IL-12 in conjunction with dendritic cells enhances antiviral CD8+ CTL responses in vitro.

Bhardwaj, Nina; Seder, Robert A.; Reddy, Anita; Feldman, M

doi:10.1172/jci118843

Cited by 101 publications

(59 citation statements)

References 43 publications

(47 reference statements)

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“…These findings are in concordance with those of others, who showed that in vitro CTL generation was augmented by the addition of IL-12 in the presence of neutralizing anti-IFN-␥ Abs (71). Unimpaired CTL generation observed in IL-12 Ϫ/Ϫ mice after immunization with allogeneic cells (46) or with LCMV (M. van den Broek, unpublished observations) probably reflects the inability of these stimuli to induce significant IL-12 levels in vivo (72) and an IL-12-independent pathway for the induction of CTL responses.…”

Section: Discussionsupporting

confidence: 93%

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

Broek¹,

Bachmann²,

Köhler

et al. 2000

The Journal of Immunology

124

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Resistance or susceptibility to most infectious diseases is strongly determined by the balance of type 1 vs type 2 cytokines produced during infection. However, for viruses, this scheme may be applicable only to infections with some cytopathic viruses, where IFN-γ is considered as mandatory for host defense with little if any participation of type 2 responses. We studied the role of signature Th1 (IL-12, IFN-γ) and Th2 (IL-4, IL-10) cytokines for immune responses against vaccinia virus (VV). IL-12−/− mice were far more susceptible than IFN-γ−/− mice, and primary CTL responses against VV were absent in IL-12−/− mice but remained intact in IFN-γ−/− mice. Both CD4+ and CD8+ T cells from IL-12−/− mice were unimpaired in IFN-γ production, although CD4+ T cells showed elevated Th2 cytokine responses. Virus replication was impaired in IL-4−/− mice and, even more strikingly, in IL-10−/− mice, which both produced elevated levels of the proinflammatory cytokines IL-1α and IL-6. Thus, IL-4 produced by Th2 cells and IL-10 produced by Th2 cells and probably also by macrophages counteract efficient anti-viral host defense. Surprisingly, NO production, which is considered as a major type 1 effector pathway inhibited by type 2 cytokines, appears to play a limited role against VV, because NO sythetase 2-deficient mice did not show increased viral replication. Thus, our results identify a new role for IL-12 in defense beyond the induction of IFN-γ and show that IL-4 and IL-10 modulate host protective responses to VV.

show abstract

Section: Discussionsupporting

confidence: 93%

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

Broek¹,

Bachmann²,

Köhler

et al. 2000

The Journal of Immunology

124

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“…IL-12 is a key cytokine in the induction of the Th-1-type immune response, and the use of IL-12 in combination with DC enhances specific cytotoxic T lymphocyte (CTL) induction in vitro 9 and in vivo. 10 However, administration of IL-12 systemically has resulted in significant toxicity in both preclinical studies and human trials.…”

mentioning

confidence: 99%

Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model

et al. 2004

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Gene-modified dendritic cells (DC) provide unique therapeutic strategies for prostate cancer; however, the comparative evaluation of specific delivery options using appropriate preclinical models has not been described. In this study, bone marrow-derived DC were genetically engineered to express high levels of interleukin-12 (IL-12) with or without the costimulatory molecule B7-1, by ex vivo infection with recombinant adenoviral vectors. We used an orthotopic metastatic mouse prostate cancer preclinical model (178-2 BMA) to compare two therapeutic protocols for DC delivery, in situ and subcutaneous. DC were generated from bone marrow of syngeneic 129/ Sv mice by culturing in the presence of GM-CSF and IL-4. In vitro DC/IL-12 or DC/IL-12/B7 produced high levels of biologically active IL-12. In situ delivery of DC/IL-12 or DC/IL-12/B7 induced a significant suppression of primary tumor growth compared to DC/bgal controls (P ¼ .0328 and P ¼ .0019, respectively), as well as reduced numbers of spontaneous lung metastatic nodules (P ¼ .1404 and P ¼ .0335, respectively). In survival experiments, in situ DC/IL-12 injection demonstrated a small but statistically significant advantage (P ¼ .0041). Subcutaneous, tumor lysate pulsed DC/IL-12 significantly decreased tumor size (P ¼ .0152) and increased survival (P ¼ 0.0433) compared to HBSS controls but the decrease in the number of spontaneous lung metastases did not achieve statistical significance. Both in situ and subcutaneous treatments enhanced cytolytic activities of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). In this preclinical model, gene-modified DC-based intratumoral immunotherapy was shown to be an effective therapeutic strategy for locally advanced prostate cancer based on tumor growth suppression, inhibition of metastasis and survival improvement.

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“…ELL strongly induced IL-12 and TNF-which play a crucial role in DCs-mediated cancer immunotherapy [7,30,31]. Especially, IL-12 directly enhances proliferation of CTL and immunological synapse formation between CTL and target cells [32,33]. In addition, IL-12 and TNF- synergistically induces IFN- positive CTL and effective antitumor activity [34].…”

Section: Discussionmentioning

confidence: 99%

Extracts of Larix Leptolepis effectively augments the generation of tumor antigen-specific cytotoxic T lymphocytes via activation of dendritic cells in TLR-2 and TLR-4-dependent manner

Koizumi

Masuko

Wakita

et al. 2012

Cellular Immunology

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IL-12 in conjunction with dendritic cells enhances antiviral CD8+ CTL responses in vitro.

Cited by 101 publications

References 43 publications

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

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

Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model

Extracts of Larix Leptolepis effectively augments the generation of tumor antigen-specific cytotoxic T lymphocytes via activation of dendritic cells in TLR-2 and TLR-4-dependent manner

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