
Author(s):  
R T Cursons ◽  
T J Brown ◽  
E A Keys ◽  
K M Moriarty ◽  
D Till
Keyword(s):  
Immune System ◽  
Inhibition Test ◽  
Delayed Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Pathogenic Species ◽  
Free Living

The role of cell-mediated immunity in defense against pathogenic free-living amoebae was examined. Both the in vitro macrophage inhibition test and the in vivo delayed hypersensitivity test showed responses to both heterologous and homologous antigens, although homologous systems were the most efficient. It is suggested that exposure to nonpathogenic species of free-living amoebae can stimulate the immune system to be effective against pathogenic species. The significance of cell-mediated immunity as a defense against invasion by pathogenic free-living amoebae is discussed.

scholarly journals Adoptive transfer of anti-cytomegalovirus effect of interleukin-2- activated bone marrow: potential application in transplantation

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 720-727 ◽  
Author(s):  
R Agah ◽  
BS Charak ◽  
V Chen ◽  
A Mazumder
Keyword(s):  
Bone Marrow ◽  
Interleukin 2 ◽  
Murine Cytomegalovirus ◽  
Mcmv Infection ◽  
Murine Bone Marrow ◽  
Therapeutic Setting ◽  
Infected Cells ◽  
Novel Strategy

Abstract This work is a continuation of our studies that showed that interleukin- 2 (IL-2)-activated murine bone marrow (ABM) cells have potent cytotoxic potential against murine cytomegalovirus (MCMV)-infected targets in vitro, without loss of reconstitutive ability in vivo. Our data show that ABM cells lyse the MCMV-infected cells in vitro, at both acute and chronic stages of infection; this lysis is specific for the MCMV- infected cells. ABM cells supplemented with IL-2 therapy virtually eradicated the viral infection and prolonged the survival of MCMV- infected Balb/c mice, whether or not they were immunocompromised by irradiation (P less than .001 in both situations). Efficacy of ABM cells alone or IL-2 alone was less than the combination of ABM cells and IL-2. The efficacy of combination treatment with ABM cells and IL-2 in improving the survival of MCMV-infected mice was comparable, whether used in a preventive or a therapeutic setting. Therapy with ABM plus IL- 2 also prevented the reactivation of chronic MCMV infection after irradiation. Preliminary findings indicate that Thy-1+ and asialo GM1+ cells limited the MCMV proliferation by approximately 30% and 80%, respectively, while BM macrophages limited the proliferation of MCMV by 100%. These results suggest that BM transplantation (BMT) with ABM cells followed by IL-2 therapy may constitute a novel strategy to improve the host resistance against cytomegalovirus infection after BMT.

scholarly journals Synergistic interactions between interferon-γ and TRAIL modulate c-FLIP in endothelial cells, mediating their lineage-specific sensitivity to thrombotic thrombocytopenic purpura plasma–associated apoptosis

Blood ◽  
2008 ◽  
Vol 112 (2) ◽  
pp. 340-349 ◽  
Author(s):  
Radu Stefanescu ◽  
Dustin Bassett ◽  
Rozbeh Modarresi ◽  
Francisco Santiago ◽  
Mohamad Fakruddin ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Interferon Γ ◽  
Microvascular Endothelial Cell ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Thrombocytopenic Purpura ◽  
Ifn Γ ◽  
Interfering Rna

Abstract Microvascular endothelial cell (MVEC) injury coupled to progression of platelet microthrombi facilitated by ADAMTS13 deficiency is characteristic of idiopathic and HIV-linked thrombotic thrombocytopenic purpura (TTP). Cytokines capable of inducing MVEC apoptosis in vitro are up-regulated in both TTP and HIV infection. However, the concentrations of these cytokines required to elicit EC apoptosis in vitro are 2- to 3-log–fold greater than present in patient plasmas. We report that clinically relevant levels of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and interferon (IFN)–γ act in synergy to induce apoptosis in dermal MVECs, but have no effect on large-vessel ECs or pulmonary MVECs. This reflects the tissue distribution of TTP lesions in vivo. Sensitivity to TTP plasma or TRAIL plus IFN-γ is paralleled by enhanced ubiquitination of the caspase-8 regulator cellular FLICE-like inhibitory protein (c-FLIP), targeting it for proteasome degradation. c-FLIP silencing with anti-FLIP short interfering RNA (siRNA) in pulmonary MVECs rendered them susceptible to TTP plasma– and cytokine-mediated apoptosis, while up-regulation of c-FLIP by gene transfer partially protected dermal MVECs from such injury. TTP plasma–mediated apoptosis appears to involve cytokine-induced acceleration of c-FLIP degradation, sensitizing cells to TRAIL-mediated caspase-8 activation and cell death. Suppression of TRAIL or modulation of immunoproteasome activity may have therapeutic relevance in TTP.

Effects of the Japanese herbal medicine ‘Inchinko-to’ (TJ-135) on concanavalin A-induced hepatitis in mice

2000 ◽  
Vol 99 (5) ◽  
pp. 421-431 ◽  
Author(s):  
Masayoshi YAMASHIKI ◽  
Akihito MASE ◽  
Ichiro ARAI ◽  
Xian-Xi HUANG ◽  
Tsutomu NOBORI ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Concanavalin A ◽  
Serum Levels ◽  
Interferon Γ ◽  
Hepatic Necrosis ◽  
Interleukin 12 ◽  
Con A ◽  
Ifn Γ

Inchinko-to (TJ-135) is a herbal medicine consisting of three kinds of crude drugs, and in Japan it is administered mainly to patients with cholestasis. The present study evaluated the effects of TJ-135 on concanavalin A (con A)-induced hepatitis in mice in vivo and con A-induced cytokine production in vitro. When mice were pretreated with oral TJ-135 for 1 week before intravenous con A injection, the activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) were significantly decreased 8 h after con A administration (-82%, -96% and -66% respectively). In histological investigations, sub-massive hepatic necrosis accompanying inflammatory cell infiltration was not observed in mice pretreated with TJ-135. Serum levels of interleukin-12 (IL-12), interferon-γ (IFN-γ) and IL-2 were significantly lower in mice pretreated with TJ-135 compared with controls, while IL-10 levels were higher in these mice. Intrasplenic IL-12 levels were significantly lower in mice pretreated with TJ-135, while intrasplenic IL-10 levels were higher in these mice. In vitro, IL-10 production by splenocytes was increased by the addition of TJ-135 to the culture medium, whereas the production of IL-12 and IFN-γ was inhibited. These results suggest that con A-induced hepatitis was ameliorated by pretreatment with TJ-135. With regard to the mechanism of these effects of TJ-135, we speculate that TJ-135 inhibits the production of inflammatory cytokine and enhances the production of anti-inflammatory cytokines. Therefore administration of TJ-135 may be useful in patients with severe acute hepatitis accompanying cholestasis or in those with autoimmune hepatitis.

scholarly journals IL-27 promotes T cell–dependent colitis through multiple mechanisms

2010 ◽  
Vol 208 (1) ◽  
pp. 115-123 ◽  
Author(s):  
Jennifer H. Cox ◽  
Noelyn M. Kljavin ◽  
Nandhini Ramamoorthi ◽  
Lauri Diehl ◽  
Marcel Batten ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Inflammation ◽  
Interferon Γ ◽  
Transfer Model ◽  
Proinflammatory Role ◽  
Immune Pathology

Interleukin-27 (IL-27) is a cytokine known to have both proinflammatory and immunoregulatory functions. The latter appear to dominate in vivo, where IL-27 suppresses TH17 responses and promotes the differentiation of Tr1 cells expressing interferon-γ and IL-10 and lacking forkhead box P3 (Foxp3). Accordingly, IL-27 receptor α (Il27ra)–deficient mice suffer from exacerbated immune pathology when infected with various parasites or challenged with autoantigens. Because the role of IL-27 in human and experimental mouse colitis is controversial, we studied the consequences of Il27ra deletion in the mouse T cell transfer model of colitis and unexpectedly discovered a proinflammatory role of IL-27. Absence of Il27ra on transferred T cells resulted in diminished weight loss and reduced colonic inflammation. A greater fraction of transferred T cells assumed a Foxp3+ phenotype in the absence of Il27ra, suggesting that IL-27 functions to restrain regulatory T cell (Treg) development. Indeed, IL-27 suppressed Foxp3 induction in vitro and in an ovalbumin-dependent tolerization model in vivo. Furthermore, effector cell proliferation and IFN-γ production were reduced in the absence of Il27ra. Collectively, we describe a proinflammatory role of IL-27 in T cell–dependent intestinal inflammation and provide a rationale for targeting this cytokine in pathological situations that result from a breakdown in peripheral immune tolerance.

scholarly journals Investigation of the Role of CD8+ T Cells in Bovine Tuberculosis In Vivo

2003 ◽  
Vol 71 (8) ◽  
pp. 4297-4303 ◽  
Author(s):  
B. Villarreal-Ramos ◽  
M. McAulay ◽  
V. Chance ◽  
M. Martin ◽  
J. Morgan ◽  
...  
Keyword(s):  
Lymph Node ◽  
Bovine Tuberculosis ◽  
The Other ◽  
Cd8 Cells ◽  
Cd8 Cell ◽  
Ifn Γ ◽  
Mycobacterial Antigens

ABSTRACT Mycobacterium bovis is the causative agent of bovine tuberculosis (TB), and it has the potential to induce disease in humans. CD8+ T cells (CD8 cells) have been shown to respond to mycobacterial antigens in humans, cattle, and mice. In mice, CD8 cells have been shown to play a role in protection against mycobacterial infection. To determine the role of CD8 cells in bovine TB in vivo, two groups of calves were infected with the virulent M. bovis strain AF2122/97. After infection, one group was injected with a CD8 cell-depleting monoclonal antibody (MAb), and the other group was injected with an isotype control MAb. Immune responses to mycobacterial antigens were measured weekly in vitro. After 8 weeks, the animals were killed, and postmortem examinations were carried out. In vitro proliferation responses were similar in both calf groups, but in vitro gamma interferon (IFN-γ) production in 24-h whole-blood cultures was significantly higher in control cattle than in CD8 cell-depleted calves. Postmortem examination showed that calves in both groups had developed comparable TB lesions in the lower respiratory tract and associated lymph nodes. Head lymph node lesion scores, on the other hand, were higher in control calves than in CD8 cell-depleted calves. Furthermore, there was significant correlation between the level of IFN-γ and the head lymph node lesion score. These experiments indicate that CD8 cells play a role in the immune response to M. bovis in cattle by contributing to the IFN-γ response. However, CD8 cells may also play a deleterious role by contributing to the immunopathology of bovine TB.

Characterization of the human intestinal CD98 promoter and its regulation by interferon-γ

2007 ◽  
Vol 292 (2) ◽  
pp. G535-G545 ◽  
Author(s):  
Yutao Yan ◽  
Guillaume Dalmasso ◽  
Shanthi Sitaraman ◽  
Didier Merlin
Keyword(s):  
Transcriptional Regulation ◽  
Intestinal Inflammation ◽  
Direct Sequencing ◽  
Interferon Γ ◽  
Initiation Site ◽  
Start Codon ◽  
Transcriptional Initiation ◽  
Ifn Γ

Growing evidence that epithelial CD98 plays an important role in intestinal inflammation focused our interest to investigate the transcriptional regulation of CD98. Our mouse-based in vivo and in vitro experiments revealed that epithelial colonic CD98 mRNA expression was transcriptionally increased in intestinal inflammation. We then isolated and characterized a 5′-flanking fragment containing the promoter region required for CD98 gene transcription. Primer extension and rapid amplification of 5′-cDNA ends were used to map a transcriptional initiation site 129 bp upstream from the translational start codon (ATG). Direct sequencing of the 5′-flanking region revealed the presence of four GC-rich stimulating protein (Sp)1 binding domains, one NF-κB binding domain, and no TATA box. Binding of Sp1 [Sp1(−874), SP1(−386), Sp1(−187), and Sp1(−177)] and NF-κB [NF-κB(−213)] to the promoter was confirmed by EMSA and supershift assays. Furthermore, chromatin immunoprecipitation experiments showed the in vivo DNA-Sp1 and DNA-NF-κB interactions under basal and IFN-γ-stimulated conditions. Reporter genes driven by serially truncated and site-mutated CD98 promoters were used to examine basal and IFN-γ-responsive transcription in transiently transfected Caco2-BBE cells. Our results revealed that Sp1(−187), Sp1(−177), and the NF-κB binding site were essential for basal and IFN-γ-stimulated CD98 promoter activities, whereas Sp1(−874) and Sp1(−386) were not. The results from additional site-mutated CD98 promoters suggested that Sp1(−187), Sp1(−177), and the NF-κB site may cooperate in mediating basal and IFN-γ-stimulated CD98 promoter activities. Finally, we demonstrated that a reduction of Sp1 or NF-κB expression reduced CD98 protein expression in unstimulated and IFN-γ-stimulated Caco2-BBE cells. Collectively, these findings indicate that the Sp1 and NF-κB transcription factors are likely to play a significant role in IFN-γ-mediated transcriptional regulation of CD98 in the intestinal epithelium, providing new insights into the regulation of CD98 expression in intestinal inflammation.

scholarly journals Potential Immunocompetence of Proteolytic Fragments Produced by Proteasomes before Evolution of the Vertebrate Immune System

1997 ◽  
Vol 186 (2) ◽  
pp. 209-220 ◽  
Author(s):  
Gabriele Niedermann ◽  
Rudolf Grimm ◽  
Elke Geier ◽  
Martina Maurer ◽  
Claudio Realini ◽  
...  
Keyword(s):  
Immune System ◽  
Mhc Class I ◽  
Structural Features ◽  
Interferon Γ ◽  
Class I ◽  
Direct Products ◽  
Vertebrate Immune System ◽  
Mhc Class I Molecules

To generate peptides for presentation by major histocompatibility complex (MHC) class I molecules to T lymphocytes, the immune system of vertebrates has recruited the proteasomes, phylogenetically ancient multicatalytic high molecular weight endoproteases. We have previously shown that many of the proteolytic fragments generated by vertebrate proteasomes have structural features in common with peptides eluted from MHC class I molecules, suggesting that many MHC class I ligands are direct products of proteasomal proteolysis. Here, we report that the processing of polypeptides by proteasomes is conserved in evolution, not only among vertebrate species, but including invertebrate eukaryotes such as insects and yeast. Unexpectedly, we found that several high copy ligands of MHC class I molecules, in particular, self-ligands, are major products in digests of source polypeptides by invertebrate proteasomes. Moreover, many major dual cleavage peptides produced by invertebrate proteasomes have the length and the NH2 and COOH termini preferred by MHC class I. Thus, the ability of proteasomes to generate potentially immunocompetent peptides evolved well before the vertebrate immune system. We demonstrate with polypeptide substrates that interferon γ induction in vivo or addition of recombinant proteasome activator 28α in vitro alters proteasomal proteolysis in such a way that the generation of peptides with the structural features of MHC class I ligands is optimized. However, these changes are quantitative and do not confer qualitatively novel characteristics to proteasomal proteolysis. The data suggest that proteasomes may have influenced the evolution of MHC class I molecules.

Humulus scandens Exhibits Immunosuppressive Effects in Vitro and in Vivo by Suppressing CD4+ T Cell Activation

2014 ◽  
Vol 42 (04) ◽  
pp. 921-934 ◽  
Author(s):  
Jinjin Feng ◽  
Yingchun Wu ◽  
Yang Yang ◽  
Weiqi Jiang ◽  
Shaoping Hu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interferon Γ ◽  
Delayed Type Hypersensitivity ◽  
Ifn Γ ◽  
Humulus Scandens

Humulus scandens, rich in flavonoids, is a traditional Chinese medicine. It is widely used in China to treat tuberculosis, dysentery and chronic colitis. In this study, the major active faction of Humulus scandens (H.S) was prepared. Then, its immunosuppressive effects and underlying mechanisms on T cell activation were investigated in vitro and in vivo. Results showed that H.S significantly inhibited the proliferation of splenocytes induced by concanavalin A, lipopolysaccharides, and mixed-lymphocyte reaction in vitro. Additionally, H.S could dramatically suppress the proliferation and interferon-γ (IFN-γ) production from T cells stimulated by anti-CD3 and anti-CD28. Flow cytometric results confirmed that H.S could suppress the differentiation of IFN-γ-producing type 1 helper T cells (Th1). Furthermore, using ovalbumin immunization-induced T cell reaction and CD4+ T-cell-mediated delayed type hypersensitivity reaction, H.S the immunosuppressive effects of H.S was also demonstrated in vivo. Western blot results showed that H.S could impede the activation of both Erk1/2 and P38 in primary T cells triggered by anti-CD3/28. Collectively, the active fraction of H.S showed promising immunosuppressive activities both in vitro and in vivo.

scholarly journals Adoptive transfer of anti-cytomegalovirus effect of interleukin-2- activated bone marrow: potential application in transplantation

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 720-727
Author(s):  
R Agah ◽  
BS Charak ◽  
V Chen ◽  
A Mazumder
Keyword(s):  
Bone Marrow ◽  
Interleukin 2 ◽  
Murine Cytomegalovirus ◽  
Mcmv Infection ◽  
Murine Bone Marrow ◽  
Therapeutic Setting ◽  
Infected Cells ◽  
Novel Strategy

This work is a continuation of our studies that showed that interleukin- 2 (IL-2)-activated murine bone marrow (ABM) cells have potent cytotoxic potential against murine cytomegalovirus (MCMV)-infected targets in vitro, without loss of reconstitutive ability in vivo. Our data show that ABM cells lyse the MCMV-infected cells in vitro, at both acute and chronic stages of infection; this lysis is specific for the MCMV- infected cells. ABM cells supplemented with IL-2 therapy virtually eradicated the viral infection and prolonged the survival of MCMV- infected Balb/c mice, whether or not they were immunocompromised by irradiation (P less than .001 in both situations). Efficacy of ABM cells alone or IL-2 alone was less than the combination of ABM cells and IL-2. The efficacy of combination treatment with ABM cells and IL-2 in improving the survival of MCMV-infected mice was comparable, whether used in a preventive or a therapeutic setting. Therapy with ABM plus IL- 2 also prevented the reactivation of chronic MCMV infection after irradiation. Preliminary findings indicate that Thy-1+ and asialo GM1+ cells limited the MCMV proliferation by approximately 30% and 80%, respectively, while BM macrophages limited the proliferation of MCMV by 100%. These results suggest that BM transplantation (BMT) with ABM cells followed by IL-2 therapy may constitute a novel strategy to improve the host resistance against cytomegalovirus infection after BMT.

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