METHODS FOR MODULATING IL-33 ACTIVITY
Provided herein are methods of modulating IL-33 activity, e.g., for the purpose of treating immune diseases and conditions, as well as methods of screening for compounds capable antagonizing IL-33 signaling.
1 . A method of modulating an immune disorder or condition, comprising inhibiting IL-33 signal transduction through ST2 and IL-1RAcP by administering to a subject in need thereof an effective amount of:
a) an antagonist of IL-33 binding to a complex of ST2 and IL-1RAcP; or
b) an antagonist of IL-1RAcP binding to a complex of IL-33 and ST2.
2 . The method of claim 1 , wherein the immune disorder or condition is selected from the group consisting of an innate response, asthma, an allergy, multiple sclerosis, inflammatory bowel disorder, arthritis, an infection, cancer, and a tumor.
3 . The method of claim 2 , wherein the infection is selected from the group consisting of an intracellular pathogen, a bacterium, a parasite and a virus.
4 . The method of claim 3 , wherein the infection is an intracellular pathogen selected from the group consisting of Leishmania sp., Mycobacterium sp., Listeria sp., Toxoplasma sp., Schistosoma sp.
5 . The method of claim 1 , wherein the immune disorder or condition comprises:
a) a TH1-type response; or
b) a TH2-type response.
6 . The method of claim 2 , wherein the arthritis is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and psoriatic arthritis.
7 . The method of claim 1 , wherein the antagonist comprises an antibody or a fragment thereof that specifically binds to:
a) IL-33;
b) IL-1RAcP;
c) ST2;
d) a complex of ST2 and IL-1RAcP;
e) a complex of IL-33 and ST2; or
f) a complex of IL-33, ST2 and IL-1RAcP.
8 . The method of claim 7 , wherein the antibody or fragment thereof does not bind to ST2 alone and does not bind to IL-33 alone.
9 . The method of claim 7 , wherein the antibody or fragment thereof is a humanized antibody or human antibody.
10 . The method of claim 7 , wherein the antibody or fragment thereof is a fragment selected from the group consisting of a Fab, an Fv fragment, and an F(ab′)2 fragment.
11 . A method of modulating blood cell counts, comprising inhibiting IL-33 signal transduction through ST2 and IL-1RAcP by administering to a subject in need thereof an effective amount of:
a) an antagonist of IL-33 binding to a complex of ST2 and IL-1RAcP; or
b) an antagonist of IL-1RAcP binding to a complex of IL-33 and ST2.
12 . The method of claim 11 , wherein the antagonist increases the count of platelets.
13 . The method of claim 11 , wherein the antagonist decreases the count of one or more of total white blood cells, neutrophils, lymphocytes, and eosinophils.
14 . The method of claim 11 , wherein the antagonist comprises an antibody or a fragment thereof that specifically binds to:
a) IL-33;
b) IL-1RAcP;
c) ST2;
d) a complex of ST2 and IL-1RAcP;
e) a complex of IL-33 and ST2; or
f) a complex of IL-33, ST2 and IL-1RAcP.
15 . The method of claim 14 , wherein the antibody or fragment thereof is a humanized antibody or human antibody.
16 . The method of claim 14 , wherein the antibody or fragment thereof is a fragment selected from the group consisting of a Fab, an Fv fragment, and an F(ab′)2 fragment.
17 - 19 . (canceled)
20 . An in vitro method of determining whether a test compound is an antagonist of i) IL-33 binding to a complex of ST2 and IL-1RAcP, or ii) IL-1RAcP binding to a complex of IL-33 and ST2, comprising an assay selected from the group consisting of:
a) an NF-κB-dependent reporter gene expression assay;
b) an MyD88 IRAK, IRAK4 or TRAF6 recruitment assay;
c) an Erk1/2, p38, IκBα or JNK phosphorylation assay;
d) an NF-κB, Erk1/2 or p38 phosphorylation assay in cells that naturally express ST2;
e) an IL-13, IL-6 or IL-5 expression assay; and
f) an IL-6 production assay in mouse mast cell line WTMC;
wherein the test compound is determined to be an antagonist if it reduces the activity of IL-33 in the assay when compared to an assay run without the test compound.