Co-expression of granulocyte-macrophage colony-stimulating factor with antigen enhances humoral and tumor immunity after DNA vaccination

Sun, Xiang; Hodge, Lisa; Jones, Harlan P.; Tabor, Leslie; Simecka, Jerry W.

doi:10.1016/s0264-410x(01)00476-5

Cited by 57 publications

(33 citation statements)

References 30 publications

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“…Furthermore, humoral and cellular immune responses have been reported after DNA immunization against b-gal. 13,14 The DNA vaccine was injected at a time (day 7) when DC had already been substantially expanded in vivo by Flt-3L, 5 Flt-3L application was then continued for another 5 days in order to achieve a high number of in vivo transfected DC.…”

Section: Discussionmentioning

confidence: 99%

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

et al. 2004

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Since transfection of dendritic cells (DC) plays a key role in DNA vaccination, in vivo expansion of DC might be a tool to increase vaccine efficacy. We asked whether Fms-like tyrosine kinase-3 ligand (Flt-3L), a growth factor for DC, can be used as an adjuvant for DNA vaccination. Betagalactosidase (b-gal) was used as a model antigen in C57BL/6 mice. Mice were immunized i.m. with DNA coding for b-gal with or without additional injection of Flt-3L. In both cases, antigen-specific CD4 þ and CD8 þ T cells were detectable after vaccination. Compared with DNA alone, additional administration of Flt-3L led to a significant increase in the antigen-specific proliferative response. However, increased cytotoxicity by T cells was not observed. The cytokines secreted by splenocytes of immunized mice upon in vitro stimulation with antigen had a TH2 profile. Humoral responses against b-gal preferentially consisted of IgG1 antibodies. Analysis of DC from Flt-3L-treated mice revealed an immature phenotype with low or absent expression levels of CD80, CD86 and CD40. We conclude that Flt-3L does not generally skew immune responses towards a TH1 type. More likely, factors determined by the antigen and/or the vaccination procedure itself are crucial for the resulting type of immune response. Flt-3L -under circumstances such as the one we have investigated -can also lead to suppression of TH1 T cell immunity, possibly by expansion of immature/ unactivated DC.

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Section: Discussionmentioning

confidence: 99%

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

et al. 2004

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“…When Sm23 DNA was coadministered with plasmid DNA encoding IL-4, it did not significantly change the level of protection (15,16). Plasmids encoding GM-CSF have been used as molecular adjuvants for enhancement of DNA vaccination (9,53,57). The mechanism by which GM-CSF enhances immunity has not yet been completely elucidated.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism by which GM-CSF enhances immunity has not yet been completely elucidated. However, evidence suggests that GM-CSF may work through its effects on antigen-presenting cells (APCs) (53). APCs can directly uptake the DNA vaccine and present the expressed antigen, or the DNA vaccine can also be expressed by somatic cells, and the released antigen is then picked up by APCs (53).…”

Section: Discussionmentioning

confidence: 99%

“…However, evidence suggests that GM-CSF may work through its effects on antigen-presenting cells (APCs) (53). APCs can directly uptake the DNA vaccine and present the expressed antigen, or the DNA vaccine can also be expressed by somatic cells, and the released antigen is then picked up by APCs (53). Major APCs involved in DNA vaccines appear to be the dendritic cells (20), and several studies have demonstrated that introduction of plasmid encoding GM-CSF results in the accumulation of dendritic cells in vivo (21,31).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to dendritic cells, GM-CSF has similar effects on macrophages, which are also important APCs (54). Therefore, it is logical that linking antigen and GM-CSF expression closely in vivo may provide a more conducive microenvironment for the uptake and presentation of antigen by dendritic cells or macrophages (53). Similarly, plasmids coding for IL-4 have also been used to preferentially augment B-cellmediated Th2 responses and Ig class switching (15,16,49).…”

Section: Discussionmentioning

confidence: 99%

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Induction of Protective Immunity againstSchistosoma mansonivia DNA Priming and Boosting with the Large Subunit of Calpain (Sm-p80): Adjuvant Effects of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-4

et al. 2003

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Considerable morbidity and mortality result from schistosomiasis, an affliction affecting an estimated 200 million people. Although schistosomicidal drugs and other control measures (including public hygiene and snail control) exist, the advent of an efficacious vaccine remains the most potentially powerful means for controlling this disease. We have targeted a vaccine candidate (large subunit of calpain, Sm-p80) because of its consistent immunogenicity, protective potential, and integral role in surface membrane biogenesis of schistosomes. Since surface membrane renewal appears to be one of the major phenomena employed by schistosomes to evade the host's immune system; an immune response directed against Sm-p80 should render the parasite susceptible to immune clearance from the host by both providing a focus of attack and by potentially impairing the membrane repair process. In the present study, we have employed DNA immunization protocols using Sm-p80 with plasmids encoding granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). Sm-p80 by itself provided 39% protection (P ‫؍‬ <0.0001) against challenge infection in C57BL/6 mice. This protection was increased to 44% (P ‫؍‬ <0.0001) when the plasmid encoding GM-CSF was coadministered with Sm-p80 DNA. Coinjection of plasmid DNA encoding IL-4 with Sm-p80 DNA yielded a protection level of 42% (P ‫؍‬ <0.0001). Statistically, the protection conferred by including GM-CSF, but not IL-4, was significantly greater than that when only Sm-p80 was used. Sm-p80 DNA by itself elicited strong responses that include IgG2A and IgG2B antibody isotypes. The introduction of GM-CSF DNA with Sm-p80 DNA led to distinct increases in total IgG and IgG1 titers, whereas the coadministration of IL-4 DNA with Sm-p80 DNA resulted in a slight elevation of IgG1 and IgG3 titers and in some reduction of IgG2A and IgG2B titers. Our data again indicate that Sm-p80 can be an excellent candidate for a schistosomiasis vaccine.

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Enhanced efficacy of DNA vaccination against Her‐2/neu tumor antigen by genetic adjuvants

Chang

Lee

et al. 2004

Intl Journal of Cancer

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Certain types of malignant tumors overexpress Her-2/neu, a transmembrane glycoprotein of the class I receptor tyrosine kinase erbB family. To develop an effective Her-2/neu vaccine for selective immunotherapy of these malignancies, we prepared Her-2/neu DNA plasmid encoding the transmembrane and extracellular domain (pHM) and tested the ability of this construct to induce antitumor immunity in animal models. In addition, we investigated the effects of cytokine used as a genetic adjuvant. Modulation by factors that affect T-cell function or hematopoiesis, including interleukin-12, interleukin-15, interleukin-18, interleukin-23, Eta-1, Flt3L and GM-CSF, was studied in the forms of monocistronic and bicistronic plasmid. Our results demonstrated that vaccination of pHM could induce successful antitumor immunity against Her-2/neu-expressing murine tumor cells in BALB/c mice. We also showed that the antitumor activity of pHM was augmented by coadministration and coexpression of different cytokines. Despite the similar levels of gene expression, the antitumor effects of bicistronic plasmids coexpressing Her-2/neu antigen and cytokine were improved in comparison with coadministration of separate monocistronic plasmid. In particular, coexpression of interleukin-18 or GM-CSF with Her-2/neu increased antitumor activity in both preventive and therapeutic experiments. These findings can help in the decision concerning which of the various cytokine adjuvants should be used for the development of a Her-2/neu DNA vaccine. In addition, our results from a large panel of cytokine adjuvants in the various tumor models may provide an insight into the important immune components of antitumor immunity.

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Co-expression of granulocyte-macrophage colony-stimulating factor with antigen enhances humoral and tumor immunity after DNA vaccination

Cited by 57 publications

References 30 publications

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

Flt-3 ligand as adjuvant for DNA vaccination augments immune responses but does not skew TH1/TH2 polarization

Induction of Protective Immunity againstSchistosoma mansonivia DNA Priming and Boosting with the Large Subunit of Calpain (Sm-p80): Adjuvant Effects of Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-4

Enhanced efficacy of DNA vaccination against Her‐2/neu tumor antigen by genetic adjuvants

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