Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2003-06-06
2004-11-16
Henley, III, Raymond J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S282100
Reexamination Certificate
active
06818221
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the field of using adjuvants to promote a specific type of immunological response.
BACKGROUND
The immune system has evolved two different types of adaptive immunity, each specialized for the elimination of a particular class of pathogens. In response to intracellular microbes, CD4+ T-helper (Th) cells differentiate into Th1 cells, which produce interferon &ggr; (IFN&ggr;) and interleukin (IL)-1, which, in turn, enhance cell-mediated immunity and inhibit the humoral immune responses. In contrast, helminths induce differentiation of CD4+ T-helper (Th) cells into Th2 cells, which produce cytokines (principally IL-4, IL-5, and IL-10) to induce immunoglobulin E (IgE) and eosinophil-mediated destruction of pathogens. The Th2 immune response inhibits cell-mediated immunity and enhances humoral immunity. The mechanism by which a given pathogen induces a Th1 or Th2 type of immune response is unknown.
Distinct subsets of dendritic cells (DCs) differentially induce Th1 and Th2 immune responses. In mice, the putative lymphoid-related CD8&agr;+ DCs in spleens induce Th1 immune responses (Shortman, K. D., et al. 1998. “The linkage between T-cell and dendritic cell development in the mouse thymus,”
Immune Rev
165:39-46). In contrast, Th2 immune responses are induced by the CD8&agr;-myeloid DCs (Maldonado-Lopez, R., et al. 1999. “CD8&agr;+ and CD8&agr;− subclasses of dendritic cells direct the development of distinct T helper cells in vivo,”
J Exp Med
189:587-592; Pulendran, B., et al. 1999. “Distinct dendritic cell subsets differentially regulate the class of immune response in vivo,”
Proc Natl Acad Sci USA
96:1036-1041; Rissoan, M. C., et al. 1999. “Reciprocal control of T helper cell and dendritic cell differentiation,”
Science
283:1183-1186). Different patterns of immunity can be elicited by activating distinct DC subsets.
Escherichia coli
lipopolysaccharide (LPS) is reported to signal through the Toll-like receptor 4 (TLR4) complex (Qureshi, S. T., et al. 1999. “Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4),”
J Exp Med
189:615-625; published erratum appears in
J Exp Med
189:1518) and promote a Th1 immune response in vivo (Khoruts, A., A., et al. 1998. “A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism,”
J Exp Med
187:225-236). In contrast,
Porphyromonas gingivalis
LPS is reported to signal through a TLR4-independent mechanism (Tanamoto, K., S., et al. 1997. “The lipid A moiety of
Porphyromonas gingivalis
lipopolysaccharide specifically mediates the activation of C3H/HeJ mice,”
J Immunol
158:4430-4436). It has now been found that although the LPS from these two different bacterial sources induce potent clonal expansion of antigen-specific CD4+ and CD8+ T cells in mice, they elicit strikingly different T cell cytokine profiles through differential cytokine expression by the CD8&agr;+ and CD8&agr;− DCs.
Although the use of adjuvants with antigen delivery to boost immunity is well known in the prior art, the adjuvants of the prior art reportedly elicit only a Th1 immune response. Currently, there is no known way to elicit a selective Th2 immune response with an adjuvant. A means of eliciting Th2 immune responses using
P. gingivalis
LPS has now been found, the application of the same to prevent and treat disease in humans and animals (mammals), increase antibody production in industrial practice, and to provide a method for studying the immune response in laboratory animals are presented herein.
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Banchereau Jacques F.
Cutler Christopher W.
Pulendran Bali
Baylor Research Institute
Henley III Raymond J.
Sidley Austin Brown & Wood LLP
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