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1.
Vaccine ; 26(5): 614-22, 2008 Jan 30.
Article in English | MEDLINE | ID: mdl-18166249

ABSTRACT

The current anthrax vaccine imparts protective immunity by generating a humoral immune response against a single antigen, the PA exotoxin subunit. While this response neutralizes the two anthrax exotoxins and protects the recipient from toxin-related mortality, the recipient is not protected from spore germination, infection, and/or bacteremia. Moreover, protective immunity against PA must be generated via a lengthy injection schedule and maintained by a yearly booster. In an effort to improve upon the current vaccine formulation, we screened six of seven known virulence factors encoded by Bacillus anthracis epigenetic elements pXO1 and pXO2 as well as the major surface proteins EA1 and SAP. Screening was carried out in conjunction with a plasmid-based technology known for its ability to generate type 1 and type 2 T-helper responses. Long-term high level antibody titers were generated against the products of eag (EA1), sap (SAP), and the capA capsule synthesis subunit in vivo. Further analysis of PA- and EA1-vaccinated mice demonstrated antigen-specific type 1 helper responses including IFN-gamma secretion and lysis of EA1- or PA-loaded macrophages; further, an EA1 T-cell epitope was identified. The results demonstrate that anthrax antigens other than PA might be suitable for the generation of durable immune responses against anthrax.


Subject(s)
Anthrax Vaccines/immunology , Anthrax/immunology , Antigens, Bacterial/immunology , Bacillus anthracis/immunology , Bacterial Toxins/immunology , Exotoxins/immunology , Plasmids/immunology , Th1 Cells/immunology , Th2 Cells/immunology , Vaccination , Animals , Antigens, Bacterial/genetics , Bacterial Proteins/genetics , Bacterial Proteins/immunology , Bacterial Toxins/genetics , Epigenesis, Genetic , Exotoxins/genetics , Female , Interferon-gamma/metabolism , Macrophages/metabolism , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Mice , Mice, Inbred BALB C , Protein Subunits/genetics , Protein Subunits/immunology , Species Specificity , Vaccines, Synthetic/immunology
2.
Cancer Lett ; 237(1): 45-55, 2006 Jun 08.
Article in English | MEDLINE | ID: mdl-16019131

ABSTRACT

We describe the use of retrogen plasmid-based vaccine technology to break tolerance and to generate a robust, dose-dependent antibody response against the self cancer antigen, survivin. We further demonstrate that this phenomenon is due to the incorporation of the survivin antigen into the retrogen system rather than to some peculiarity unique to survivin. In contrast to other genetic immunization methods designed to produce antibody responses, the retrogen system results in a broad range of antibody isotypes, indicative of both a Th-1 and a Th-2 CD4+ response. Additional evidence of a Th-1 response is demonstrated by tumor growth inhibition in a mouse model of colon cancer metastasis. We speculate that this cost-effective technology could one day bolster or even supplant the use of monoclonal antibodies in the targeting of cell surface cancer antigens.


Subject(s)
Antibodies/blood , Cancer Vaccines/administration & dosage , Colorectal Neoplasms/prevention & control , Vaccines, DNA/administration & dosage , Animals , Antigens, Neoplasm/biosynthesis , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Cancer Vaccines/immunology , Colorectal Neoplasms/blood , Colorectal Neoplasms/immunology , Dose-Response Relationship, Immunologic , Female , Inhibitor of Apoptosis Proteins , Mice , Mice, Inbred BALB C , Microtubule-Associated Proteins/biosynthesis , Microtubule-Associated Proteins/genetics , Microtubule-Associated Proteins/immunology , Neoplasm Transplantation , Repressor Proteins , Survivin , Th1 Cells/immunology , Th2 Cells/immunology , Vaccination/methods , Vaccines, DNA/immunology
3.
Mol Ther ; 6(5): 627-36, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12409261

ABSTRACT

Gene therapy for cancer using suicide genes such as the herpes simplex virus thymidine kinase gene (HSVtk) has been explored extensively in preclinical and clinical studies. We have improved the use of HSVtk by combining it with two cytokine genes encoding granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2), and determined their additive/synergistic effects on tumor regression and inhibition of metastases in the non-immunogenic, spontaneously metastatic mammary tumor model, 4T1. Two adenoviral vectors (AV) were constructed, one carrying HSVtk (AV-TK) and the second (AV-GM/IL2) carrying Gm-CSf and Il2. Only the combination of AV-TK/GCV and AV-GM/IL2 showed a significant decrease in tumor growth and reduction of distant metastases with 25% of the tumors undergoing complete regression. When surgical excision of primary tumors was included in the regimen, local treatment with AV-TK/GCV plus AV-GM/IL2 further enhanced long-term survival. A fraction of the treated mice developed anti-tumor immunity and survived a second challenge with 4T1. Functional analyses demonstrated infiltration of lymphocytes within the tumor and a strong tumor-specific cytotoxic T lymphocyte response in TK- plus cytokine-treated animals. These data indicate that the coexpression of GM-CSF and IL-2 can augment the effect of HSVtk suicide gene therapy.


Subject(s)
Gene Transfer Techniques , Genetic Therapy/methods , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Interleukin-2/genetics , Mammary Neoplasms, Animal/immunology , Mammary Neoplasms, Animal/therapy , Simplexvirus/enzymology , Thymidine Kinase/genetics , Adenoviridae/genetics , Animals , Lung Neoplasms/secondary , Lymphocytes/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neoplasm Metastasis , Neoplasm Transplantation , Time Factors , Transgenes
4.
Bioorg Med Chem Lett ; 12(5): 775-8, 2002 Mar 11.
Article in English | MEDLINE | ID: mdl-11859000

ABSTRACT

Novel phenol bis-Mannich adducts were identified as IL-2 expression inhibitors in a T cell proliferation screening assay. Analogues of the lead compound were prepared through parallel synthesis and a highly selective IL-2 inhibitor was discovered that provided a suitable compound for further optimization.


Subject(s)
Interleukin-2/antagonists & inhibitors , Mannich Bases/chemistry , Phenols/chemistry , Piperazines/chemical synthesis , Piperazines/pharmacology , Actins/genetics , Actins/metabolism , DNA Adducts/chemistry , Humans , Inhibitory Concentration 50 , Jurkat Cells/drug effects , Luciferases/metabolism , Promoter Regions, Genetic
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