Mucosal cytotoxic T lymphocyte responses

a technology of mucosal immune response and cytotoxic t lymphocytes, which is applied in the direction of antibody medical ingredients, dsdna viruses, peptide sources, etc., can solve the problems of inability prior investigations have failed to identify fundamental mechanisms linking immune responses to protection, and administration of antigens via parenteral routes (subcutaneously). , to achieve the effect of enhancing the ctl response, reducing

Inactive Publication Date: 2005-10-20
HEALTH & HUMAN SERVICES THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPT OF
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Benefits of technology

[0020] In yet additional aspects of the invention, immunogenic compositions are provided which include an adjuvant which enhances the CTL response. Suitable adjuvants are detoxified bacterial toxins, for example detoxified cholera toxin (CT), mutant cholera toxin (MCT), mutant—E. coli heat labile enterotoxin, and pertussis toxin. Preferably, the adjuvant is conjugated to a mucosal tissue or T cell binding agent, such as protein A, an antibody that binds a mucosal tissue- or T-cell-specific protein, or a ligand or ...

Problems solved by technology

While a number of studies have shown a role for CTL in protection against infections such as influenza that have a mucosal component (Taylor and Askonas, Immunology 58:417-420, 1986; Epstein et al., J. Immunol. 160:322-327, 1998; Kulkarni et al., J. Virol. 69:1261-1264, 1995), these reports have not established whether the CTL need to be in a local mucosal site to protect.
Thus, although the role of CTL in protection against-mucosal infections has been of interest for decades, especially in the case of influenza virus, prior investigations have failed to identify fundament...

Method used

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  • Mucosal cytotoxic T lymphocyte responses
  • Mucosal cytotoxic T lymphocyte responses
  • Mucosal cytotoxic T lymphocyte responses

Examples

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example 1

Comparison of Mucosal and Systemic-CTL Responses After Mucosal and Systemic Immunization

[0104] Mice were immunized IR with 4 doses (on days 0, 7, 14 and 21) of the HIV-1 CLUVAC PCLUS3-18IIIB (SEQ ID NO:2) (50 μg / mouse). 5 weeks to 6 months after the first dose, antigen-specific T cells were isolated from PP, LP and SP and tested for the presence of HIV-1 P18IIIB peptide specific CTL (FIG. 1), as described above. Closed squares show killing of P18IIIB-I10 (SEQ ID NO:16) -pulsed targets and open diamonds show killing on unpulsed targets. IR immunization induced long-lasting protective immune responses: antigen-specific CTL were detected in mucosal inductive (PP) and effector (LP) sites and in a systemic site (SP) at least 6 months after immunization. In contrast, systemic immunization (s.c. in incomplete Freund's adjuvant) induced CTL in the spleen but not in the mucosal immune system (i.e., PP and LP).

example 2

Comparison of CTL Responses with and without a Mucosal Adjuvant

[0105] BALB / c mice were immunized IR with 4 doses of the synthetic HIV-1 CLUVAC PCLUS3-18IIIB (SEQ ID NO:2) (50 μg / mouse per immunization) alone, i.e., in the absence of adjuvant or cytokine on days 0, 7, 14 and 21. In parallel, another group of mice was immunized IR with PCLUS3-P18IIIB (SEQ ID NO:2) HIV-1 peptide in combination with CT (1 μg / mouse). On day 35 antigen-specific T cells were isolated from PP, LP and SP. Immune cells from SP, PP, or LP were cultured and tested for antigen specific CTL (FIG. 2), as described above. Closed squares show killing of P18IIIB-I10 (SEQ ID NO:16) pulsed targets, and open diamonds show killing of unpulsed targets. IR administration of peptide alone induced a significant response. The response was enhanced by the co-administration of CT.

example 3

CTL Induced by Mucosal Immunization Lyse Targets Expressing HIV-1 gp160 Envelope Protein

[0106] Mice were immunized IR with 4 doses (on days 0, 7, 14 and 21) of the HIV-1 CLUVAC PCLUS3-18IIIB (SEQ ID NO:2) (5 μg / mouse per immunization) in the presence of CT (1 μg / mouse). on day 35, antigen-specific T cells were isolated from PP, LP and SP. Immune cells from SP, PP, or LP were cultured as described above. Cytolytic activity of CTL was measured using a standard 51Cr release assay (FIG. 3).

[0107] Three different cell lines were used as target cells: 15-12 cells, 3T3 18 Neo BALB / c cells and P815 cells. 15-12 cells are BALB / c 3T3 fibroblasts transfected with a vector encoding HIV-1 gp160 (Takahashi et al. Proc. Natl. Acad. Sci. USA 85:3105 (1988)); 3T3 18 Neo BALB / c cells are BALB / c 3T3 fibroblasts transfected with an expression vector containing a Neor gene but no gp160 gene; and P815 cells are untransfected cells that present antigenic peptides added to the culture. CTL lysis of gp160...

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Abstract

The invention provides methods for induction of an antigen-specific, mucosal cytotoxic T lymphocyte response useful in preventing and treating infections with pathogens that gain entry via a mucosal surface.

Description

RELATED APPLICATIONS [0001] The present application is a continuation-in-part application of, and claims the benefit under Title 35 of U.S. Provisional Application Nos. 60 / 058,523 filed on Sep. 11, 1997, and 60 / 074,894 filed on Feb. 17, 1998.TECHNICAL FIELD [0002] The present invention relates to methods and compositions for stimulating immune responses in mammals. More particularly, the invention relates to methods and compositions for stimulating mucosal immunity. BACKGROUND OF THE INVENTION [0003] Many infectious pathogens, e.g., HIV-1, enter their mammalian hosts via a mucosal tissue prior to establishing a systemic infection. Veazey, et al., Science 280:427-431, 1998. Accordingly, vaccines capable of protecting against HIV should be capable of inducing long-term mucosal immune responses. A number of recent studies have shown that such immune responses require direct stimulation of mucosal tissues, and may be achieved with live attenuated virus, Cranage, et al., Virology 229:143...

Claims

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Application Information

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IPC IPC(8): A61K39/21C07K14/16
CPCA61K39/21A61K2039/5256A61K2039/541A61K2039/55522A61K2039/55538A61K2039/55544A61K2039/55566C07K14/005C12N2710/24143C12N2740/16122C12N2740/16134Y10S530/826A61K2039/545A61K2039/6037A61K39/12
Inventor BERZOFSKY JAY A.BELYAKOV IGOR M.DERBY MICHAEL A.KELSALL BRIAN L.STROBER WARREN
Owner HEALTH & HUMAN SERVICES THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPT OF
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