Method of formulating a pharmaceutical composition comprising administering an immune modulator to the small intestine

1. A method of formulating a pharmaceutical composition comprising an immune modulator, the method comprising:

(a) topically administering a dose of an immune modulator to a predetermined site in a small intestine or a predetermined site in a colon of a mammal;

(b) selecting an immune modulator whose topical administration in step (a) has been determined to result in:

(i) a decrease in the level of one or more of T cells, B cells, natural killer (NK) cells, macrophages, M cells, and dendritic cells, in MALT, GALT, Peyer's patches, mesenteric lymph nodes, paraaortic lymph nodes, or any of the other tissues originating from the endoderm, and/or

(ii) a decrease in the level of one or more of IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, interferon-kappa, TGF-β, tumor necrosis factor, and GM-CSF, in MALT, GALT, Peyer's patches, mesenteric lymph nodes, paraaortic lymph nodes, or any of the other tissues originating from the endoderm, in the mammal, each as compared to the corresponding level in a control mammal systemically administered the same dose or a therapeutically effective dose of the immune modulator; and

(c) formulating a pharmaceutical composition comprising the selected immune modulator.

2. The method of claim 1 , wherein the immune modulator is administered to a predetermined site in the proximal portion of the small intestine.

3. The method of claim 1 , wherein the immune modulator is administered to a predetermined site in the distal portion of the small intestine.

4. The method of claim 1 , wherein the immune modulator is an antisense nucleic acid.

5. The method of claim 1 , wherein the immune modulator is a peptide or an antibody.

6. The method of claim 1 , wherein the immune modulator is selected from the group consisting of: IL-12/IL-23 inhibitors, TNFα inhibitors, IL-6 receptor inhibitors, CD40/CD40L inhibitors, IL-1 inhibitors, IL-13 inhibitors, IL-10 receptor agonists, integrin inhibitors, TGF-beta inhibitors, and FGF receptor agonists.

7. The method of claim 1 , wherein the tissue originating from the endoderm is selected from the group consisting of: the stomach, the colon, the liver, the pancreas, the urinary bladder, the epithelial parts of the trachea, the lungs, the pharynx, the thyroid, the parathyroid, the small intestine, and the gallbladder.

8. The method of claim 1 , wherein the topical administration is performed using an ingestible device.

9. The method of claim 1 , wherein the topical administration is performed using a surgical procedure or an endoscopic procedure.

10. A method of formulating a pharmaceutical composition comprising an immune modulator, the method comprising:

(a) administering a dose of an immune modulator into gastrointestinal tissue at a predetermined site in a small intestine and/or a predetermined site in a colon of a mammal

(b) selecting an immune modulator whose topical administration in step (a) has been determined to result in

(i) a decrease in the level of one or more of one or more of T cells, B cells, natural killer (NK) cells, macrophages, M cells, dendritic cells, and any of the other effector cells described herein or known in the art, in MALT, GALT, Peyer's patches, mesenteric lymph nodes, paraaortic lymph nodes, or any of the other tissues originating from the endoderm, and/or

(ii) a decrease in the level of one or more of IL-1, IL-2, IL-6, IL-8, IL-12, IL-18, interferon-kappa, TGF-β, tumor necrosis factor, and GM-CSF, in MALT, GALT, Peyer's patches, mesenteric lymph nodes, paraaortic lymph nodes, or any of the other tissues originating from the endoderm, in the mammal, each as compared to the corresponding level in a control mammal systemically administered the same dose or a therapeutically effective dose of the immune modulator at a site not in the small intestine or colon; and

(c) formulating a pharmaceutical composition comprising the selected immune modulator.

11. The method of claim 1 or claim 10 , wherein the means for systemically administering the same dose or a therapeutically effective dose of the immune modulator at a site not in the small intestine or colon is selected from the group consisting of subcutaneous, intravenous, and oral administration of the immune modulator.

12. A method of formulating a pharmaceutical composition comprising an immune modulator, the method comprising:

(a) administering a dose of an immune modulator into gastrointestinal tissue at a predetermined site in a small intestine and/or a predetermined site in a colon of a mammal

(b) selecting an immune modulator whose topical administration in step (a) has been determined to result in the method of claim 1 , wherein release of the formulation from the device (a) to the small intestine or (b) to the large intestine provides one or more of the following pharmacodynamic effects:

(i) decreased immune response in diseased tissue, lymph nodes or lymph tissues;

(ii) decreased T cells measured in diseased tissue, lymph nodes or lymph tissues;

(iii) increased T cells in peripheral circulation as measured in blood, plasma or serum;

(iv) changed anatomical features, including suppressed or reduced development, aggregation, or accumulation of one or more of intestinal lymphoid tissues, isolated lymphoid follicles (ILFs), intestinal lymphoid aggregates, or hepatic lymphoid aggregates;

(v) decreased differentiation of immune cells in the diseased tissue;

(vi) decreased levels of inflammatory cytokine levels in the diseased tissue; or

(vii) improved efficacy of treatment using one or more clinical assessments of a treatment, such as endoscopic scoring for IBD, or evidence of hepatic steatosis by imaging or by histology for NAFLD; and

(c) formulating a pharmaceutical composition comprising the selected immune modulator.

13. A pharmaceutical composition prepared by the method of claim 1, 10, or 12 .

14. The pharmaceutical composition of claim 13 , wherein the pharmaceutical composition is useful for the treatment of an inflammatory disease or condition that arises in a tissue originating from the endoderm in a subject.

15. The pharmaceutical composition of claim 14 , wherein the inflammatory disease or condition originating from the endoderm is selected from the group consisting of: gastritis, Celiac disease, hepatitis, alcoholic lever disease, fatty liver disease (hepatic steatosis), non-alcoholic fatty liver disease (NASH), cirrhosis, primary schlerosing cholangitis, pancreatitis, interstitial cystitis, asthma, chronic obstructic pulmonary disease, pulmonary fibrosis, pharyngitis, thyroiditis, hyperthyroidism, parathyroiditis, nephritis, Hashimoto's disease, Addison's disease, Graves' disease, Sjogren syndrome, type 1 diabetes, pelvic inflammatory disease, auditory canal inflammation, tinnitus, vestibular neuritis, otitis media, auditory canal inflammation, tracheitis, cholestatic liver disease, primary biliary sclerosis, liver parenchyma, an inherited metabolic disorder of the liver, Byler syndrome, cerebrotendinous, xanthomatosis, Zellweger's syndrome, neonatal hepatitis, cystic fibrosis, ALGS (Alagilles syndrome), PFIC (progressive familial intrahepatic cholestasis), autoimmune hepatitis, primary biliary cirrhosis (PBC), liver fibrosis, NAFLD, portal hypertension, general cholestasis, such as in jaundice due to drugs or during pregnancy, intra- and extrahepatic cholestasis, such as hereditary forms of cholestasis, such as PFIC1, gall stones and choledocholithiasis, malignancy causing obstruction of the biliary tree, symptoms (scratching, pruritus) due to cholestasis/jaundice, chronic autoimmune liver disease leading to progressive cholestasis, and pruritus of cholestatic liver disease, duodenal ulcers, enteritis (radiation-, chemotherapy-, or infection-induced enteritis), diverticulitis, pouchitis, cholecystitis, and cholangitis.