Compositions and methods for eliciting CTL immunity

Details Compositions and methods for eliciting CTL immunity Compositions and methods for eliciting CTL immunity

1994-02-16

2002-07-16

Wortman, Donna C. (Department: 1648)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Combination of viral and bacterial antigens

C424S204100, C424S208100, C424S227100, C424S228100

Reexamination Certificate

active

06419931

ABSTRACT:

BACKGROUND OF THE INVENTION
Cytotoxic T lymphocytes (“CTL”) represent an important component of an animal's immune response against a variety of pathogens and cancers. CTL which have been specifically activated against a particular antigen are capable of killing the cell that contains or expresses the antigen. CTL are particularly important in providing an effective immune response against intracellular pathogens, such as a wide variety of viruses, and some bacteria and parasites. CTL responses are also believed to be capable of contributing to anti-tumor responses in afflicted or susceptible individuals.
The receptors on the surface of the CTL cannot recognize a foreign antigen directly, however. The CTL express an &agr;-&bgr; heterodimeric T cell receptor which is capable of recognizing foreign antigen fragments bound to major histocompatibility complex (MHC) class I molecules on the surface of the effected (e.g., infected) cells. CTL also express the non-polymorphic CD8 antigen. This cell surface protein interacts with the third domain of the class I molecule on the antigen presenting cells and plays a role in both stabilizing the interaction between the CTL and the antigen presenting cell and in CTL activation (Salter et al.,
Nature
345:41-46 (1990)).
There are a number of mechanisms by which CTL are thought to disrupt the infectious or tumorigenic process. Among these, one involves the production of lymphokines such as gamma interferon (IFN&ggr;) and tumor necrosis factor alpha (TNFa), which are known to act directly on infected cells to inhibit viral replication (Gilles et al.,
J. Virol
. 66:3955-3960 (1992)). In addition, IFN&ggr; causes increased expression of MHC class I molecules on the surface of virus infected cells and enhances their ability to be recognized by CTL and trigger immune intervention (Hayata et al.,
Hepatology
13:1022-1028 (1991)).
A second mechanism by which CTL combat infections or tumors is through direct killing of the afflicted cell, e.g., those which are infected by the targeted virus (Cohen et al.,
Ann. Rev. Immunol
. 10:267-293 (1992) and Henkart et al.,
Ann. Rev. Immunol
. 3:31-58 (1985)). For example, since viruses must replicate within the host cell the lysis of infected cells destroys virus production prior to the liberation of infectious particles. The exact mechanism(s) by which CTL kill infected target cells remains unclear. Once CTL recognized an antigen presenting cell, close contact between the cells is established over a large surface area. A “direct hit” is then delivered by translocating enzymes present in cytoplasmic vacuoles of CTL to the antigen presenting cell, which enzymes kill the cell or perhaps induce programmed cell death, “apoptosis”. Once CTL have delivered their “lethal hit” to the antigen presenting cells, they can detach and go on to kill other antigen presenting cells through repetition of the antigen-specific recognition, lymphokine release and target cell killing mechanisms.
The means by which CTL distinguish infected from non-infected cells is through the T cell receptor and its ability to specifically recognize a peptide fragment of viral protein that is bound to the peptide-binding cleft of the MHC class I molecule (Monaco et al.,
Immunol. Today
13:173-179 (1992) and Townsend et al.,
Ann. Rev. Immunol
. 7:601-624 (1989)). Several viral fragments that can serve an antigenic peptides have been identified.
The biochemical events that take place in the cytoplasm of infected cells leading to CTL recognition are termed antigen processing and presentation. While not completely defined, it seems clear that during the synthesis and assembly of the infecting viral or bacterial proteins, some proteolysis takes place in the cytoplasm (Monaco et al.,
Immunol. Today
13:173-179 (1992)). Structures called proteosomes cleave the foreign proteins into peptide fragments. These fragments are then transported into the endoplasmic reticulum (ER) by means of specific transporter proteins where newly synthesized MHC class I molecules are present. Those peptides that are capable of specifically binding to a given MHC class I molecule do so in the ER. The non-polymorphic class I &bgr; chain, &bgr;
2
microglobulin binds to the antigenic peptide-class I complex, thus forming a stable trimolecular complex that is transported to the cell surface and displayed as an integral membrane component.
The selection of which peptides bind to a particular MHC class I molecule is based on the ability of the peptide to bind within the binding pocket or cleft which resides at the outermost apex of the extra-cellular portion of the MHC molecule. For several MHC molecules, this peptide binding pocket has been precisely defined by X-ray crystallographic procedures allowing a visualization of the types and location of the chemical bonds that form to stabilize the interaction (Saper et al.,
J. Mol. Biol
. 219:277-319 (1991)).
Because of the differences in the structure of the peptide binding pocket between the diverse set of histocompatibility alleles, e.g., the human HLA alleles, a distinct population of antigenic peptides is bound by each allele, although in some cases the population of antigenic peptides may overlap for closely related alleles. Thus, the specificity of the CTL for a foreign antigen resides at the level of the ability of MHC class I molecules to bind to a specific peptide as well as for the T cell receptor on the CTL to recognize the foreign protein fragment bound to that specific MHC class I allele.
In animals, CT8+, MHC class I-restricted cytotoxic T cells play an important role in the immune mediated clearance of viral infections (e.g., Oldstone et al.,
Nature
321:239-243 (1986); Mackenzie et al.,
Immunol
. 67:375 (1989); and Robertson et al.,
J. Virol
. 66:3271-3277 (1992)). While similar studies have not been possible in humans, and thus direct proof is still lacking, all of the evidence points to a similar role for CTL.
The importance of CTL in viral clearance in animals is evidenced by lymphocytic choriomeningitis virus (LCMV) infection in mice (Oldstone et al.,
Nature
321:239-243 (1986); Mackenzie et al.,
Immunol
. 67:375 (1989); Robertson et al.,
J. Virol
. 66:3271-3277 (1992); and Ahmed et al.,
J. Virol
. 61:3920-3929 (1987)). When LCMV infects newborns or immune-suppressed adult animals, they become chronically infected and virus is expressed in nearly all tissues of the body. In contrast, adult mice infected with LCMV mount a vigorous cellular and humoral response against the virus and clear the infection within one to two weeks. When chronic carriers of LCMV are adoptively treated by transfer of CD8+LCMV-specific, MHC class I-restricted CTL, the viral infection is cleared and the mice become resistant to subsequent LCMV challenge. Additional studies have shown that CTL are necessary and sufficient for LCMV clearance and that other aspects of the immune system need not be functioning (Oldstone et al.,
Nature
321:239-243 (1986) and Schulz et al.
Proc. Natl. Acad. Sci. USA
88:991-993 (1991)).
In addition to mediating the clearance of virus from chronically infected animals, studies have demonstrated that CTL generated in vivo against a synthetic peptide which presents an antigenic epitope of LCMV are able to protect mice against acute infection (Schulz et al.,
Proc. Natl. Acad. Sci. USA
88:991-993 (1991)). Mice injected with 100 &mgr;g of a synthetic 15 amino acid peptide in complete Freund's adjuvant were fully protected from a lethal LCMV challenge.
With regard to the role of CTL in other viral infections, studies with influenza virus and respiratory syncytial virus in mice have similarly demonstrated the importance of CTL activation in the rapid and effective recovery from these infections.
Strong evidence from animal studies indicates that an acute infection can become chronic when there is an inadequate immune response to clear the infection (Ahmed,
Concepts in Viral Pathogenesis III
, Notkins and Oldstone eds., Springer-Verlag, New York, 304-310 (1989)). Once the chronic i

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