Effect of a combination therapy between IL-12 and soluble IL-4 receptor (sIL-4R) onCandida albicansand herpes simplex virus type 1 infections in thermally injured mice

2002 ◽  
Vol 48 (10) ◽  
pp. 886-894 ◽  
Author(s):  
Makiko Kobayashi ◽  
Hitoshi Takahashi ◽  
David N Herndon ◽  
Richard B Pollard ◽  
Fujio Suzuki
Keyword(s):  
T Cells ◽  
Candida Albicans ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Cell Responses ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

The effectiveness of a combination using IL-12 and soluble IL-4 receptor (sIL-4R) to treat severe infections of herpes simplex virus type 1 (HSV-1) and Candida albicans in thermally injured mice was investigated. Although sIL-4R decreased burn-associated type 2 T-cell responses, the effect of sIL-4R was minimal on the morbidity and mortality of thermally injured mice exposed to 250 times LD50of HSV-1 or 10 times LD50of C. albicans. Compared with 100% mortality in control mice, mortality for HSV-1 and C. albicans was 40 and 20%, respectively, in thermally injured mice that received IL-12 and sIL-4R in combination. After stimulation with anti-CD3 monoclonal antibody, splenic T cells from thermally injured mice exposed to large amounts of HSV-1 or C. albicans did not produce gamma interferon (IFN-γ) into their culture fluids. However, IFN-γ was produced by splenic T cells from thermally injured and infected mice treated with IL-12 and sIL-4R in combination. These results suggest that therapeutic treatment with a combination of IL-12 and sIL-4R may be effective by inducing type 1 T-cell responses in thermally injured mice exposed to large amounts of HSV-1 or C. albicans.Key words: burn, IL-12, soluble IL-4 receptor, herpesvirus, Candida albicans.

scholarly journals Natural infection with herpes simplex virus type 1 (HSV-1) induces humoral and T cell responses to the HSV-1 glycoprotein H:L complex

2000 ◽  
Vol 81 (8) ◽  
pp. 2011-2015 ◽  
Author(s):  
Douwe F. Westra ◽  
Georges M. G. M. Verjans ◽  
Albert D. M. E. Osterhaus ◽  
Adriaan van Kooij ◽  
Gjalt W. Welling ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Herpes Simplex Virus Type ◽  
T Cell Responses ◽  
Cell Responses ◽  
Simplex Virus ◽  
Hsv 1

The glycoproteins of herpes simplex virus type 1 (HSV-1) are important targets for the immune system in the control of HSV-1 infections. The humoral and T cell responses to the glycoprotein (g)Ht(His):gL complex of HSV-1 were studied in seven HSV-1-seropositive and three HSV-1-seronegative healthy adults. In addition, responses to HSV-1 gDt were determined. As antigens, purified soluble recombinant forms of the gHt(His):gL complex produced by insect cells and of gDt produced by yeast cells were used. In contrast to seronegative donors, sera of all seropositive donors contained gHt(His): gL-specific IgG. Using peripheral blood (PB) T cells, gHt(His):gL-specific proliferative T cell responses were detected in all seropositive donors. Culture supernatants of PB T cells stimulated with recombinant gHt(His):gL contained high levels of interferon-γ and no detectable interleukin-4, indicating their Th1 phenotype. These results show that naturally acquired HSV-1 infection induces gH:gL-specific humoral and T cell responses.

scholarly journals Gamma Interferon Can Prevent Herpes Simplex Virus Type 1 Reactivation from Latency in Sensory Neurons

2001 ◽  
Vol 75 (22) ◽  
pp. 11178-11184 ◽  
Author(s):  
Ting Liu ◽  
Kamal M. Khanna ◽  
Brian N. Carriere ◽  
Robert L. Hendricks
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Ex Vivo ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT We recently demonstrated that CD8+ T cells could block herpes simplex virus type 1 (HSV-1) reactivation from latency in ex vivo trigeminal ganglion (TG) cultures without destroying the infected neurons. Here we establish that CD8+ T-cell prevention of HSV-1 reactivation from latency is mediated at least in part by gamma interferon (IFN-γ). We demonstrate that IFN-γ was produced in ex vivo cultures of dissociated latently infected TG by CD8+ T cells that were present in the TG at the time of excision. Depletion of CD8+ T cells or neutralization of IFN-γ significantly enhanced the rate of HSV-1 reactivation from latency in TG cultures. When TG cultures were treated with acyclovir for 4 days to insure uniform latency, supplementation with recombinant IFN-γ blocked HSV-1 reactivation in 80% of cultures when endogenous CD8+ T cells were present and significantly reduced and delayed HSV-1 reactivation when CD8+ T cells or CD45+ cells were depleted from the TG cultures. The effectiveness of recombinant IFN-γ in blocking HSV-1 reactivation was lost when its addition to TG cultures was delayed by more than 24 h after acyclovir removal. We propose that when the intrinsic ability of neurons to inhibit HSV-1 gene expression is compromised, HSV-specific CD8+ T cells are rapidly mobilized to produce IFN-γ and perhaps other antiviral cytokines that block the viral replication cycle and maintain the viral genome in a latent state.

scholarly journals Comparison of Adjuvant Efficacy of Herpes Simplex Virus Type 1 Recombinant Viruses Expressing TH1 and TH2 Cytokine Genes

2003 ◽  
Vol 77 (10) ◽  
pp. 5774-5783 ◽  
Author(s):  
Yanira Osorio ◽  
Homayon Ghiasi
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Recombinant Virus ◽  
Recombinant Viruses ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The adjuvant effects of cytokines in humoral and cell-mediated immunity to herpes simplex virus type 1 (HSV-1) have been examined in mice using HSV-1 recombinant viruses expressing murine interleukin-2 (IL-2), IL-4, or gamma interferon (IFN-γ) gene. Groups of naive BALB/c mice were immunized intraperitoneally with one or three doses of the HSV-1 recombinant viruses expressing IL-2, IL-4, or IFN-γ or with parental control virus. Despite similar replication kinetics, these three recombinant viruses elicited different immune responses to HSV-1 on immunization. Immunization with the recombinant virus expressing IL-4 elicited a humoral response of greater magnitude than immunization with the recombinant viruses expressing IL-2 or IFN-γ or with parental virus. In contrast, immunization with recombinant virus expressing IL-2 elicited a higher cytotoxic T-cell response than immunization with viruses expressing IL-4 or IFN-γ. Stimulation in vitro of splenocytes obtained from the mice immunized with UV-inactivated HSV-1 McKrae resulted in a TH1 pattern of cytokine expression irrespective of the recombinant virus used in the immunization. As observed for the parental virus, both CD4+ and CD8+ T cells contributed equally to the production of IL-2 by the splenocytes of mice immunized with any of the three recombinant viruses. However, the pattern of IFN-γ production by CD4+ and CD8+ T cells differed according to the recombinant virus used. After lethal ocular challenge, all immunized mice were protected completely against death and manifestations of eye disease caused by HSV-1, which are typical responses in unimmunized mice. Mice immunized with IL-4-expressing virus cleared the virus from their eyes more rapidly than mice immunized with IL-2- or IFN-γ-expressing virus. Taken together, our results suggest that, in contrast to IFN-γ which did not exhibit an adjuvant effect, both IL-4 and IL-2 act as adjuvants in immunization with HSV, with IL-4 showing greater efficacy.

scholarly journals Gamma Interferon Can Block Herpes Simplex Virus Type 1 Reactivation from Latency, Even in the Presence of Late Gene Expression

2005 ◽  
Vol 79 (16) ◽  
pp. 10339-10347 ◽  
Author(s):  
Vilma Decman ◽  
Paul R. Kinchington ◽  
Stephen A. K. Harvey ◽  
Robert L. Hendricks
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Promoter Activity ◽  
Latently Infected ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Herpes simplex virus type 1 (HSV-1)-specific CD8+ T cells and the cytokine gamma interferon (IFN-γ) are persistently present in trigeminal ganglia (TG) harboring latent HSV-1. We define “latency” as the retention of functional viral genomes in sensory neurons without the production of infectious virions and “reactivation” as a multistep process leading from latency to virion assembly. CD8+ T cells can block HSV-1 reactivation in ex vivo mouse TG cultures and appear to be the sole source of IFN-γ in these cultures. Here we demonstrate that IFN-γ alone can block HSV-1 reactivation in some latently infected neurons, and we identify points of intervention in the life cycle of the reactivating virus. Cell suspensions of TG that were latently infected with recombinant RE HSV-1 expressing enhanced green fluorescent protein from the promoter for infected cell protein 0 (ICP0) or glycoprotein C (gC) were depleted of endogenous CD8+ or CD45+ cells and cultured in the presence or absence of IFN-γ. Our results demonstrate that IFN-γ acts on latently infected neurons to inhibit (i) HSV-1 reactivation, (ii) ICP0 promoter activity, (iii) gC promoter activity, and (iv) reactivation in neurons in which the ICP0 or gC promoter is active. Interestingly, we detected transcripts for ICP0, ICP4, and gH in neurons that expressed the ICP0 promoter but were prevented by IFN-γ from reactivation and virion formation. Thus, the IFN-γ blockade of HSV-1 reactivation from latency in neurons is associated with an inhibition of the expression of the ICP0 gene (required for reactivation) and a blockade of a step that occurs after the expression of at least some viral structural genes.

scholarly journals Interleukin-12- and Gamma Interferon-Dependent Innate Immunity Are Essential and Sufficient for Long-Term Survival of Passively Immunized Mice Infected with Herpes Simplex Virus Type 1

2001 ◽  
Vol 75 (20) ◽  
pp. 9596-9600 ◽  
Author(s):  
Sabine Vollstedt ◽  
Marco Franchini ◽  
Gottfried Alber ◽  
Mathias Ackermann ◽  
Mark Suter
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Interleukin 12 ◽  
Type I ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Interferon (IFN) type I (alpha/beta IFN [IFN-α/β]) is very important in directly controlling herpes simplex virus type I (HSV-1) replication as well as in guiding and upregulating specific immunity against this virus. By contrast, the roles of IFN type II (IFN-γ) and antibodies in the defense against HSV-1 are not clear. Mice without a functional IFN system and no mature B and T cells (AGR mice) did not survive HSV-1 infection in the presence or absence of neutralizing antibodies to the virus. Mice without a functional IFN type I system and with no mature B and T cells (AR129 mice) were unable to control infection with as little as 10 PFU of HSV-1 strain F. By contrast, in the presence of passively administered neutralizing murine antibodies to HSV-1, some AR129 mice survived infection with up to104PFU of HSV-1. This acute immune response was dependent on the presence of interleukin-12 (IL-12) p75. Interestingly, some virus-infected mice stayed healthy for several months, at which time antibody to HSV-1 was no longer detectable. Treatment of these virus-exposed mice with dexamethasone led to death in approximately 40% of the mice. HSV-1 was found in brains of mice that did not survive dexamethasone treatment, whereas HSV-1 was absent in those that survived the treatment. We conclude that in the presence of passively administered HSV-1-specific antibodies, the IL-12-induced IFN-γ-dependent innate immune response is able to control low doses of virus infection. Surprisingly, in a significant proportion of these mice, HSV-1 appears to persist in the absence of antibodies and specific immunity.

scholarly journals Alpha/Beta Interferon and Gamma Interferon Synergize To Inhibit the Replication of Herpes Simplex Virus Type 1

2002 ◽  
Vol 76 (22) ◽  
pp. 11541-11550 ◽  
Author(s):  
Bruno Sainz ◽  
William P. Halford
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Vero Cells ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In vivo evidence suggests that T-cell-derived gamma interferon (IFN-γ) can directly inhibit the replication of herpes simplex virus type 1 (HSV-1). However, IFN-γ is a weak inhibitor of HSV-1 replication in vitro. We have found that IFN-γ synergizes with the innate IFNs (IFN-α and -β) to potently inhibit HSV-1 replication in vitro and in vivo. Treatment of Vero cells with either IFN-β or IFN-γ inhibits HSV-1 replication by <20-fold, whereas treatment with both IFN-β and IFN-γ inhibits HSV-1 replication by ∼1,000-fold. Treatment with IFN-β and IFN-γ does not prevent HSV-1 entry into Vero cells, and the inhibitory effect can be overcome by increasing the multiplicity of HSV-1 infection. The capacity of IFN-β and IFN-γ to synergistically inhibit HSV-1 replication is not virus strain specific and has been observed in three different cell types. For two of the three virus strains tested, IFN-β and IFN-γ inhibit HSV-1 replication with a potency that approaches that achieved by a high dose of acyclovir. Pretreatment of mouse eyes with IFN-β and IFN-γ reduces HSV-1 replication to nearly undetectable levels, prevents the development of disease, and reduces the latent HSV-1 genome load per trigeminal ganglion by ∼200-fold. Thus, simultaneous activation of IFN-α/β receptors and IFN-γ receptors appears to render cells highly resistant to the replication of HSV-1. Because IFN-α or IFN-β is produced by most cells as an innate response to virus infection, the results imply that IFN-γ secreted by T cells may provide a critical second signal that potently inhibits HSV-1 replication in vivo.

scholarly journals CD4+ T Cells Are Required for the Priming of CD8+ T Cells following Infection with Herpes Simplex Virus Type 1

2009 ◽  
Vol 83 (10) ◽  
pp. 5256-5268 ◽  
Author(s):  
Naveen K. Rajasagi ◽  
Sadik H. Kassim ◽  
Christina M. Kollias ◽  
Xiangyi Zhao ◽  
Robert Chervenak ◽  
...  
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Herpes Simplex Virus Type ◽  
T Cell Response ◽  
Simplex Virus ◽  
T Cell Help ◽  
Hsv 1

ABSTRACT The role of CD4+ helper T cells in modulating the acquired immune response to herpes simplex virus type 1 (HSV-1) remains ill defined; in particular, it is unclear whether CD4+ T cells are needed for the generation of the protective HSV-1-specific CD8+-T-cell response. This study examined the contribution of CD4+ T cells in the generation of the primary CD8+-T-cell responses following acute infection with HSV-1. The results demonstrate that the CD8+-T-cell response generated in the draining lymph nodes of CD4+-T-cell-depleted C57BL/6 mice and B6-MHC-II−/− mice is quantitatively and qualitatively distinct from the CD8+ T cells generated in normal C57BL/6 mice. Phenotypic analyses show that virus-specific CD8+ T cells express comparable levels of the activation marker CD44 in mice lacking CD4+ T cells and normal mice. In contrast, CD8+ T cells generated in the absence of CD4+ T cells express the interleukin 2 receptor α-chain (CD25) at lower levels. Importantly, the CD8+ T cells in the CD4+-T-cell-deficient environment are functionally active with respect to the expression of cytolytic activity in vivo but exhibit a diminished capacity to produce gamma interferon and tumor necrosis factor alpha. Furthermore, the primary expansion of HSV-1-specific CD8+ T cells is diminished in the absence of CD4+-T-cell help. These results suggest that CD4+-T-cell help is essential for the generation of fully functional CD8+ T cells during the primary response to HSV-1 infection.

scholarly journals The Cytotoxic T-Cell Response to Herpes Simplex Virus Type 1 Infection of C57BL/6 Mice Is Almost Entirely Directed against a Single Immunodominant Determinant

1999 ◽  
Vol 73 (9) ◽  
pp. 7619-7626 ◽  
Author(s):  
Morgan E. Wallace ◽  
Rachael Keating ◽  
William R. Heath ◽  
Francis R. Carbone
Keyword(s):  
T Cells ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
Herpes Simplex Virus Type ◽  
Cell Response ◽  
T Cell Response ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT Many virus infections give rise to surprisingly limited T-cell responses directed to very few immunodominant determinants. We have been examining the cytotoxic T-lymphocyte (CTL) response to herpes simplex virus type 1 (HSV-1) infection. Previous studies have identified the glycoprotein B-derived peptide from residues 498 to 505 (gB498–505) as one of at least three determinants recognized by HSV-1-specific CTLs isolated from C57BL/6 mice. We had previously found that in vitro-derived CTLs directed to gB498–505 show a characteristic pattern of T-cell receptor (TCR) usage, with 60% of gB498–505-specific CD8+ T cells expressing BV10+ TCR β chains and a further 20% expressing BV8S1. In this report, we confirm that this TCR V-region bias is also reflected in the ex vivo response to HSV-1 infection. A high proportion of activated CD8+draining lymph node cells were found to express these dominant V regions, suggesting that a substantial number of in vivo responding T cells were directed to this one viral determinant. The use of an HSV-1 deletion mutant lacking the gB498–505 determinant in combination with accurate intracellular gamma interferon staining allowed us to quantify the extent of gB-specific T-cell dominance. Together, these results suggested that between 70 and 90% of all CD8+ HSV-1-specific T cells target gB498–505. While deletion of this determinant resulted in an attenuated CD8+ T-cell response, it also permitted the emergence of one or more previously unidentified cryptic specificities. Overall, HSV-1 infection of C57BL/6 mice results in an extremely focused pattern of CD8+ T-cell selection in terms of target specificity and TCR expression.

scholarly journals Primary herpes simplex virus type 1 infection of the eye triggers similar immune responses in the cornea and the skin of the eyelids

2002 ◽  
Vol 83 (7) ◽  
pp. 1579-1590 ◽  
Author(s):  
Thomas H. Stumpf ◽  
Rachel Case ◽  
Carolyn Shimeld ◽  
David L. Easty ◽  
Terry J. Hill
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Disease Process ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

Herpetic stromal keratitis (HSK) and blepharoconjunctivitis in humans are thought partly to result from immunopathological responses to herpes simplex virus type 1 (HSV-1). The corneas of NIH mice were inoculated with HSV-1 (strain McKrae) and mice were examined for signs of disease and infection on days 1, 4, 7, 10, 14 and 21. The eyes and eyelids of infected and control mice were processed for immunohistochemistry and double stained for viral antigens and one of the following cell surface markers (Gr-1, F4/80, CD4, CD8, CD45R or MHC class II) or one of the following cytokines (IL-2, IL-4, IL-6, IL-10, IL-12 or IFN-γ). All infected mice developed signs of HSK by day 4 and blepharitis by day 7 and these both persisted until day 21, when signs of resolution where apparent. Virus was detected during the first week of infection and became undetectable by day 10. Large numbers of Gr-1+ cells (neutrophils) infiltrated infected corneas and eyelids in areas of viral antigen and CD4+ T cells increased significantly in number after virus clearance. In both sites, the predominant cytokines were IL-6, IL-10, IL-12 and IFN-γ, with few IL-2+ and IL-4+ cells. These observations suggest that the immune responses in the cornea are similar to those in the eyelids but, overall, the responses are not clearly characterized as either Th1 or Th2. In both sites, the neutrophil is the predominant infiltrating cell type and is a likely source of the cytokines observed and a major effector of the disease process.

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