Primary adenovirus-specific cytotoxic T lymphocyte response occurs after viral clearance and liver enzyme elevation

Chen, J; Aj, Zajac; Sa, McPherson; Hc, Hsu; Yang, PingAr; Wu, Qiulian; Xu, Xiaojun; Wang, X; Fujihashi, Kohtaro; Curiel, DT; Jd, Mountz

doi:10.1038/sj.gt.3302494

Cited by 19 publications

(8 citation statements)

References 44 publications

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“…We measured cytokine expression on total T cell subpopulations, since a previous report has shown that most of the CD4 + and CD8 + T cells are virus-specific during the Ad infection (49). Our data suggest to us that IL-33 drove robust CD8 + and CD4 + T cells responses in the liver, which induced equally strong type-1 cytokine (IL-2 and IFN-γ) as well as type 2 cytokines (IL-4, IL-5, IL-6 and IL-13) in the liver and serum (Figs.…”

Section: Discussionmentioning

confidence: 99%

IL-33 Induces Nuocytes and Modulates Liver Injury in Viral Hepatitis

Liang

Jie

Hou

et al. 2013

The Journal of Immunology

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Molecules containing damage-associated molecular patterns (DAMP) play an important role in many pathogenic processes. Our aim was to investigate the role of IL-33, a DAMP molecule, in adenovirus (Ad)-induced liver inflammation. Ad-infected mice exhibited a steadily increased IL-33 and its receptor ST2 expression in the liver during the first week of the infection. Treatment of exogenous IL-33 resulted in a great decrease in the serum alanine aminotransferase (ALT) levels and the number of Councilman bodies in the liver. Attenuated liver injury by IL-33 correlated with an increase in T regulatory (Treg) cells but with a decrease in macrophages, dendritic cells and NK cells in the liver. IL-33 enhanced both type 1 (IL-2 and IFN-γ) and type 2 (IL-5 and IL-13) immune responses in infected mice. However, IL-33 inhibited TNF-α expression in hepatic T cells and macrophages, and significantly reduced TNF-α levels in the liver. We found that in addition to its direct effects, IL-33 strongly induced novel nuocytes in the livers and spleens of infected mice. When co-cultured with nuocytes, hepatic T cells and macrophages expressed lower levels of TNF-α. The IL-33-treated mice also demonstrated a slight delay, but no significant impairment, in eliminating an intrahepatic infection with Ad. In conclusion, this study reveals that IL-33 acts as a potent immune stimulator and a hepatoprotective cytokine in acute viral hepatitis. Its direct immunoregulatory functions and ability to induce novel nuocytes further suggest to us that it may be a potentially promising therapeutic candidate for the management of viral hepatitis.

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Section: Discussionmentioning

confidence: 99%

IL-33 Induces Nuocytes and Modulates Liver Injury in Viral Hepatitis

Liang

Jie

Hou

et al. 2013

The Journal of Immunology

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“…Thus, "lymphocytopenia" in blood could reflect redistribution of cells to tissues where they are needed for mounting an immune response, and could in fact constitute a surrogate for immunological activity, as reported in mice or in humans treated with another immunotherapeutic. [34][35][36] When measuring lymphocytes 3 weeks later they are normally back to pretreatment values [25][26]33 but this was not the case with Ad3-hTERT-E1A-treated patients that had received previous Ad5 treatments (Figure 1a). These patients had some T-cells reactive against Ad3-hTERT-E1A already before treatment, but the median amount in blood did not change after the treatment (Figure 1b).…”

Section: Discussionmentioning

confidence: 99%

Ad3-hTERT-E1A, a Fully Serotype 3 Oncolytic Adenovirus, in Patients With Chemotherapy Refractory Cancer

et al. 2012

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Twenty-five patients with chemotherapy refractory cancer were treated with a fully serotype 3-based oncolytic adenovirus Ad3-hTERT-E1A. In mice, Ad3 induced higher amounts of cytokines but less liver damage than Ad5 or Ad5/3. In humans, the only grade 3 adverse reactions were self-limiting cytopenias and generally the safety profile resembled Ad5-based oncolytic viruses. Patients that had been previously treated with Ad5 viruses presented longer lasting lymphocytopenia but no median increase in Ad3-specific T-cells in blood, suggesting immunological activity against antigens other than Ad3 hexon. Frequent alterations in antitumor T-cells in blood were seen regardless of previous virus exposure. Neutralizing antibodies against Ad3 increased in all patients, whereas Ad5 neutralizing antibodies remained stable. Treatment with Ad3-hTERT-E1A resulted in re-emergence of Ad5 viruses from previous treatments into blood and vice versa. Signs of possible efficacy were seen in 11/15 (73%) patients evaluable for tumor markers, four of which were treated only intravenously. Particularly promising results were seen in breast cancer patients and especially those receiving concomitant trastuzumab. Taken together, Ad3-hTERT-E1A seems safe for further clinical testing or development of armed versions. It offers an immunologically attractive alternative, with possible pharmacodynamic differences and a different receptor compared to Ad5.

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“…The phenotype of cells was examined by standard flow cytometry procedures as previously described (Chen et al, 2005). This involved six-color immunofluorescence staining of cell samples using a combination of FITC-, PE-, APC-, pacific-blue, PE-Cy7, and APC-Cy7 conjugated antibodies for anti-CD8, anti-CD28, anti-CD95, anti-CD45RO, anti-CD45RA, and anti-CD127.…”

Section: Methodsmentioning

confidence: 99%

Maintenance of naïve CD8 T cells in nonagenarians by leptin, IGFBP3 and T3

Chen

Lim

et al. 2010

Mechanisms of Ageing and Development

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Research into the age-associated decline in the immune system has focused on the factors that contribute to the accumulation of senescent CD8 T cells. Less attention has been paid to the non-immune factors that may maintain the pool of naïve CD8 T cells. Here, we analyzed the status of the naïve CD8 T-cell population in healthy nonagenarians (≥90-year-old), old (60–79-year-old), and young (20–34-year-old) subjects. Naïve CD8 T cells were defined as CD28+CD95− as this phenotype showed a strong co-expression of the CD45RA+, CD45RO−, and CD127+ phenotypes. Although there was an age-associated decline in the percentage of CD28+CD95− CD8 T cells, the healthy nonagenarians maintained a pool of naïve CD28+CD95− cells that contained T-cell receptor excision circles (TREC)+ cells. The percentages of naïve CD28+CD95− CD8 T cells in the nonagenarians correlated with the sera levels of insulin-like growth factor binding protein 3 (IGFBP3) and leptin. Higher levels of triiodothyronine (T3) negatively correlated with the accumulation of TREC−CD28−CD95+ CD8 T cells from nonagenarians. These results suggest a model in which IGFBP3, leptin and T3 act as non-immune factors to maintain a larger pool of naïve CD8 T cells in healthy nonagenarians.

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Primary adenovirus-specific cytotoxic T lymphocyte response occurs after viral clearance and liver enzyme elevation

Cited by 19 publications

References 44 publications

IL-33 Induces Nuocytes and Modulates Liver Injury in Viral Hepatitis

IL-33 Induces Nuocytes and Modulates Liver Injury in Viral Hepatitis

Ad3-hTERT-E1A, a Fully Serotype 3 Oncolytic Adenovirus, in Patients With Chemotherapy Refractory Cancer

Maintenance of naïve CD8 T cells in nonagenarians by leptin, IGFBP3 and T3

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