Life-long systemic protection in mice vaccinated with and adenovirus IL-12 vector requires active infection, macrophages and intact lymph nodes

Gabaglia, Claudia Raja; Sercarz, Eli E.; Diaz-de-Durana, Yaiza; Hitt, Mary; Graham, Frank L.; Gauldie, Jack; Braciak, Todd A.

doi:10.1016/j.vaccine.2004.05.012

Cited by 10 publications

(3 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We previously demonstrated that the 12/15-LOX-dependent pathway to IL-12 is the predominant source of IL-12 production in atherosclerotic plaques (58). Together with the data we have presented in this report with regard to toxoplasmosis, as well as the fact that macrophage activity is important for many other chronic diseases (10,15,19), it may be that IL-12 production by macrophages is preferentially involved during the chronic response. Studies employing macrophage-specific knockouts of IL-12 will be required to formally test this hypothesis.…”

Section: Discussionsupporting

confidence: 75%

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

et al. 2009

View full text Add to dashboard Cite

Interleukin-12 (IL-12) is critical for resistance to Toxoplasma gondii during both the acute and chronic stages of infection. However, the cellular and molecular pathways that regulate IL-12 production during chronic toxoplasmosis are incompletely defined. We recently discovered that 12/15-lipoxygenase (12/15-LOX), which oxidizes unsaturated lipids in macrophages, is a novel and selective regulator of IL-12 production. We now demonstrate the essential role of this enzyme in the chronic phase of toxoplasmosis. Although 12/15-LOXdeficient mice were resistant to acute T. gondii infection, 80% of 12/15-LOX-deficient mice died during chronic toxoplasmosis, compared to no deaths in wild-type controls. The morbidity of chronically infected 12/15-LOX mice was associated with an increase in brain inflammation and parasite burden. These data suggest that the evolution of the immune response to T. gondii is accompanied by an increasing requirement for 12/15-LOXmediated signaling. Consistent with this conclusion, 12/15-LOX activity was enhanced during chronic, but not acute, toxoplasmosis. Furthermore, the enhanced susceptibility of 12/15-LOX-deficient mice to chronic toxoplasmosis was associated with reduced production of IL-12 and gamma interferon (IFN-␥) that was not evident during acute infection. Importantly, ex vivo IFN-␥ production by 12/15-LOX-deficient splenocytes could be rescued by the addition of recombinant IL-12. These data establish that 12/15-LOX is a critical mediator of the chronic type 1 inflammatory response and that immune mediators can be subject to distinct cellular and/or molecular mechanisms of regulation at different stages of inflammation.Lipoxygenase and cyclooxygenase families are critical regulators of chronic inflammation that seem to play little role in acute processes (26, 37). Because of this potential specificity, these lipid-metabolizing enzymes have been targeted for years in the search for pathways that selectively impact chronic inflammatory disease. Several studies demonstrated an important role for cyclooxygenase and lipoxygenase products in regulating interleukin-12 (IL-12) production, and lipoxygenases in particular contribute toward the response to Toxoplasma gondii. Specifically, lipoxin A 4 (LxA 4 ), a product of both 15-lipoxygenase (15-LOX) and 5-lipoxygenase (5-LOX) (45), downregulates IL-12 produced by toxoplasma antigen-activated dendritic cells (DCs), thereby tempering the immune response (3,42,57). Indeed, 5-LOX-deficient mice infected with T.

show abstract

Section: Discussionsupporting

confidence: 75%

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

et al. 2009

View full text Add to dashboard Cite

show abstract

“…It was toward this goal that we decided to test the recombinant adenovirus vector expressing IL-12 (Ad5IL-12) in this study for its effect on s.c. established tumors formed by the human prostate tumor LNCaP cell line in NOD.scid mice. The recombinant Ad5IL-12 vector tested in this study was previously shown to induce protection against leishmaniasis in susceptible BALB/c mice by enhancing Th1 response (16,17). This vector was also shown to have potent antitumor effects causing complete regression of established breast cancers (18).…”

Section: Introductionmentioning

confidence: 84%

Attenuation of the Glucocorticoid Response during Ad5IL-12 Adenovirus Vector Treatment Enhances Natural Killer Cell–Mediated Killing of MHC Class I–Negative LNCaP Prostate Tumors

et al. 2007

View full text Add to dashboard Cite

Tumor cells can evolve to evade immune responses by down-modulating surface MHC class I expression and become refractory to T cell-directed immunotherapy. We employed a strategy to bypass this escape mechanism using a recombinant adenovirus vector expressing interleukin-12 (Ad5IL-12) to target natural killer (NK) cell-mediated killing of human prostate tumors in NOD.scid mice. Fluorescence-activated cell sorting analysis revealed that LNCaP tumor cells bear negligible levels of MHC class I molecules; yet, they express MICA/B molecules, ligands for the NKG2D receptors found on NK cells. Transduction of LNCaP cells with the Ad5IL-12 vector prevented tumor formation in NOD.scid mice, indicating that NK cells alone can conduct tumor immunosurveillance and mediate protection. Intratumor injection of the Ad5IL-12 vector to established LNCaP tumors in NOD.scid mice resulted in a significant delay of tumor growth mediated by NK cell killing activity. The dependency of NK cells in this protective response was shown by the complete loss of Ad5IL-12 therapeutic efficacy on LNCaP tumors established in NOD.Cg-Rag1(tm1Mom)Prf1(tm1Sdz) congenic mice, which are devoid of NK cell activity. More pronounced attenuation of tumor growth and enhanced NK killing activity was observed when pharmacologic adrenalectomy with mitotane was done in combination with Ad5IL-12 vector treatment. The Ad5IL-12 vector treatment also induced killing of MICA/B-negative MHC class I-positive PC3 tumors formed in NOD.scid mice. Together, these results indicate that a targeted NK cell response could provide a generic approach for cancer immunotherapy, and that enhancing the NK cell response via control of cortisol levels may provide an additional therapeutic avenue in cancer.

show abstract

“…In this regard, rAd5 represent an interesting alternative when compared to other formulations of recombinant vaccines. They are extremely efficient in inducing high levels of expression of recombinant antigen in host cells in vivo [5], including professional antigen presenting cells such as dendritic cells, Kupffer cells and macrophages [7, 58]. In addition, viral particles are endowed with different components ( e.g.…”

Section: Discussionmentioning

confidence: 99%

MyD88-dependent protective immunity elicited by adenovirus 5 expressing the surface antigen 1 from Toxoplasma gondii is mediated by CD8+ T lymphocytes

Mendes

Caetano

Penido

et al. 2011

Vaccine

View full text Add to dashboard Cite

Toxoplasma gondii is an intracellular parasite widely spread around the world. The Surface Antigens (SAG) 1, 2 and 3 are the main proteins expressed on the surface of T. gondii tachyzoites. Replication-defective adenovirus serotype 5 (rAd5) is one of the most potent recombinant viral vectors for eliciting T cell-mediated immunity in mice and humans. Here we show that vaccination with rAd5 expressing SAG1 (AdSAG1), but neither SAG2 nor SAG3, induces protective immunity in the highly susceptible C57BL/6 mice challenged with T. gondii. Furthermore, we evaluated different immunological components involved on viral induced protective immunity. We observed that host protection elicited by AdSAG1 is highly dependent on IL-12, IFN-γ and CD8+ T lymphocytes. Importantly, the induction of protective immunity (T cell-derived IFN-γ) was also dependent on Myeloid Differentiation Factor 88 (MyD88), and thus, likely to involve Toll-Like receptors. We conclude that protective parasite specific-CD8+ T cells are elicited by a mechanism that involves MyD88-dependent induction of IL-12.

show abstract

Life-long systemic protection in mice vaccinated with and adenovirus IL-12 vector requires active infection, macrophages and intact lymph nodes

Cited by 10 publications

References 39 publications

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

12/15-Lipoxygenase-Dependent Myeloid Production of Interleukin-12 Is Essential for Resistance to Chronic Toxoplasmosis

Attenuation of the Glucocorticoid Response during Ad5IL-12 Adenovirus Vector Treatment Enhances Natural Killer Cell–Mediated Killing of MHC Class I–Negative LNCaP Prostate Tumors

MyD88-dependent protective immunity elicited by adenovirus 5 expressing the surface antigen 1 from Toxoplasma gondii is mediated by CD8+ T lymphocytes

Contact Info

Product

Resources

About