Immunobiology of lnterleukin-12

Trinchieri, Giorgio

doi:10.1007/bf02786451

Cited by 178 publications

(127 citation statements)

References 88 publications

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“…Recombinant IL-12 has generated interest as a potential cancer therapeutic agent due to the ability of murine IL-12 to induce tumor regression and to cure in various mouse models of cancer. Studies examining the anti-tumor mechanisms of IL-12 have implicated various cellular mediators including CD8 T cells, NK cells, and NK T cells [26,27] . Taking full advantages of characters of DCs and IL-12 respectively, constitutive production of IL-12 by AdVIL-12/DCs, coupled with their ability to take up and process tumor antigens, migrate to tumor site or lymph nodes can induce an effective immune response.…”

Section: Discussionmentioning

confidence: 99%

An effective vaccine against colon cancer in mice: Use of recombinant adenovirus interleukin-12 transduced dendritic cells

Wang²,

Zhang³

2008

WJG

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CT26 TP DCs 383 ± 65 mm 3 , P < 0.05) and protective models. Moreover, the CT26 TP AdVIL-12/DC vaccination enhances tumor-specific CTL activity, producing high levels of IFNγ in immunized mice. Ex vivo primed T cells with AdVIL-12/DCs were able to induce more effective CTL activity than in primed T cells with CT26 TP/DCs (E:T = 100:1, 69.49% ± 6.11% specific lysis vs 37.44% ± 4.32% specific lysis, P < 0.05). CONCLUSION:Vaccination with recombinant AdVIL-12 transduced DC pulsed tumor cell lysate enhance antitumor immunity specific to colon cancer in mice. INTRODUCTIONColon cancer is one of the most common cancers [1] . Although there has been great progress in colon cancer therapy, it is still difficult to treat advanced colon cancer because it has usually metastasized to lymph glands and other organs. Currently, radical surgery represents the standard method of therapy. Adjuvant therapy such as chemotherapy and radiation therapy have been widely applied, but colon cancer control at the advanced stage remains difficult [2,3] . A new adjuvant therapeutic method is needed in order to improve the 5-year survival rate of patients with colon cancer. Today, tumor immunotherapy for colon cancer is extremely appealing [4,5] .Dendritic cells (DCs) are professional antigen presenting cells (APCs) that both initiate and modulate the immune response [6] . DCs are cells in the pathway of antigen capture and presentation to T cells, with the Abstract AIM: To investigate the effect of a vaccine with recombinant adenovirus interleukin-12 (AdVIL-12) transduced dendritic cells (DCs) against colon cancer in mice. M E T H O D S :

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Section: Discussionmentioning

confidence: 99%

An effective vaccine against colon cancer in mice: Use of recombinant adenovirus interleukin-12 transduced dendritic cells

Wang²,

Zhang³

2008

WJG

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“…17,18,55,62,63,65,67,68 The timing, dose, and location of IL -12 administration have been shown to have immunostimulatory, 22,44,67,68 immune -suppressive, 30,31,62 -65 and antiangiogenic 25,57 effects in different models. Therefore, its effect as a vaccine adjuvant should be carefully studied and used with caution, as it may in fact inhibit instead of potentiating vaccines.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive effects of interleukin-12 coexpression in melanoma antigen gene–modified dendritic cell vaccines

et al. 2002

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Genetic immunotherapy with tumor antigen gene -modified dendritic cells ( DC ) generates robust immunity, although antitumor protection is not complete in all models. Previous experience in a model in which C57BL / 6 mice immunized with DC transduced with adenoviral vectors expressing MART -1 demonstrated a 20 -40% complete protection to a tumor challenge with B16 melanoma cells. Tumors that did develop in immunized mice had slower growth kinetics compared to tumors implanted in naïve mice. In the present study, we wished to determine if the supraphysiological production of the Th1 -skewing cytokine interleukin -12 ( IL -12 ) could enhance immune activation and antitumor protection in this model. In a series of experiments immunizing mice with DC cotransduced with MART -1 and IL -12, antitumor protection and antigen -specific splenocyte cytotoxicity and interferon g production inversely correlated with the amount of IL -12 produced by DC. This adverse effect of IL -12 could not be explained by a direct cytotoxic effect of natural killer cells directed towards DC, nor the production of nitric oxide leading to down -regulation of the immune response -the two mechanisms previously recognized to explain immune -suppressive effects of IL -12 -based vaccine therapy. In conclusion, in this animal model, IL -12 production by gene -modified DC leads to a cytokine -induced dose -dependent inhibition of antigen -specific antitumor protection.

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“…Moreover, in the case of extracellular pathogens that can readily be controlled with complement activation and humoral immunity, the phagocytosis of iC3b-coated bacteria by CR3 would help control potentially destructive inflammation through IL-12 downregulation. In fact, inhibition of IL-12 would not only suppress T helper type 1 cell-mediated immunity but would also upregulate T helper type 2 responses required for effective humoral (antibody) responses (Trinchieri, 1998). It is thus possible that P. gingivalis has co-opted a physiological anti-inflammatory CR3-dependent mechanism to evade innate immune clearance.…”

Section: In Vivo Evidence For Cr3 Exploitation By P Gingivalis and Imentioning

confidence: 99%

Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

Hajishengallis

Wang²,

Liang³

et al. 2008

Advances in Experimental Medicine and Biology

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The capacity of certain pathogens to exploit innate immune receptors enables them to undermine immune clearance and persist in their host, often causing disease. Here we review subversive interactions of Porphyromonas gingivalis, a major periodontal pathogen, with the complement receptor-3 (CR3; CD11b/CD18) in monocytes/macrophages. Through its cell surface fimbriae, P. gingivalis stimulates Toll-like receptor-2 (TLR2) inside-out signaling which induces the highaffinity conformation of CR3. Although this activates CR3-dependent monocyte adhesion and transendothelial migration, P. gingivalis has co-opted this TLR2 proadhesive pathway for CR3 binding and intracellular entry. In CR3-deficient macrophages, the internalization of P. gingivalis is reduced 2-fold but its ability to survive intracellularly is reduced 1000-fold, indicating that CR3 is exploited by the pathogen as a relatively safe portal of entry. The interaction of P. gingivalis fimbriae with CR3 additionally inhibits production of bioactive (p70) interleukin-12, which mediates immune clearance. In vivo blockade of CR3 leads to reduced persistence of P. gingivalis in the mouse host and diminished ability to cause periodontal bone loss, the hallmark of periodontal disease. Strikingly, the ability of P. gingivalis to interact with and exploit CR3 depends upon quantitatively minor components (FimCDE) of its fimbrial structure, which predominantly consists of polymerized fimbrillin (FimA). Indeed, isogenic mutants lacking FimCDE but expressing FimA are dramatically less persistent and virulent than the wild-type organism both in vitro and in vivo. This model of immune evasion through CR3 exploitation by P. gingivalis supports the concept that pathogens evolved to manipulate innate immune function for promoting their adaptive fitness.

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Immunobiology of lnterleukin-12

Cited by 178 publications

References 88 publications

An effective vaccine against colon cancer in mice: Use of recombinant adenovirus interleukin-12 transduced dendritic cells

An effective vaccine against colon cancer in mice: Use of recombinant adenovirus interleukin-12 transduced dendritic cells

Immunosuppressive effects of interleukin-12 coexpression in melanoma antigen gene–modified dendritic cell vaccines

Subversion of Innate Immunity by Periodontopathic Bacteria via Exploitation of Complement Receptor-3

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