Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Parasitic organism or component thereof or substance...
Reexamination Certificate
1999-05-19
2002-06-04
Wortman, Donna C. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Parasitic organism or component thereof or substance...
C424S085100, C424S085200, C424S265100
Reexamination Certificate
active
06399077
ABSTRACT:
BACKGROUND OF THE INVENTION
The role of immune cytokines in determining the outcome of intracellular infection has become more evident. In mice,
Toxoplasma gondii
infection stimulates the production of IFN-&ggr;, which is the principal mediator of protection against acute and chronic recrudescent infection. Of the ILs studied, IL-12 appears to be an essential cytokine for stimulating a protective host response (Gazzinelli et al., 1994
J. Immunol
., 153:2533; Khan et al., 1994
Infec. Immun
., 62:1639; Hunter et al., 1995
Immunology
, 84:16). It has been reported that administration of exogenous IL-12 to immunocompetent or SCID mice (Gazzinelli et al., 1993
Proc. Natl. Acad. Sci. USA
, 90:6115) protects against subsequent parasite challenge. Both macrophages and CD4
+
T cells produce IL-12 that, in turn, stimulates the proliferation of NK cells and CD8
+
cytotoxic T cells (Seder et al., 1993
Proc. Natl. Acad. Sci. USA
, 90:10188). The role of IL-2 in host protective immunity to Toxoplasma infection is less clear. In mice, administration of exogenous IL-2 can protect against parasite challenge (Sharma et al., 1985 J. Immunol.) 155:4798. The mechanism for this partial protection may be due to an increase in the proliferation of NK cells. It was recently reported that IL-7 can protect against acute Toxoplasma infection (Kasper et al., 1995
J. Immunol
., 155:4798). Protection is most evident when IL-7 is administered early and continued throughout the course of infection. The principal T cell subset that mediates protection by IL-7 consists of CD8
+
cells. In vitro, these T cells produce IFN-&ggr; and exhibit enhanced TL activity against macrophages infected with
T. gondii.
IL-15 is a recently identified cytokine that is abundantly expressed by a wide variety of tissues and activated monocyte/macrophages (Grabstein et al., 1994
Science
, 264:965). The gene for this cytokine has now been isolated from simian kidney epithelial cells (Grabstein, supra). Although the sequence of IL-15 is not homologous with that of IL-2, IL-15 uses components of the IL-2R for bonding and signal transduction (Carson et al., 1994
J. Exp. Med
., 180:1395). IL-15 is also a potent growth factor for activated T cells, and it enhances the cytolytic function of both NK and effector T cells. IL-15 appears to enhance LAK cell activity against certain tumors (Gamero et al., 1995
Cancer Res
., 55:4988). Although limited information is available on the role of IL-15 in response to infection, recent studies indicate that it stimulates the proliferation it T cells induced by Salmonella infection (Nishimura et al., 1996
J. Immunol
., 156:663) and may have a role in the host response to HIV infection (Seder et al., 1995
J. Exp. Med
., 182:1067). Endogenous production of IL-15 has now been observed to be important for optimal production of IFN-&ggr; T by NK cells in vitro (Carson et al., 1995
J. Clin. Invest
., 96:2578).
It has now been found that mice immunized with
Toxoplasma gondii
soluble parasite Ag (TLA) and exogenous rIL-15 are protected against lethal Toxoplasma infection. Immunization increases the production IFN-&ggr; and Ag-specific CD8
+
T cell proliferation. Adoptive transfer of these CD8
+
T cells into a naive host are protective against a lethal
T. gondii
challenge.
SUMMARY OF THE INVENTION
Cytokines of the Th1 profile are important mediators of protective host immunity against
Toxoplasma gondii
infection in mice. It has now been found that administration of exogenous rIL-15 with soluble Toxoplasma lysate Ag (TLA) provides complete protection against a lethal parasite challenge, whereas treatment with either rIL-15 or TLA alone is not protective. Following immunization with TLA/rIL-15, there is a significant proliferation of splenocytes expressing the CD8
+
phenotype in response to TLA. A significant rise in the level of serum IFN&ggr; was observed in vaccinated mice. Adoptive transfer of CD8
+
T cells, but not CD4
+
T cells, from TLA/rIL-15-vaccinated mice protects naive mice from a lethal parasite challenge. These CD8
+
T cells exhibit enhanced CTL activity against target macrophages infected with
T. gondii
. Mice that have been immunized are protected against lethal parasite challenge for at least 1 month postvaccination. These results demonstrate that TLA when administered with exogenous rIL-15 generates toxoplasmacidal Ag-specific CD8
+
cells. These T cells proliferate upon exposure to parasite Ag, exhibit long term memory CTL against infected target cells, and may be involved in host immune memory to this parasite. Accordingly, a novel method of augmenting T cell-mediated immunity against
Toxoplasma gondii
is provided.
REFERENCES:
patent: 4564592 (1986-01-01), Gaafar et al.
Doherty et al. (Journal of Immunology, vol. 156 No. 2, Jan. 1996, pp. 735-741).*
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Carson et al., “Interleukin (IL) 15 Is a Novel Cytokine That Activates Human Natural Killer Cells via Components of the IL-2 Receptor”, 1994J. Exp. Med., 180:1395.
Carson et al., “Endogenous Production of Interleukin 15 by Activated Human Monocytes Is Critical for Optimal Production of Interferon-y by Natural Killer Cells In Vitro”, 1995J. Clin. Invest., 96:2578.
Denkers et al., “Bone Marrow Macrophages Process ExogenousToxoplasma gondiiPolypeptides for Recognition by parasite-Specific Cytolytic T Lymphocytes”, 1993J. Immunol., 150:517.
Gamero et al., Interleukin 15 Induction of Lymphokine-activated Killer Cell Function against 1995Cancer Res., 55:4988.
Gazzinelli et al., “Interleukin 12 is required for the T-lymphocyte-independent induction of interferon &ggr; by an intracellular parasite and induces resistance in T-cell-deficient hosts”, 1993Proc. Natl. Acad. Sci. USA, 90:6115.
Gazzinelli et al., “Synergistic Role of CD4+T Lymphocytes in IFN-&ggr; Production and Protective Immunity Induced by An AttenuatedToxoplasma gondiiVaccine”, 1991J. Immunol., 146:286.
Gazzinelli et al., Parasite-Induced IL-12 Stimulates Early IFN-&ggr; Synthesis and Resistance During Acute Infection withToxoplasma gondii′, 1994J. Immunol., 153:2533.
Grabstein et al., “Cloning of a T Cell Growth Factor That Interacts with the &bgr; Chain of the Interleukin-2 Receptor”, 1994Science, 264:965.
Hunter et al., “Studies on the role of interleukin-12 in acute murine toxoplasmosis”, 1995Immunology, 84:16.
Kasper et al., “Antigen-Specific (p30) Mouse CD8+T Cells Are Cytotoxic AgainstToxoplasma gondii-Infected peritoneal Macrophages1”, 1992J. Immunol., 148:1493.
Kasper et al., “IL-7 Stimulates Protective Immunity in Mice Against the Intracellular Pathogen,Toxoplasma gondii1”, 1995J. Immunol., 155:4798.
Khan et al., “Induction of Antigen-Specific Parasiticidal Cytotoxic T Cell Splenocytes by a Major Membrane Protein (P30) ofToxoplasma gondii1”, 1988J. Immunol., 141:3600.
Khan et al., “Induction of Antigen-specific human Cytotoxic T cells byToxoplasma gondii”, 1990J. Clin. Invest., 85:1879.
Khan et al., “Interleukin-12 Enhances Murine Survival against Acute Toxoplasmosis”, 1994Infec. Immun., 62:1639.
Khan et al., “Antigen-Specific CD8+T Cell Clone Protects Against AcuteToxoplasma gondiiInfection in Mice1”, 1994J. Immunol., 152:1856.
Lau et al., “Cytotoxic T-cell memory without antigen”, 1994Nature, 369:648.
Nishimura et al., “IL-15 Is a Novel Growth Factor for Murine &ggr;&dgr; T Cells Induced by Salmonella Infection1”, 1996J. Immunol., 156:663.
Seder et al., “Interleukin 12 acts directly on CD4+cells to enhance priming for interferon &ggr; production and diminshes interleukin 4 inhibition of such priming”, 1993Proc. Natl. Acad. Sci. USA, 90:10188.
Seder et al., “Cytokine Interactions in Human Immunodeficiency Virus-infected Individuals:Roles of Interleukin (IL)-2, IL-12, and IL-15”, 1995J. Exp. Med., 182:1067.
Subauste et al., “Murine CD8+Cytotoxic T Lymphocytes LyseToxoplasma gondii-Infected Cells1”, 1991J. Immunol., 147:3955.
Sharma et al., “In V
Kasper Lloyd H.
Khan Imtiaz A.
Licata & Tyrrell P.C.
Trustees of Dartmouth College
Wortman Donna C.
Zeman Robert A.
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