Methods and compositions for decreasing T-cell activity
The present invention relates to a novel member of the TNF-Ligand superfamily. More specifically, isolated nucleic acid molecules are provided encoding a human Apoptosis Inducing Molecule II (AIM II). AIM II polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of AIM II activity. Also provided are therapeutic methods for treating lymphadenopathy, aberrant bone development, autoimmune and other immune system diseases, graft versus host disease, rheumatoid arthritis, osteoarthritis and to inhibit neoplasia, such as tumor cell growth.
1. A method for decreasing a T-cell activity in an individual suffering from acute graft-versus-host disease comprising administering to the individual therapeutically effective amounts of:
a) a first therapeutic agent comprising an antibody which specifically binds to the polypeptide consisting of SEQ ID NO: 2, wherein the antibody decreases a T-cell activity in vitro; and
b) a second therapeutic agent selected from the group consisting of:
(i) a tumor necrosis factor;
(ii) an immunosuppressive agent;
(iii) an antibiotic;
(iv) an anti-inflammatory agent;
(v) a chemotherapeutic agent;
(vi) a cytokine;
(vii) an angiogenic agent; and
(viii) a fibroblast growth factor;
wherein decreasing a T-cell activity comprises one or more of:
decreasing T-cell proliferation;
decreasing gamma-IFN secretion by T-cells; and
decreasing the activation of CD8+ T-cells.
2. The method of claim 1 , wherein said first and second therapeutic agents are administered to the individual at the same time.
3. The method of claim 1 , wherein said tumor necrosis factor is selected from the group consisting of:
a) TNF-α;
b) TNF-β; and
c) TNF-γ.
4. The method of claim 1 , wherein said immunosuppressive agent is selected from the group consisting of:
a) cyclosporine;
b) cyclophosphamide methylprednisone;
c) prednisone;
d) azathioprine;
e) FK-506; and
f) 15-deoxyspergualin.
5. The method of claim 1 , wherein said cytokine is selected from the group consisting of:
a) IL-2;
b) IL-3;
c) IL-4;
d) IL-5;
e) IL-6;
f) IL-7;
g) IL-10;
h) IL-12;
i) IL-13;
j) IL-15; and
k) IFN-γ.
6. A method for decreasing a T-cell activity in an individual suffering from acute graft-versus-host disease comprising administering to said individual an effective amount of a composition comprising an isolated antibody which specifically binds to the polypeptide consisting of SEQ ID NO: 39, wherein the antibody decreases a T-cell activity in vitro; wherein decreasing a T-cell activity comprises one or more of:
decreasing T-cell proliferation;
decreasing gamma-IFN secretion by T-cells; and
decreasing the activation of CD8+ T-cells.
7. A method for decreasing a T-cell activity in an individual suffering from acute graft-versus-host disease comprising administering to said individual an effective amount of a composition comprising an isolated antibody which specifically binds to the polypeptide consisting of SEQ ID NO: 39, and a pharmaceutically acceptable carrier;
wherein the antibody decreases a T-cell activity in vitro, and
wherein decreasing a T-cell activity comprises one or more of:
decreasing T-cell proliferation;
decreasing gamma-IFN secretion by T-cells; and
decreasing the activation of CD8+ T-cells.
8. A method for decreasing a T-cell activity in an individual suffering from acute graft-versus-host disease comprising administering to said individual an effective amount of a composition comprising an isolated antibody which specifically binds to the polypeptide consisting of SEQ ID NO: 2, wherein the antibody decreases a T-cell activity in vitro, and
wherein decreasing a T-cell activity comprises one or more of:
decreasing T-cell proliferation;
decreasing gamma-IFN secretion by T-cells; and
decreasing the activation of CD8+ T-cells.
9. An isolated antibody which specifically binds to the polypeptide consisting of amino acid residues selected from the group consisting of:
a) amino acids 69-79 of SEQ ID NO:2;
b) amino acids 85-94 of SEQ ID NO:2;
c) amino acids 167-178 of SEQ ID NO:2;
d) amino acids 184-196 of SEQ ID NO:2; and
e) amino acids 221-233 of SEQ ID NO:2.
10. A composition comprising the antibody of claim 9 and a pharmaceutically acceptable carrier.
11. A method for decreasing a T-cell activity in an individual suffering from acute graft-versus-host disease comprising administering to said individual an effective amount of a composition comprising the isolated antibody of claim 9 and a pharmaceutically acceptable carrier;
wherein the antibody decreases a T-cell activity in vitro, and wherein decreasing a T-cell activity comprises one or more of:
decreasing T-cell proliferation;
decreasing gamma-IFN secretion by T-cells; and
decreasing the activation of CD8+ T-cells.
12. An isolated antibody which specifically binds to a polypeptide consisting of amino acid residues selected from the group consisting of:
a) amino acids 13-20 of SEQ ID NO:2; and
b) amino acids 23-36 of SEQ ID NO:2.