Immunomodulation using placental stem cells

• US 20070190034A1
• Filed: 10/13/2006
• Published: 08/16/2007
• Est. Priority Date: 10/13/2005
• Status: Active Grant

• Current Assignee: Celularity, Inc.
• Original Assignee: Anthrogenesis Corporation (Bristol-Myers Squibb Company)
• Inventors: Murray, RoseAnn, Paludan, Casper, Harbacheuski, Ryhor, Edinger, James, Hariri, Robert
• Granted Patent: US 7,682,803 B2
• Time in Patent Office: Days
• US Class Current: 424/93.7
• CPC Class Codes: A61K 35/50 Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 2502/11 blood or immune system cells
• CPC Class Codes: C12N 5/0605 Cells from extra-embryonic tissues, e.g. placenta, amnion, yolk sac, Wharton's jelly
• CPC Class Codes: C12N 5/0668 Mesenchymal stem cells from other natural sources

Abstract

The present invention provides methods of immunomodulation using placental stem cells and placental stem cell populations. The invention also provides methods of producing and selecting placental cells and cell populations on the basis of immunomodulation, and compositions comprising such cells and cell populations.

Claims

1. A method of suppressing an immune response comprising contacting a plurality of immune cells with a plurality of placental stem cells for a time sufficient for said placental stem cells to detectably suppress an immune response, wherein said placental stem cells detectably suppress T cell proliferation in a mixed lymphocyte reaction (MLR) assay.

2. The method of claim 1, wherein said plurality of placental stem cells:

express CD200 and HLA-G;

express CD73, CD105, and CD200;

express CD200 and OCT-4;

express CD73, CD105, and HLA-G;

express CD73 and CD105, and facilitate the formation of one or more embryoid-like bodies in a population of placental cells that comprise the stem cell, when said population is cultured under conditions that allow formation of embryoid-like bodies; and

/or

express OCT-4 and facilitate the formation of one or more embryoid-like bodies in a population of placental cells that comprise the stem cell, when said population is cultured under conditions that allow formation of embryoid-like bodies.

3. The method of claim 1, wherein said plurality of immune cells are T cells or NK (natural killer) cells.

4. The method of claim 3, wherein said T cells are CD4⁺ T cells.

5. The method of claim 3, wherein said T cells are CD8⁺ T cells.

6. The method of claim 1, wherein said contacting is performed in vitro.

7. The method of claim 1, wherein said contacting is performed in vivo.

8. The method of claim 7, wherein said contacting is performed in a mammalian subject.

9. The method of claim 8, wherein said mammalian subject is a human subject.

10. The method of claim 7, wherein said contacting comprises administering said placental cells intravenously.

11. The method of claim 7, wherein said contacting comprises administering said placental cells intramuscularly.

12. The method of claim 7, wherein said contacting comprises administering said placental cells into an organ in said subject.

13. The method of claim 12, wherein said organ is a pancreas.

14. The method of claim 8, additionally comprising administering an anti-macrophage inflammatory protein (MIP)-1α

or anti-MIP-1β

antibody to said subject, wherein said antibody is administered in an amount sufficient to cause a detectable drop in the amount of MIP-1α

or anti-MIP-1β

in blood from said subject.

15. The method of claim 1, wherein said immune response is graft-versus-host disease.

16. The method of claim 15, wherein said immune response is an autoimmune disease.

17. The method of claim 16, wherein said autoimmune disease is diabetes, lupus erythematosus, rheumatoid arthritis, or multiple sclerosis.

18. The method of claim 1, wherein said plurality of immune cells are also contacted with non-placental cells.

19. The method of claim 18, wherein said non-placental cells comprise CD34⁺ cells.

20. The method of claim 19, wherein said CD34⁺ cells are peripheral blood hematopoietic progenitor cells, cord blood hematopoietic progenitor cells, or placental blood hematopoietic progenitor cells.

21. The method of claim 18, wherein said non-placental cells comprise mesenchymal stem cells.

22. The method of claim 21, wherein said mesenchymal stem cells are bone marrow-derived mesenchymal stem cells.

23. The method of claim 16, wherein said non-placental cells are contained within an allograft.

24. The method of claim 1, wherein said plurality of placental stem cells comprises 1×

10⁵ placental stem cells.

25. The method of claim 1, wherein said plurality of placental stem cells comprises 1×

10⁶ placental stem cells.

26. The method of claim 1, wherein said plurality of placental stem cells comprises 1×

10⁷ placental stem cells.

27. The method of claim 1, wherein said plurality of placental stem cells comprises 1×

10⁸ placental stem cells.

28. A method of producing a placental cell population comprising

(a) assaying a plurality of placental cells in a mixed lymphocyte reaction (MLR) assay;

and

(b) selecting said plurality of placental stem cells if said plurality of placental stem cells detectably suppresses CD4⁺ or CD8⁺ T cell proliferation in an MLR (mixed lymphocyte reaction), wherein said placental stem cells;

(i) adhere to a substrate; and

(ii) express CD200 and HLA-G, or

express CD73, CD105, and CD200, or

express CD200 and OCT-4, or

express CD73, CD105, and HLA-G, or

express CD73 and CD105, and facilitate the formation of one or more embryoid-like bodies in a population of placental cells that comprise the stem cell, when said population is cultured under conditions that allow formation of embryoid-like bodies, or

express OCT-4, and facilitate the formation of one or more embryoid-like bodies in a population of placental cells that comprise the stem cell, when said population is cultured under conditions that allow formation of embryoid-like bodies.

29. The method of claim 28, wherein said T cells and said placental stem cells are present in said MLR at a ratio of about 5:

1.

30. The method of claim 28, wherein said placental stem cells are derived from amnion, amnion and chorion.

31. The method of claim 28, wherein said placental stem cells suppress CD4⁺ or CD8⁺ T cell proliferation by at least 50% in said MLR compared to an amount of T cell proliferation in said MLR in the absence of said placental stem cells.

32. The method of claim 28, wherein said placental stem cells suppress CD4⁺ or CD8⁺ T cell proliferation by at least 75% in said MLR compared to an amount of T cell proliferation in said MLR in the absence of said placental stem cells.

33. The method of claim 28, wherein said placental stem cells suppress CD4⁺ or CD8⁺ T cell proliferation by at least 90% in said MLR compared to an amount of T cell proliferation in said MLR in the absence of said placental stem cells.

34. The method of claim 28, wherein said placental stem cells suppress CD4⁺ or CD8⁺ T cell proliferation by at least 95% in said MLR compared to an amount of T cell proliferation in said MLR in the absence of said placental stem cells.

35. The method of claim 28, wherein said placental stem cells additionally detectably suppress an activity of natural killer (NK) cells.

36. An isolated placental stem cell population produced according to the method of claim 28.

37. An isolated population of placental stem cells, wherein said placental stem cells:

(a) adhere to a substrate;

(b) express CD200 and HLA-G, or

express CD73, CD105, and CD200, or

express CD200 and OCT-4, or

express CD73, CD105, and HLA-G, or

express CD73 and CD105, and facilitate the formation of one or more embryoid-like bodies in a population of placental cells that comprise the placental stem cells, when said population is cultured under conditions that allow formation of embryoid-like bodies, or

express OCT-4 and facilitate the formation of one or more embryoid-like bodies in a population of placental cells that comprise the placental stem cells, when said population is cultured under conditions that allow formation of embryoid-like bodies; and

(c) have been identified as detectably suppressing CD4⁺ or CD8⁺ T cell proliferation in an MLR.

38. A composition comprising supernatant from a culture of the cell population of claim 37.

39. A composition comprising culture medium from a culture of placental stem cells, wherein said placental stem cells

(a) adhere to a substrate;

(b) express CD200 and HLA-G, or

express CD73, CD105, and CD200, or

express CD200 and OCT-4, or

express CD73, CD105, and HLA-G, or

express CD73 and CD105, and facilitate the formation of one or more embryoid-like bodies in a population of placental cells that comprise the placental stem cells, when said population is cultured under conditions that allow formation of embryoid-like bodies, or

express OCT-4 and facilitate the formation of one or more embryoid-like bodies in a population of placental cells that comprise the placental stem cells, when said population is cultured under conditions that allow formation of embryoid-like bodies; and

(c) have been identified as detectably suppressing CD4⁺ or CD8⁺ T cell proliferation in an MLR,

wherein said culture of placental stem cells has been cultured in said medium for 24 hours or more.

40. The composition of claim 39, further comprising a plurality of said placental stem cells.

41. The composition of claim 39, further comprising a plurality of non-placental cells.

42. The composition of claim 41, wherein said non-placental cells comprise CD34⁺ cells.

43. The composition of claim 42, wherein said CD34⁺ cells are peripheral blood hematopoietic progenitor cells, cord blood hematopoietic progenitor cells, or placental blood hematopoietic progenitor cells.

44. The composition of claim 42, wherein said non-placental cells comprise mesenchymal stem cells.

45. The composition of claim 44, wherein said mesenchymal stem cells are bone marrow-derived mesenchymal stem cells.

46. The composition of claim 39, further comprising an anti-MIP-1α

or anti-MIP-1β

antibody.