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Modulation of cellular responses by plasmid CD40L: CD40L plasmid vectors enhance antigen-specific helper T cell type 1 CD4+ T cell-mediated protective immunity against herpes simplex virus type 2 in vivo.
- Source :
-
Human gene therapy [Hum Gene Ther] 2001 Jun 10; Vol. 12 (9), pp. 1091-102. - Publication Year :
- 2001
-
Abstract
- Engineering gene therapy vectors to modulate the immune response is an important goal. In this regard, costimulation of T cells is a critical determinant in immune activation. The costimulatory molecule CD40, expressed on antigen-presenting cells, is thought to interact with CD40 ligand (CD40L) expressed on activated CD4(+) or CD8(+) T cells to further drive interleukin-2 receptor (IL-2R) expression and antigen-specific T cell expansion necessary for both class II and class I responses. To compare the specific roles of these two costimulatory molecules in immune induction in a herpes simplex virus (HSV) model, we constructed plasmid DNAs expressing CD40 and CD40L, coimmunized these molecules with a gD plasmid vaccine, and then analyzed immune modulatory effects as well as protection against lethal HSV-2 challenge. We observed that gD-specific IgG production was unaffected by these molecules. However, a higher production of IgG2a isotype was induced by CD40L coinjection, suggesting that CD40L drives immune responses towards a helper T cell type 1 (Th1) phenotype. CD40L also enhanced Th cell proliferative responses and production of Th1-type cytokines (IL-2 and IFN-gamma) and beta-chemokines (RANTES and MIP-1alpha) from splenocytes. In contrast, CD40 showed slightly increasing effects on T cell proliferation responses and cytokine and chemokine production. When animals were challenged with a lethal dose of HSV-2, CD40L-coimmunized animals exhibited a significantly enhanced survival rate, as compared with CD40 coinjection or gD DNA vaccine alone. This enhanced protection appears to be mediated by Th1-type CD4(+) T cells, as determined by in vitro and in vivo T cell subset deletion. CD40L also promoted migration of CD4(+) T cells into the muscle sites. These studies demonstrate that CD40L can play an important role in protective antigen-specific immunity in a gene-based model system through increased expansion of the CD4(+) Th1 T cell subset in vivo.
- Subjects :
- Adjuvants, Immunologic genetics
Administration, Intravaginal
Animals
CD40 Ligand genetics
Cell Movement immunology
Chemokines biosynthesis
Cytokines biosynthesis
Female
Genetic Vectors administration & dosage
Genetic Vectors chemical synthesis
Genetic Vectors immunology
Herpes Genitalis mortality
Humans
Immunity, Cellular genetics
Immunoglobulin G biosynthesis
Injections, Intramuscular
Lymphocyte Activation genetics
Mice
Mice, Inbred BALB C
Plasmids administration & dosage
Plasmids genetics
Vaccines, DNA administration & dosage
Vagina
Adjuvants, Immunologic therapeutic use
CD40 Ligand therapeutic use
Epitopes, T-Lymphocyte immunology
Herpes Genitalis immunology
Herpes Genitalis prevention & control
Herpesvirus 2, Human immunology
Plasmids immunology
Th1 Cells immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1043-0342
- Volume :
- 12
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Human gene therapy
- Publication Type :
- Academic Journal
- Accession number :
- 11399230
- Full Text :
- https://doi.org/10.1089/104303401750214302