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1.
J Immunol ; 177(2): 1197-207, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16818778

ABSTRACT

Intradermal (i.d.) immunization is a promising route of vaccine administration. Suitable i.d. adjuvants are important to increase vaccine efficacy in poorly responding populations such as the elderly or for dose-sparing strategies in the face of vaccine shortages. Bacterial exotoxins, such as Escherichia coli heat-labile enterotoxin (LT), exert strong immunostimulatory effects through binding to monosialoganglioside (GM1) cell surface receptors; however, injection is hampered by local inflammation. We demonstrate that the injection of LT formulations deficient in GM1 binding by mutation (LT(G33D)) or in vitro ligand coupling does not cause localized edema and inflammation in mice, yet these formulations retain potent adjuvant activity by enhancing functional Ab and cellular immune responses to coadministered Ags. Complete protection against in vivo lethal tetanus toxin challenge and the induction of Ag-specific CTL responses capable of killing target cells in vivo indicated in vivo efficacy of the induced immune responses. LT(G33D) proved superior to standard alum adjuvant regarding the magnitude and breadth of the induced immune responses. Immunizations in complex ganglioside knockout mice revealed a GM1-independent pathway of LT adjuvanticity. Immunostimulation by i.d. LT(G33D) is explained by its ability to induce migration of activated APCs to the proximal draining lymph nodes. LT(G33D) is a promising candidate adjuvant for human trials of parenteral vaccines in general and for current i.d. vaccine development in particular.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Exotoxins/administration & dosage , G(M1) Ganglioside , Adjuvants, Immunologic/metabolism , Alum Compounds/administration & dosage , Alum Compounds/metabolism , Animals , Antibodies, Bacterial/biosynthesis , Antibodies, Bacterial/blood , Antigen-Presenting Cells/cytology , Antigen-Presenting Cells/immunology , Bacterial Toxins/administration & dosage , Cell Line, Tumor , Cell Movement/immunology , Cytotoxicity, Immunologic/genetics , Enterotoxins/administration & dosage , Escherichia coli Proteins/administration & dosage , Exotoxins/metabolism , Female , G(M1) Ganglioside/metabolism , Inflammation/immunology , Inflammation/prevention & control , Injections, Intradermal , Lymph Nodes/cytology , Lymph Nodes/immunology , Melanoma, Experimental , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Knockout , N-Acetylgalactosaminyltransferases/deficiency , N-Acetylgalactosaminyltransferases/genetics , Protein Binding/genetics , Protein Binding/immunology , T-Lymphocytes, Cytotoxic/immunology , Tetanus/genetics , Tetanus/immunology , Tetanus/prevention & control , Tetanus Toxoid/administration & dosage , Tetanus Toxoid/immunology , Tetanus Toxoid/metabolism
2.
Expert Rev Vaccines ; 2(2): 253-67, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12899576

ABSTRACT

The skin is an attractive target for vaccine delivery. Topical application of adjuvants results in potent immune responses and good safety profiles. Adjuvants can be coadministered in a patch with vaccine antigens (transcutaneous immunization) or similar delivery format, or administered separately with an injection or IS patch (Iomai), leading to enhanced immune responses. These observations have moved into the clinic, highlighting the likelihood that skin delivery of vaccines will play an important future role in vaccine applications.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Skin/immunology , Vaccines/administration & dosage , Administration, Cutaneous , Animals , Guinea Pigs , Humans , Immunity, Mucosal , Immunocompetence , Langerhans Cells/immunology , Mice
3.
J Med Virol ; 66(3): 378-83, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11793390

ABSTRACT

Corticosteroid use in transplant recipients increases the incidence and severity of Kaposi's sarcoma (KS), a disease associated with KS-associated herpesvirus (KSHV) infection. Recently, the prototypic corticosteroid, hydrocortisone, was shown to directly induce lytic cycle reactivation of KSHV in latently-infected BCBL-1 cells. The purpose of this study was to examine this phenomenon in further detail. After incubation with dexamethasone (

Subject(s)
Dexamethasone/pharmacology , Glucocorticoids/pharmacology , Herpesvirus 8, Human/drug effects , Hydrocortisone/pharmacology , Virus Activation , Virus Latency/drug effects , Adrenal Cortex Hormones/pharmacology , B-Lymphocytes/cytology , B-Lymphocytes/virology , Cell Line , Glycoproteins/biosynthesis , Herpesvirus 8, Human/growth & development , Herpesvirus 8, Human/metabolism , Humans , Sarcoma, Kaposi/virology , Tetradecanoylphorbol Acetate/pharmacology , Viral Proteins/biosynthesis
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