Uses of mammalian cytokine; related reagents
Provided are methods of treatment for inflammatory and autoimmune disorders of the central nervous system and gastrointestinal tract. Also provided are methods of diagnosis.
1 . A method of treating an IL-23 mediated disorder comprising administering an effective amount of an:
a) agonist of IL-23; or
b) antagonist of IL-23.
2 . The method of claim 1 , wherein the disorder is a:
a) gastrointestinal disorder; or
b) nervous system disorder.
3 . The method of claim 1 , wherein the agonist or antagonist specifically binds to a polypeptide or nucleic acid of:
a) p19; or
b) IL-23R.
4 . The method of claim 1 , wherein the agonist or antagonist comprises a:
a) nucleic acid; or
b) small molecule.
5 . The method of claim 4 , wherein the nucleic acid comprises:
a) anti-sense nucleic acid; or
b) small interfering RNA (siRNA).
6 . The method of claim 1 , wherein the agonist or antagonist comprises:
a) an antigen binding fragment of an antibody; or
b) a soluble receptor derived from IL-23R.
7 . The method of claim 6 , wherein the agonist or antagonist is:
a) a polyclonal antibody;
b) a monoclonal antibody;
c) a humanized antibody or binding fragment thereof;
d) an Fab, Fv, or F(ab′) 2 fragment;
e) a peptide mimetic of an antibody;
f) detectably labeled.
8 . The method of claim 2 , wherein treatment is with an antagonist of IL-23 and the nervous system disorder comprises a:
a) central nervous system (CNS) disorder; or
b) peripheral nervous system (PNS) disorder.
9 . The method of claim 1 , wherein treatment is with an antagonist of IL-23 and the condition or disorder comprises:
a) multiple sclerosis;
b) neuropathic pain;
c) amyotrophic lateral sclerosis (ALS);
d) ischemic brain injury; or
e) inflammatory bowel disorder.
10 . The method of claim 9 , wherein the inflammatory bowel disorder comprises:
a) Crohn's disease;
b) ulcerative colitis;
c) celiac disease;
d) mucosal thickening;
e) epithelial hyperplasia;
f) inflammation of the submucosa or tunica muscularis; or
g) infiltration by granulocytes or macrophages.
11 . The method of claim 1 , wherein the agonist or antagonist if IL-23 is co-administered with an agonist or antagonist of:
a) IL-12;
b) interferon-gamma (IFNgamma);
c) IL-6;
d) IL-17; or
e) IL-10.
12 . The method of claim 2 , wherein the nervous system disorder is exacerbated by an antagonist of:
a) IL-12; or
b) IFNgamma.
13 . The method of claim 2 , wherein the nervous system disorder:
a) comprises an increase in microglial expression of p19;
b) comprises an increase of CNS macrophage expression of IL-23R or p19; or
c) can be generated in human or animal subject by administration of exogenous IL-17 producing cells to the subject.
14 . The method of claim 1 , wherein treatment with the antagonist of IL-23 inhibits activation of a resident microglial cell.
15 . The method of claim 14 , wherein the:
a) microglial cell is CD11b + CD45 low ; or
b) activation comprises up-regulation of MHC-Class II.
16 . The method of claim 1 , wherein the antagonist of IL-23 inhibits:
a) expression of IL-1beta by a macrophage;
b) expression of tumor necrosis factor (TNF) by a macrophage; or
c) infiltration of a macrophage into the central nervous system (CNS).
17 . The method of claim 16 , wherein the macrophage is:
a) F4/80 + ;
b) CD11b + ;
c) CD11c − ; or
d) B220 − .
18 . A purified or isolated IL-17 producing CD4 + T cell that upon treatment with IL-23 has a 10-fold higher expression of at least one gene of Table 10B when compared to treatment with IL-12.
19 . The IL-17 producing T cell of claim 18 that is:
a) CD62L lo CD44 hi ; or
b) CD45RB lo .
20 . A method of generating the IL-17 producing CD4 + T cell of claim 18 , comprising contacting a T cell with a substantially pure preparation of IL-23 or an agonist thereof.