Composition for inducing proliferation or accumulation of regulatory T cells

• US 9,808,519 B2
• Filed: 05/09/2017
• Issued: 11/07/2017
• Est. Priority Date: 06/04/2010
• Status: Active Grant

• Current Assignee: University of Tokyo
• Original Assignee: University of Tokyo
• Inventors: Honda, Kenya, Atarashi, Koji, Itoh, Kikuji, Tanoue, Takeshi
• Primary Examiner(s): Gangle, Brian J
• Application Number:
  US15/590,257
• Publication Number:
  US 20170246283A1
• Time in Patent Office: 182 Days
• Field of Search: None
• CPC Class Codes: A01K 2217/072 maintaining or altering function, i.e. knock in
• CPC Class Codes: A01K 2217/203 Animal model comprising inducible/conditional expression system, e.g. hormones, tet
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0325 Animal model for autoimmune diseases
• CPC Class Codes: A01K 67/0275 Genetically modified vertebrates, e.g. transgenic
• CPC Class Codes: A61K 2039/52 Bacterial cells; Fungal cells; Protozoal cells
• CPC Class Codes: A61K 2039/542 oral/gastrointestinal
• CPC Class Codes: A61K 2039/55594 from bacteria
• CPC Class Codes: A61K 2039/57 characterised by the type of response, e.g. Th1, Th2
• CPC Class Codes: A61K 2039/577 tolerising response
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/00 Medicinal preparations containing materials or reaction products thereof with undetermined constitution
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 35/742 Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
• CPC Class Codes: A61K 39/0008 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• CPC Class Codes: A61K 39/08 Clostridium, e.g. Clostridium tetani
• CPC Class Codes: A61K 39/39 characterised by the immunostimulating additives, e.g. chemical adjuvants
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/48 : Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61P 1/00 : Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 : for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/12 : Antidiarrhoeals
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/689 : for bacteria
• CPC Class Codes: C12Q 2600/158 : Expression markers
• CPC Class Codes: G01N 2333/33 : from Clostridium (G)
• CPC Class Codes: G01N 2500/10 : involving cells
• CPC Class Codes: G01N 33/505 : involving T-cells

Abstract

It was found that bacteria belonging to the genus Clostridium induce accumulation of regulatory T cells (Treg cells) in the colon. Moreover, the present inventors found that regulatory T cells (Treg cells) induced by from these bacteria suppressed proliferation of effector T-cells. From these findings, the present inventors found that the use of bacteria belonging to the genus Clostridium or a physiologically active substance derived therefrom made it possible to induce proliferation or accumulation of regulatory T cells (Treg cells), and further to suppress immune functions.

Claims

1. A pharmaceutical composition comprising a spore-forming fraction of human fecal matter formulated for delivery to the intestine, wherein the composition induces proliferation and/or accumulation of regulatory T cells, wherein the spore-forming fraction is resistant to chloroform, and wherein the composition is formulated for oral administration.

2. The pharmaceutical composition of claim 1, wherein the spore-forming fraction is obtained by chloroform treatment of human fecal matter.

3. The pharmaceutical composition of claim 2, wherein the chloroform treatment includes an incubation step with chloroform of about 1 hour.

4. The pharmaceutical composition of claim 3, wherein the chloroform treatment includes a step of removal of chloroform with nitrogen gas.

5. The pharmaceutical composition of claim 1, wherein the composition further comprises a pharmacologically acceptable carrier.

6. The pharmaceutical composition of claim 1, wherein the composition is in the form of a capsule.

7. The pharmaceutical composition of claim 1, wherein the composition is formulated for delivery to the colon.

8. The pharmaceutical composition of claim 1, wherein the composition further comprises a pH sensitive composition comprising one or more enteric polymers.

27. The pharmaceutical composition of claim 1, wherein the composition does not include Bacteroides.

9. A pharmaceutical composition comprising a spore-forming fraction of human fecal matter formulated for delivery to the intestine, wherein the composition induces proliferation and/or accumulation of regulatory T cells, wherein the spore-forming fraction is resistant to heat, and wherein the composition is formulated for oral administration.

10. The pharmaceutical composition of claim 9, wherein the spore-forming fraction is obtained by chloroform treatment of human fecal matter.

11. The pharmaceutical composition of claim 10, wherein the chloroform treatment includes an incubation step with chloroform of about 1 hour.

12. The pharmaceutical composition of claim 11, wherein the chloroform treatment includes a step of removal of chloroform with nitrogen gas.

13. The pharmaceutical composition of claim 9, wherein the composition further comprises a pharmacologically acceptable carrier.

14. The pharmaceutical composition of claim 9, wherein the composition is in the form of a capsule.

15. The pharmaceutical composition of claim 9, wherein the composition is formulated for delivery to the colon.

16. The pharmaceutical composition of claim 9, wherein the composition further comprises a pH sensitive composition comprising one or more enteric polymers.

28. The pharmaceutical composition of claim 9, wherein the composition does not include Bacteroides.

17. A pharmaceutical composition comprising an active ingredient, wherein the active ingredient consists of a spore-forming fraction of human fecal matter, wherein the composition is formulated for delivery to the intestine, wherein the composition induces proliferation and/or accumulation of regulatory T cells, and wherein the composition is formulated for oral administration.

18. The pharmaceutical composition of claim 17, wherein the spore-forming fraction is resistant to chloroform.

19. The pharmaceutical composition of claim 18, wherein the spore-forming fraction is obtained by chloroform treatment of human fecal matter.

20. The pharmaceutical composition of claim 19, wherein the chloroform treatment includes an incubation step with chloroform of about 1 hour.

21. The pharmaceutical composition of claim 20, wherein the chloroform treatment includes a step of removal of chloroform with nitrogen gas.

22. The pharmaceutical composition of claim 17, wherein the spore-forming fraction is resistant to heat.

23. The pharmaceutical composition of claim 17, wherein the composition further comprises a pharmacologically acceptable carrier.

24. The pharmaceutical composition of claim 17, wherein the composition is in the form of a capsule.

25. The pharmaceutical composition of claim 17, wherein the composition is formulated for delivery to the colon.

26. The pharmaceutical composition of claim 17, wherein the composition further comprises a pH sensitive composition comprising one or more enteric polymers.