Plasmid Vaccine Expressing Granulocyte-Macrophage Colony-Stimulating Factor Attracts Infiltrates Including Immature Dendritic Cells into Injected Muscles

Haddad, Diana; Ramprakash, Jayanthi; Sedegah, Martha; Charoenvit, Yupin; Baumgartner, Roxanne E.; Kumar, Sanjai; Hoffman, Stephen L.; Weiss, Walter R.

doi:10.4049/jimmunol.165.7.3772

Cited by 95 publications

(62 citation statements)

References 47 publications

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“…It is not known whether these cells are recruited to the gastric mucosa, arise from local proliferation or both. Similar findings have been observed following intramuscular injections with plasmids encoding GM-CSF (53). In these studies, expression of GM-CSF in muscle resulted in local accumulation of macrophages, dendritic cells and granulocytes but not CD4 T cells.…”

Section: Discussionsupporting

confidence: 74%

Local Transgenic Expression of Granulocyte Macrophage-Colony Stimulating Factor Initiates Autoimmunity

Biondo

Nasa

Marshall

et al. 2001

The Journal of Immunology

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Mechanisms leading to breakdown of immunological tolerance and initiation of autoimmunity are poorly understood. Experimental autoimmune gastritis is a paradigm of organ-specific autoimmunity arising from a pathogenic autoimmune response to gastric H/K ATPase. The gastritis is accompanied by autoantibodies to the gastric H/K ATPase. The best characterized model of experimental autoimmune gastritis requires neonatal thymectomy. This procedure disrupts the immune repertoire, limiting its usefulness in understanding how autoimmunity arises in animals with intact immune systems. Here we tested whether local production of GM-CSF, a pro-inflammatory cytokine, is sufficient to break tolerance and initiate autoimmunity. We generated transgenic mice expressing GM-CSF in the stomach. These transgenic mice spontaneously developed gastritis with an incidence of about 80% after six backcrosses to gastritis-susceptible BALBc/CrSlc mice. The gastritis is accompanied by mucosal hypertrophy, enlargement of draining lymph nodes and autoantibodies to gastric H/K ATPase. An infiltrate of dendritic cells and macrophages preceded CD4 T cells into the gastric mucosa. T cells from draining lymph nodes specifically proliferated to the gastric H/K ATPase. CD4 but not CD8 T cells transferred gastritis to nude mouse recipients. CD4+ CD25+ T cells from the spleen retained anergic suppressive properties that were reversed by IL-2. We conclude that local expression of GM-CSF is sufficient to break tolerance and initiate autoimmunity mediated by CD4 T cells. This new mouse model should be useful for studies of organ-specific autoimmunity.

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Section: Discussionsupporting

confidence: 74%

Local Transgenic Expression of Granulocyte Macrophage-Colony Stimulating Factor Initiates Autoimmunity

Biondo

Nasa

Marshall

et al. 2001

The Journal of Immunology

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“…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). Dendritic cells stimulated with GM-CSF are also known to differentiate and mature into increasingly effective APCs (42).…”

Section: Discussionmentioning

confidence: 99%

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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“…10 Furthermore, GM-CSF has been shown to actively recruit DC in vivo. 6,18,19 However, the therapeutic efficacy of cytokine gene transfer by replication-incompetent vector has often met disappointing results, especially in pre-established tumors.…”

Section: Introductionmentioning

confidence: 99%

Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect

et al. 2006

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Oncolytic adenoviral vectors are currently being developed as biologic anticancer agents. Coupling the lytic function of an oncolytic adenovirus (Ad) with its ability as a transgene delivery system represents a powerful extension of this methodology. A clear advantage is the amplification of a therapeutic gene, as replicating vectors would be able to infect and deliver the gene of interest to neighboring cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one of the most potent stimulators of a specific and long-lasting antitumor immunity and its important role in the maturation of antigen-presenting cells to induce T-cell activation has been well documented. Similarly, the B7 family has also been shown to play an integral role in mediating an antitumor response. Most tumor cells, however, lack the expression of these costimulatory molecules on their surface, thus escaping immune system recognition. To increase the antitumor effect of an oncolytic Ad, we have generated an E1B 55 kDa-deleted oncolytic adenoviral vector, YKL-GB, that expresses both GM-CSF and B7-1. The therapeutic efficacy of YKL-GB Ad was evaluated in immunocompetent mice bearing murine melanoma B16-F10 tumors. Significant inhibition of tumor growth was seen in mice treated with YKL-GB compared to those treated with the analogous vector, YKL-1. Moreover, YKL-GB oncolytic Ad demonstrated enhanced antitumor activity and higher incidences of tumor regression compared to a replication-incompetent Ad, dl-GB, which coexpresses GM-CSF and B7-1. Localized GM-CSF and B7-1 gene transfer also conferred long-lasting immunity against a tumor re-challenge. To establish that the observed antitumor effect is associated with the generation of a tumorspecific immune response, we carried out interferon-g enzymelinked immune spot assay. We observed that YKL-GB induced significantly higher immune cell activation than YKL-1. Furthermore, immunohistochemical studies demonstrated robust dendritic cells and CD4 + /CD8 + T-cell infiltration in these mice compared to the YKL-1-treated groups. In agreement with these results, splenocytes from tumor-bearing mice treated with YKL-GB expressed high levels of the costimulatory and activation molecules. These findings demonstrate the effectiveness of enhancing the immune response against tumors with an oncolytic Ad expressing both GM-CSF and B7-1 and provide a potential therapeutic strategy for the management of neoplasia.

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Plasmid Vaccine Expressing Granulocyte-Macrophage Colony-Stimulating Factor Attracts Infiltrates Including Immature Dendritic Cells into Injected Muscles

Cited by 95 publications

References 47 publications

Local Transgenic Expression of Granulocyte Macrophage-Colony Stimulating Factor Initiates Autoimmunity

Local Transgenic Expression of Granulocyte Macrophage-Colony Stimulating Factor Initiates Autoimmunity

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

Concurrent delivery of GM-CSF and B7-1 using an oncolytic adenovirus elicits potent antitumor effect

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