IL-4 and IL-10 Antagonize IL-12-Mediated Protection Against Acute Vaccinia Virus Infection with a Limited Role of IFN-γ and Nitric Oxide Synthetase 2

Broek, Maries van den; Bachmann, Martin F.; Köhler, Gabriele; Barner, Marijke; Escher, Robert; Rm, Zinkernagel; Köpf, Manfred

doi:10.4049/jimmunol.164.1.371

Cited by 125 publications

(101 citation statements)

References 90 publications

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“…More importantly, blocking IL-10 signaling did not abrogate or impair VACV replication in the ovaries and the other visceral organs, and did not positively affect the generation of antibodies against VACV. The reasons for the discrepancy noted between our data and those of another publication (23), that claimed that IL-10 -/ -mice had reduced replication of VACV in the ovaries, is not clear. The onset and severity of both spontaneous and experimentally-induced inflammation in IL-10 -/ -mice may be strongly influenced by the conditions in which these mice are kept.…”

Section: Discussioncontrasting

confidence: 56%

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Preferential Replication of Vaccinia Virus in the Ovaries is Independent of Immune Regulation Through IL-10 and TGF-β

Zhao

Adams²,

Croft³

2011

Viral Immunology

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Vaccinia virus (VACV) exhibits a strong tropism for ovarian tissue and can cause ovary pathology and sterility. Why VACV preferentially accumulates in this organ is not known. Here we show that multiple immune cell populations infiltrated the ovaries following VACV infection, including virus-specific CD8 T cells making both IFN-c and TNF. This was also accompanied by the induction of interleukin (IL)-10 and TGF-b, suggesting that VACV may exploit the ovarian environment for immune evasion via induction of these suppressive cytokines. To test this we used several strategies, including neutralizing these cytokines, and exogenous targeting of the T-cell response, to determine if this inhibited virus replication in the ovaries. We found that the VACV-specific CD8 T-cell immunity and the clearance of virus were not enhanced in the ovaries of infected mice in which IL-10 receptor (IL-10R) was blocked with antagonist antibody. VACV replication was also only moderately affected in the ovaries of infected IL-10 knockout mice. Similarly, blockade of TGF-b with antagonist antibody demonstrated no effect on CD8 T-cell immunity or VACV replication. Lastly, an agonist antibody targeting the tumor necrosis factor receptor superfamily member OX40 (TNFRSF4) enhanced the number of VACV-specific CD8 T cells producing IFN-c in lymphoid tissue, but had no effect on CD8 T-cell infiltration of the ovaries or on the viral load. Collectively, the results indicate that preferential replication of VACV in the ovaries may not be dependent on immune suppressive mechanisms in this tissue.

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Section: Discussioncontrasting

confidence: 56%

“…4f ). However, this is in contrast with the 10,000-fold reduction reported in the prior report (23). Virus titers were not significantly different in IL-10 -/ -mice in the ovaries at day 15 post-infection (Fig.…”

Section: Il-10 and Tgf-b Do Not Control Vacv Replicationcontrasting

confidence: 56%

Preferential Replication of Vaccinia Virus in the Ovaries is Independent of Immune Regulation Through IL-10 and TGF-β

Zhao

Adams²,

Croft³

2011

Viral Immunology

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“…Several groups have reported that insertion of Th2 -like cytokines such as IL -4 or IL -10 into vaccinia virus increases in vivo viral replication and slows host clearance of infection. 25,48 However, creation of a virus that is not recognized by the immune system obviously creates serious safety concerns for the population as a whole, as unforeseen events could …”

Section: Improving In Vivo Replication Efficacy Of Vaccinia Virus By mentioning

confidence: 99%

“…Van Den et al 25 examined the effect of Th1 (IFN -g, IL -12 ) and Th2 ( IL-4, IL -10 ) balance in the clearance of vaccinia virus in mice using cytokine knockouts. Vaccinia viral replication was enhanced in IL -12 and IFN -g knockout mice, with IL -12( À / À ) demonstrating greater susceptibility to infection than IFN -g -deficient mice.…”

Section: Vaccinia Virus Biologymentioning

confidence: 99%

Development of a replication-selective, oncolytic poxvirus for the treatment of human cancers

Zeh

Bartlett

2002

Cancer Gene Ther

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Tumor directed gene therapy for the purpose of destroying cancer cells through replicative "oncolysis" or by intratumoral expression of toxic or immunostimulatory genes requires an efficient, tumor targeted vector. Vectors are limited by inefficient replication in vivo, inefficient tumor targeting, and safety concerns. As a unique approach to addressing these limitations, our laboratory has studied poxviruses as tumor selective replicating vectors. The best in vivo antitumor results achieved to date have been with a mutated WR strain of vaccinia virus. The unique advantage of this strain of vaccinia over other vectors currently being explored for this purpose is the efficiency of in vivo replication. Intradermal injection of 10 6 pfu of the wild type ( non -mutated ) vaccinia in non -human primates leads to a 108 cm 2 zone of necrosis in 8 days -directly related to cellular destruction from viral replication. We have mutated the virus through insertional deletion of both the thymidine kinase ( TK ) gene and vaccinia growth factor ( VGF ) gene. The mutant virus no longer causes destruction of normal tissue, but has completely preserved replication efficiency in tumor tissue and can safely be delivered systematically to successfully treat subcutaneous tumors in mice. Plans are now underway for clinical trials.

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“…IL-4 and IL-10 promote VV spread (4,5). In contrast, IFN-␥ (6), IgG antibody (7), CD8 ϩ cytotoxic T cells (8), NK cells (9), and the cathelicidin family of antimicrobial peptides (AMPs) (10) are thought to contribute to VV containment.…”

mentioning

confidence: 99%

Vaccinia virus inoculation in sites of allergic skin inflammation elicits a vigorous cutaneous IL-17 response

Oyoshi

Elkhal

Kumar

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Eczema vaccinatum (EV) is a complication of smallpox vaccination occurring in patients with atopic dermatitis. In affected individuals, vaccinia virus (VV) spreads through the skin, resulting in large primary lesions and satellite lesions, and infects internal organs. BALB/c mice inoculated with VV at sites of Th2-biased allergic skin inflammation elicited by epicutaneous ovalbumin (OVA) sensitization exhibited larger primary lesions that were erosive, more satellite lesions, and higher viral loads in skin and internal organs than mice inoculated in saline-exposed skin, unsensitized skin, or skin sites with Th1-dominant inflammation. VV inoculation in OVA-sensitized skin induced marked local expression of IL-17 transcripts and massive neutrophil infiltration compared to VV inoculation in saline-exposed skin. Treatment with anti-IL-17 decreased the size of primary lesions, numbers of satellite lesions, and viral loads. Addition of IL-17 promoted VV replication in skin explants. These results suggest that IL-17 may be a potential therapeutic target in EV.atopic dermatitis ͉ eczema vaccinatum V accinia virus (VV) belongs to the orthopoxvirus genus of the Poxviridae family, which includes variola virus, the agent that causes smallpox, and is a potent vaccine against smallpox (1). Smallpox was eradicated in 1980 and vaccination ceased in the U.S. in 1972 and in the rest of the world in 1979 (1). Recent concern that VV might be used as a bioterror weapon has led to selective vaccination of military personnel and to contingency plans for mass vaccination. A major concern is that patients with atopic dermatitis (AD), which affects 15-20% of children in industrialized countries, are susceptible to eczema vaccinatum (EV), a life-threatening complication in which VV disseminates in the skin, resulting in satellite skin lesions, and spreads to internal organs (2). Although smallpox vaccination is contraindicated in AD patients, they are at risk for EV following contact with recently immunized individuals (3).IL-4 and IL-10 promote VV spread (4, 5). In contrast, IFN-␥ (6), IgG antibody (7), CD8 ϩ cytotoxic T cells (8), NK cells (9), and the cathelicidin family of antimicrobial peptides (AMPs) (10) are thought to contribute to VV containment. It has been suggested that IL-4 driven down-regulation of AMPs in AD skin lesions predisposes to EV (10). IL-17 is expressed in acute skin lesions of patients with AD and in their peripheral blood CD4 ϩ T cells (11,12). There is controversy as to whether IL-17 promotes or attenuates VV infection (13,14).We have previously shown that epicutaneous (EC) sensitization of BALB/c mice with ovalbumin (OVA) results in skin inflammation with similarities to AD skin lesions, characterized by infiltration with CD4 ϩ cells and eosinophils and by increased expression of mRNA for Th2 cytokines and IL-17, but not 16). In this study, we show that inoculation of VV in OVA-sensitized skin results in larger primary lesions, more satellite lesions, and higher viral loads and markedly higher local expression...

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IL-4 and IL-10 Antagonize IL-12-Mediated Protection Against Acute Vaccinia Virus Infection with a Limited Role of IFN-γ and Nitric Oxide Synthetase 2

Cited by 125 publications

References 90 publications

Preferential Replication of Vaccinia Virus in the Ovaries is Independent of Immune Regulation Through IL-10 and TGF-β

Preferential Replication of Vaccinia Virus in the Ovaries is Independent of Immune Regulation Through IL-10 and TGF-β

Development of a replication-selective, oncolytic poxvirus for the treatment of human cancers

Vaccinia virus inoculation in sites of allergic skin inflammation elicits a vigorous cutaneous IL-17 response

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