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  Identification and use of high efficacy vaccine antigens which modulate antigen presenting cellsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus ContainingIdentification and use of high efficacy vaccine antigens which modulate antigen presenting cells description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060073116, Identification and use of high efficacy vaccine antigens which modulate antigen presenting cells. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation of and claims the benefit of priority of U.S. patent application Ser. No. 09/313,487 filed May 17, 1999; which is hereby expressly incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention relates to the field of immunology. More specifically, novel biotechnological tools, therapeutics and phophylactics, which modulate antigen presenting cell activity are disclosed. BACKGROUND OF THE INVENTION [0003] The mature, circulating, antigen specific cells of the immune system face a challenge that does not trouble most other cells of the body. They must find each other, and they must do it often and quickly, every time there is need of an immune response. The problem is compounded by the rarity of the communicating partners, since only about 1 in 10.sup.4 circulating B lymphocytes can react to any particular antigen and the frequency of antigen specific T cells is thought to be similarly low. (Kennedy et al., J. Immuno. 96:973-980 (1966) and Vann, D. C. and Dotson, D. R., J. Immunol. 112:1149-1157 (1974)). Thus, a rare T helper cell specific for a particular pathogen needs to find an equally rare B cell specific for the same antigen. The fact that these encounters occur at all is due to the circulation patterns of these cells in lymph nodes and other specialized organs, as well as, the B cell's ability to act as an antigen presenting cell (APC) and attract the appropriate helper by creating a surface display of MHC class II molecules loaded with peptides from the antigen the B cell has captured. (Tony, H. P. and Parker, D. C., J. Exp. Med. 161:223-241 (1985) and Lanzavecchia, A., Nature 314:537-539 (1985)). [0004] Once a B cell has attracted the right T helper cell, it uses a family of receptor-ligand pairs such as B7, CD40, and various cytokine receptors to stimulate the T cell and receive stimuli in turn. (Foy, T. M. et al., Semin. Immunol. 6:259-266 (1994)). T killer cells cannot do this and, if the two cell exchange between rare T and B cells seems challenging enough, the problem is far worse for communication between T helpers and T killer cells where the interaction requires a third participant, an APC, that brings the T helpers and T killers together by displaying antigens to both. (Keene, J. A. & Forman, J., J. Exp. Med. 155:768-782 (1982); Mitchison, N. A. & O'Malley, C., Eur. J. Immunol. 17:1579-1583 (1987); and Bennett, S. R. et al., J. Exp. Med. 186:65-70 (1997)). [0005] The problem is two fold. First there is the challenge of bringing together three rare circulating cells. Second, since T killers do not express the sorts of co-stimulatory molecules expressed by B cells and APCs, (and, in mice, do not express MHC class II molecules with which to present antigen to helper T cells) the question of how help is stimulated and delivered remains. [0006] Currently, investigators believe that dendritic cells exist in only two states: resting (an "immature" state) and activated (a "mature" state). In the activated state, a dendritic cell can present antigen and stimulate T helper cells, but not T killers. The successful priming of killer T cells is believed to require a three cell interaction between rare antigen loaded APCs and rare antigen specific helper T cells and killer T cells. In the model set forth by Keene and Forman, for example, the presenting cell has a rather passive relationship with the killer T cell and, like a B cell, the APC functions mainly to stimulate the helper cell, which then secretes cytokines necessary for the growth and activation of the neighboring killer T cell. (Keene, J. A. & Forman, J., J. Exp. Med. 155:768-782 (1982)). [0007] For several reasons this picture is not completely satisfying. First, there is no guarantee that a rare T helper and an equally rare T killer should find the same APC at the same time. Because resting killers recognizing antigen become tolerant if there is no help available, many potentially useful killers would be rendered useless by the lack of immediate help. (Guerder, S. & Matzinger, P., J. Exp. Med. 176:553-564 (1992); Guerder, S. & Matzinger, P., Cold Spring Harb. Symp. Quant. Biol. 54:799 (1989); and Rees, M. A. et al., Proc. Natl. Acad. Sci. U.S.A. 87:2765-2769 (1990)). Second, the T helper would wastefully secrete its cytokines into an environment that may contain no killers to receive them. Third, killer responses to certain viruses are unimpaired by the absence of helper cells. (Tripp, R. A., et al., J. Immunol. 155:2955-2959 (1995); Buller, R. M. et al., Nature 328:77-79 (1987); Cardin, R. D. et al., J. Exp. Med. 184:863-871 (1996); Hou, S. et al., J. Virol. 69:1429-1434 (1995); Ahmed, R. et al. J. Virol. 62:2102-2106 (1988); and Leist, T. P. et al., Scand. J. Immunol. 30:679-686 (1989)). The three cell interaction model offers no explanation for the existence of these helper independent killer responses. In view of the foregoing and not withstanding the various efforts exemplified in the prior art, clearly several crucial pieces of the puzzle are missing. BRIEF SUMMARY OF THE INVENTION [0008] In the present invention, we demonstrate that an APC, preferably a dendritic cell, can be stimulated to a third state--a "superactivated" state. T helper cells, some viruses, and some antigens induce the dendritic cell to manifest the superactivated state. In contrast to activated dendritic cells, superactivated dendritic cells have the ability to activate a killer T cell by forming a two cell complex having the superactivated dendritic cell and the killer T cell. Notably, the superactivated APC activates a killer cell in the absence of a T helper cell. Additionally, we have discovered that specific agents which interact with the APC superactivate the APC or block, inhibit, or prevent the activation of killer T cells by interacting with the APC. We show that through modulation of the activation state of an APC, such as a dendritic cell by, for example, administering antibodies which interact with the APC, the activation of a T cell is concordantly governed. [0009] In embodiments of the present invention, we reveal novel biotechnological tools, prophylactics, therapeutics, and methods of use of the foregoing for modulating the activation state of an APC and thereby modulating the activation of a killer T cell. These embodiments have several uses and applications in the field of immunology, and enable one of skill in the art to manufacture novel pharmaceuticals, therapeutic and prophylactic agents, and vaccine components for the treatment and prevention of cancer, systemic infection, and autoimmune responses. BRIEF DESCRIPTION OF THE DRAWINGS [0010] FIG. 1 illustrates two models of the delivery of help to CD8 killers. Panel A depicts the "passive" model in which the dendritic cell presents antigen to both the T helper and the killer but delivers co-stimulatory signals only to the helper, which is thereby stimulated to produce IL-2 for use by the nearby killer. Panel B depicts the "dynamic" model in which the dendritic cell offers co-stimulatory signals to both cells in that it initially stimulates the T helper, which, in turn, stimulates and "conditions" the dendritic cell to differentiate to a state where it can now directly co-stimulate the killer. [0011] FIG. 2 shows four ways to help a killer T cell. Set 1) Unseparated (a) or CD4 depleted (b, c) spleen cells from female B6 mice were stimulated in vitro with B6 male spleen cells with or without CAS. Set 2) B6 female CD4 depleted spleen cells were stimulated in vitro with B6 male dendritic cells (dc) (d); dc+Marilyn (e); CD40 modulated dc (f); MHC class II dc (g); CD40 modulated MHC II KO dc (h); MHC II KO dc infected with Influenza (i). Solid lines indicate the killing on male targets, whereas, dashed lines indicate female targets and diamonds represent unprimed controls. [0012] FIG. 3 shows a summary of 117 tests that demontrate five ways to help a killer T cell. Spleen cells from anti-H-Y primed female B6 mice were depeleted or not of CD4 T cells and then stimulated with various normal (.circle-solid.) or MHC II KO (.largecircle.) male stimulators. Reading left to right: spleen cells, dendritic cells (dc), dc incubated overnight with Marilyn, dc incubated overnight with Marilyn and then sorted to remove the T cells (.+-.Marilyn), dc+10% CAS, dc modulated with a hamster(H) or a rat (R) anti-CD40 mAb, dc infected with influenza virus. Each point represents the killing from a single culture at an R:T ratio at which killing shown by cultures from control mice drops off plateau. Background killing on female targets is subtracted. Horizontal lines are the group average. [0013] FIG. 4 shows that B7.1 and B7.2 are involved in stimulation by condtioned dendritic cells. Unseparated (expt.1) or CD4 depleted (expt.2) responders were stimulated respectively with CD40 modulated B6 or MHC II KO dc in the presence of titrated amounts of various blocking reagents. [0014] FIG. 5 shows that virgin killer T cells can be primed in vivo by CD40 modulated dendritic cells. A total of 173 B6 or MHC class II female mice were left untreated (.diamond-solid.)or injected once or twice with B6 ( ) or MHC II KO (.largecircle.) male spleen or dendritic cells that were untreated or modulated with hamster anti CD40 mAb. The in vitro cultures contained 10% CAS, which substitutes for help and allows us to concentrate on whether the mouse was primed in vivo. All mice generated CTLs to third party CBA/J targets. Representation of killing activity is as in FIG. 3. DETAILED DESCRIPTION OF THE INVENTION [0015] In the present invention, we demonstrate that activation of a killer T cell need not require the formation of a three-member complex having an APC, a T helper cell, and a T killer cell. (See FIG. 1, Panel A). Rather, the activation of a killer T cell can occur in a two cell complex and two sequential steps. (See FIG. 1, Panel B). Accordingly, in the first step, an APC stimulates a T helper T cell, which in turn stimulates or "superactivates" the APC to differentiate to a state where it can independently stimulate a killer T cell. In the second step, the APC encounters the killer T cell and stimulates it so that killer T cell priming is achieved in a helper independent fashion. Furthermore, we have discovered that the first step ("help") can be bypassed altogether by viral infection or an interaction with certain molecules at the cell surface of APCs. Novel biotechnological tools, prophylactics, therapeutics, diagnostics, and methods of use of the foregoing for modulating the superactivation of an APC and thereby resulting in the activation of a killer T cell are provided. [0016] In the following disclosure several mechanisms are postulated to describe how an APC is stimulated to a state capable of killer T cell activation. These explanations are offered only to aid in the understanding of the field of the invention and consequently, they should be viewed as examples only and not limitations to embodiments of the present invention. Accordingly, the antigen specific T helper cells may stimulate the APC in a complex without a killer T cell and superactivated APCs can then prime the CD8 killer T cell. Rare, antigen-specific T helpers would then be able to make up for their scarcity by inducing the differentiation of several APCs and thereby assist many CTL precursors without the need to simultaneously contact the antigen. This model advantageously explains helper independent killer responses to certain viruses if, for example, an infected APC responds to the infection by directly undergoing superactivation. [0017] In the discussion that follows, we disclose our discovery that help for killers can be delivered through an APC without a T helper cell/APC/killer T cell complex. Notably, we have found that CD4.sup.+ T helpers can route their activity through dendritic cells (labeled by the literature as the best professional APCs). (Lassila, O. et al., Nature 318:59-62 (1985); and Steinman, R. M., Annu. Rev. Immunol. 9:271-296 (1991)). We demonstrate that activated dendritic cells cannot activate killers, although they can present antigen and stimulate CD4.sup.+ T helpers to proliferate and produce cytokines. However, after an interaction with a helper T cell or antibodies to the surface molecule CD40 or viral infection, activated dendritic cells differentiate into a superactivated state in which they are able to activate killer T cells in the absence of any further need for T help. [0018] Memory Killers are Helper Dependent [0019] We chose to study the response to the male antigen H-Y for several reasons. First, unlike killer T cells which respond to many viruses, killer T cells which respond to H-Y have long been known to be dependent on T helper cells. (Tripp, R. A., et al., J. Immunol. 155:2955-2959 (1995); Buller, R. M. et al., Nature 328:77-79 (1987); Cardin, R. D. et al., J. Exp. Med. 184:863-871 (1996); Hou, S. et al., J. Virol. 69:1429-1434 (1995); Ahmed, R. et al. J. Virol. 62:2102-2106 (1988); Leist, T. P. et al., Scand. J. Immunol. 30:679-686 (1989); Guerder, S. & Matzinger, P., J. Exp. Med. 176:553-564 (1992); Simpson, E. & Gordon, R. D., Immunol. Rev. 35:59-75 (1977); and von Boehmer, H. et al., Proc. Natl. Acad. Sci. U.S.A. 75:2439-2442 (2978)). Second, there are few, if any, environmental antigens that cross react with H-Y. Third, T cells from normal virgin female mice do not respond to H-Y in vitro unless they have first been primed in vivo, allowing us to differentiate easily between primary and secondary responses. (Simpson, E. & Gordon, R. D., Immunol. Rev. 35:59-75 (1977) and Gray, D. & Matzinger, P., J. Exp. Med. 174:969-974 (1991)). Continue reading about Identification and use of high efficacy vaccine antigens which modulate antigen presenting cells... 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