Using undifferentiated embryonic stem cells to control the immune system

• US 20050282272A1
• Filed: 09/24/2004
• Published: 12/22/2005
• Est. Priority Date: 12/07/2001
• Status: Active Grant

• Current Assignee: Asterias Biotherapeutics Incorporated (Lineage Cell Therapeutics, Inc.), University of Western Ontario
• Original Assignee: Geron Corporation, Robarts Research Institute
• Inventors: Madrenas, Joaquin, Majumdar, Anish Sen, Ferber, Iris A., Bhatia, Mickie
• Granted Patent: US 7,799,324 B2
• Time in Patent Office: Days
• US Class Current: 435/366
• CPC Class Codes: A61K 35/545 Embryonic stem cells; Pluripotent stem cells; Induced pluripotent stem cells; Uncharacterised stem cells
• CPC Class Codes: A61K 41/0023 Agression treatment or altering
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: C12N 2501/125 Stem cell factor [SCF], c-kit ligand [KL]
• CPC Class Codes: C12N 2501/155 Bone morphogenic proteins [BMP]; Osteogenins; Osteogenic factor; Bone inducing factor
• CPC Class Codes: C12N 2501/22 Colony stimulating factors (G-CSF, GM-CSF)
• CPC Class Codes: C12N 2501/23 Interleukins [IL]
• CPC Class Codes: C12N 2501/41 Hedgehog proteins; Cyclopamine (inhibitor)
• CPC Class Codes: C12N 2506/02 from embryonic cells
• CPC Class Codes: C12N 5/0634 Cells from the blood or the immune system

Abstract

This disclosure provides a system for minimizing the alloreactivity of tissue transplants. The patient is administered with undifferentiated embryonic stem cells or early progenitor cells. This induces a state of inflammatory quiescence or immune unresponsiveness, which in turn enhances engraftment of cells derived from the same stem cell line given for purposes of regenerative medicine.

Claims

1. A method for making a pharmaceutical combination, comprising:

a) dividing a culture of undifferentiated human embryonic stem (hES) cells into two populations;

b) formulating the first cell population for human administration without differentiating the cells;

c) differentiating the second cell population into cells for tissue regeneration; and

d) formulating the second cell population for human administration after they have been differentiated;

whereupon administration of the first cell population to a subject improves engraftment of the second cell population.

3. The method of claim 1, further comprising inactivating the undifferentiated hES cells in the first cell population.

4. The method of claim 3, wherein the undifferentiated hES cells are inactivated by irradiation or treatment with mitomycin c.

5. The method of claim 3, wherein the undifferentiated hES cells are inactivated by fixing with paraformaldehyde and/or glutaraldehyde.

6. The method of claim 1, wherein the second cell population is differentiated into hepatocytes, neurons, oligodendrocytes, cardiomyocytes, osteogenic cells, mesenchymal cells, hematopoietic cells, islet cells, or chondrocytes.

2. A method for making a pharmaceutical combination, comprising:

a) dividing a culture of undifferentiated hES cells into two populations;

b) differentiating the first cell population into embryoid body cells;

c) differentiating the second cell population into cells for tissue regeneration; and

d) formulating both the first and the second cell population for human administration after they have been differentiated;

whereupon administration of the first cell population to a subject improves engraftment of the second cell population.

7. A pharmaceutical combination for simultaneous or sequential administration to the same subject, comprising together or in separate containers:

a) a first cell population comprising inactivated undifferentiated hES cells or embryoid body cells derived from hES cells, formulated to be suitable for human administration; and

b) a second cell population comprising cells that have been differentiated from the same hES cells into cells for tissue regeneration, formulated to be suitable for human administration.

8. The pharmaceutical combination of claim 7, wherein the first and second cell populations are in separate containers.

9. The pharmaceutical combination of claim 7, wherein the first and second cell population are combined.

10. The pharmaceutical combination of claim 7, wherein administration of the first cell population to a subject improves engraftment of the second cell population.

11. The pharmaceutical combination of claim 7, wherein the first cell population has been inactivated by irradiation, treatment with mitomycin c, or fixation with paraformaldehyde.

12. The pharmaceutical combination of claim 7, wherein the second cell population is a population of hepatocytes, neurons, oligodendrocytes, cardiomyocytes, osteogenic cells, mesenchymal cells, hematopoietic cells, islet cells, or chondrocytes.

13. A method of inducing immune unresponsiveness in a subject, comprising administering to the subject a cell population comprising undifferentiated hES cells or embryoid body cells obtained therefrom, thereby rendering the subject unresponsive to the MHC type of the hES cells.

14. The method of claim 13, wherein the cell population has been inactivated by irradiation, treatment with mitomycin c, or fixation with paraformaldehyde.

15. A method of treating an inflammatory or autoimmune disease, comprising administering at or around the site of the disease undifferentiated hES cells or embryoid body cells obtained therefrom.

16. The method of claim 15, comprising administering at or around the site of the disease undifferentiated hES cells.

17. The method of claim 15, comprising administering at or around the site of the disease embryoid body cells.

18. The method of claim 15, wherein the cell population has been inactivated by irradiation, treatment with mitomycin c, or fixation with paraformaldehyde.

19. The method of claim 15, wherein the autoimmune or inflammatory disease is selected from multiple sclerosis, Type I diabetes, thyroiditis, and arthritis.

20. A method for reconstituting cellular function in a subject, comprising:

a) administering to the subject a first cell population comprising undifferentiated hES cells or embryoid body cells obtained therefrom; and

b) administering to the subject a second cell population differentiated from the same line of hES cells;

wherein administration of the first cell population to a subject improves engraftment of the second cell population.

wherein administration of the second cell population reconstitutes the cellular function in the subject.

21. The method of claim 20, wherein the first cell population comprises undifferentiated hES cells.

22. The method of claim 20, wherein the first cell population comprises embryoid body cells.

23. The method of claim 20, wherein the first cell population has been inactivated by irradiation, treatment with mitomycin c, or fixation with paraformaldehyde.

24. The method of claim 20, wherein the second cell population is a population of hepatocytes, neurons, oligodendrocytes, cardiomyocytes, osteogenic cells, mesenchymal cells, hematopoietic cells, islet cells, or chondrocytes.