Mucosal cytotoxic T lymphocyte responses

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...

AI Technical Summary

Benefits of technology

[0018] In other preferred aspects, the immunogenic compositions of the invention are formulated in a suppository. The suppository is comprised of a base or carrier specifically adapted for intrarectal delivery of the antigen. Preferred bases may be selected from a polyethyleneglycol, witepsol H15, witepsol W35, witepsol E85, propyleneglycol dicaprylate (Sefsol 228), Miglyol810, hydroxypropylcellulose-H (HPC), or carbopol-934P (CP). More preferably, the suppository comprises at least two base materials to optimize structural and delivery performance. In other aspects, the suppository includes a stabilizing agent to minimize intrarectal degradation of the soluble antigen.

[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 peptide that binds a mucosal tissue- or T-cell-specific protein. In more preferred aspects, the adjuvant is a recombinant cholera toxin (CT) having a B chain of CT substituted by protein A conjugated to a CT A chain, which exhibits reduced toxicity and enhances mucosal tissue binding mediated by protein A. Alternatively the adjuvant may be conjugated to a protein or peptide that binds specifically to T cells, for example by binding CD4 or CD8 (eg., the HIV V3 loop or a T cell-binding peptide fragment of the HIV V3 loop).

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 fundamental mechanisms linking immune responses to protection.

In some cases, administration of antigens via parenteral routes (subcutaneous, intramuscular, intravenous or intraperitoneal, for example) either fails to induce mucosal immunity or does so extremely inefficiently.

However, it is not clear if either of such responses is relevant to protection against viral infection in general, or HIV infection in particular.

However, these studies have not addressed the question of whether CTL must be present at the mucosal site of infection, or if their principal activity occurs systemically.

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