Treatment methods for disease using co-localized cells and Sertoli cells obtained from a cell line

• US 5,958,404 A
• Filed: 06/07/1996
• Issued: 09/28/1999
• Est. Priority Date: 04/13/1994
• Status: Expired due to Term

• Current Assignee: Research Corporation Technologies
• Original Assignee: Research Corporation Technologies
• Inventors: Selawry, Helena P.
• Primary Examiner(s): Naff, David M.
• Assistant Examiner(s): Ware, Deborah K.
• Application Number:
  US08/660,258
• Time in Patent Office: 1,208 Days
• Field of Search: 424/93.7, 435/325, 435/373, 435/404, 435/284.1
• US Class Current: 424/93.7
• CPC Class Codes: A61K 2035/122 for inducing tolerance or supression of immune responses
• CPC Class Codes: A61K 2035/126 Immunoprotecting barriers, e.g. jackets, diffusion chambers
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• 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 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 35/39 Pancreas; Islets of Langerhans Langerhans cells of epidermis A61K35/36
• CPC Class Codes: A61K 35/48 Reproductive organs
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 38/28 Insulins
• 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 2502/246 Cells of the male genital tract, non-germinal testis cells
• CPC Class Codes: C12N 2510/00 Genetically modified cells
• CPC Class Codes: C12N 2510/04 Immortalised cells
• CPC Class Codes: C12N 5/0677 Three-dimensional culture, tissue culture or organ culture; Encapsulated cells
• CPC Class Codes: C12N 5/0683 Cells of the male genital tract, e.g. prostate, epididymis; Non-germinal cells from testis, e.g. Leydig cells, Sertoli cells spermatogonia C12N5/061

Abstract

A method of treating a disease is provided that results from a deficiency of a biological factor which comprises administering to a mammal Sertoli cells and cells that produce the biological factor. A method of treating diabetes mellitus is carried out by transplanting pancreatic islet of Langerhans cells in conjunction with Sertoli cells to create an immunologically privileged site. A method of creating an immunologically privileged site and providing cell stimulatory factors in a mammal for transplants is also carried out. A method of co-localizing islet cells with Sertoli cells and the use of the co-localized product for treating diabetes mellitus is further provided. Further described is a method of creating systemic tolerance to foreign antigens. A method of enhancing the viability, maturation, proliferation of functional capacity of cells in tissue culture is also provided. In addition, a pharmaceutical composition comprising Sertoli cells and cells that produce a biological factor is provided.

Claims

1. A method of treating a disease that results from a deficiency of a biological factor in a mammal wherein said method comprises administering Sertoli cells obtained from a cell line and a therapeutically effective amount of cells that produce said biological factor to a mammal in need of such treatment, wherein said Sertoli cells are administered in an amount effective to create an immunologically privileged site.

2. The method of claim 1 wherein said mammal is a human.

3. The method of claim 1 wherein said biological factor is a hormone.

4. The method of claim 1 wherein said biological factor is insulin and said disease is diabetes mellitus.

5. The method of claim 4 wherein said cells that produce said biological factor are pancreatic islet of Langerhans cells.

6. The method of claim 1 wherein said cells that produce said biological factor are cells transformed by a nucleic acid encoding said biological factor.

7. The method of claim 1 wherein said administering is by transplantation.

8. The method of claim 1 wherein said Sertoli cells are administered in a dosage ranging from 10⁵ to 10¹⁰ cells.

9. The method of claim 1 wherein said cells that produce said biological factor are administered in a dosage of from 10⁵ to 10¹⁰ cells.

10. The method of claim 7 wherein said transplantation is by xenograft.

11. The method of claim 7 wherein said transplantation is by allograft.

12. The method of claim 1 which further comprises administering an immunosuppressive agent.

13. The method of claim 12 wherein said immunosuppressive agent is administered for a time sufficient to permit said transplanted cells to be functional.

14. The method of claim 12 wherein said immunosuppressive agent is cyclosporine.

15. The method of claim 14 wherein said cyclosporine is administered at a dosage of from 5 to 40 mg/kg body wt.

16. The method of claim 1 which further comprises administering a therapeutically effective amount of exogenous biological factor following the transplantation of said cells that produce said biological factor.

17. The method of claim 1 wherein said cells that produce said biological factor are co-cultured with Sertoli cells in tissue culture.

18. The method of claim 17 wherein said cells that produce said biological factor are cryopreserved prior to co-culturing with Sertoli cells in tissue culture.

19. The method of claim 1 wherein said Sertoli cells are obtained by the steps comprising:

(a) isolating mammalian Sertoli cells from mammalian tissue;

(b) incubating said isolated mammalian Sertoli cells with virus producing cells under conditions sufficient to transform said Sertoli cells; and

(c) isolating said transformed cells from the virus producing cells.

20. The method of claim 1 wherein said Sertoli cells are obtained by the steps comprising:

(a) isolating mammalian Sertoli cells from mammalian tissue;

(b) incubating said isolated mammalian Sertoli cells with a mutagen under conditions sufficient to transform said Sertoli cells; and

(c) collecting said transformed Sertoli cells.

21. The method of claim 19, wherein said virus producing cells are SV40 or polyoma virus.

50. The method of claim 19, 20, 37, 38, 42 or 43 wherein said transformed Sertoli cells are screened for expression of an appropriate isolate for cloning.

22. A method of treating diabetes mellitus in a mammal wherein said method comprises administering to a diabetic mammal Sertoli cells obtained from a cell line in an amount effective to create an immunologically privileged site and a therapeutically effective amount of pancreatic islet of Langerhans cells.

23. The method of claim 22 wherein said diabetes mellitus is type I or type II.

24. The method of claim 22 wherein said mammal is a human.

25. The method of claim 22 wherein said Sertoli cells are human, bovine or porcine.

26. The method of claim 22 wherein said pancreatic islet of Langerhans cells are human, bovine or porcine.

27. The method of claim 22 wherein said administering is by transplantation.

28. The method of claim 27 wherein said transplantation is by injection into the renal subcapsular space.

29. The method of claim 27 wherein said transplantation is by injection into the subcutaneous facie.

30. The method of claim 22 wherein said Sertoli cells are administered at a dosage ranging from 10⁵ to 10¹⁰ cells.

31. The method of claim 22 wherein said islet of Langerhans cells are administered at a dosage ranging from 5-1000 islet cells/g body wt.

32. The method of claim 22 which further comprises the administration of an immunosuppressive agent.

33. The method of claim 32 wherein said immunosuppressive agent is administered for a time sufficient to permit the transplanted islets to be functional.

34. The method of claim 32 wherein said immunosuppressive agent is cyclosporine.

35. The method of claim 32 wherein said cyclosporine is administered at a dosage of 5 to 40 mg/kg body wt.

36. The method of claim 22 which further comprises administering a therapeutically effective amount of insulin following transplantation of said pancreatic islet of Langerhans cells.

37. The method of claim 22 wherein said Sertoli cells are obtained by the steps comprising:

(a) isolating mammalian Sertoli cells from mammalian tissue;

(b) incubating said isolated mammalian Sertoli cells with virus producing cells under conditions sufficient to transform said Sertoli cells; and

(c) isolating said transformed Sertoli cells from the virus producing cell.

38. The method of claim 22 wherein said Sertoli cells are obtained by the steps comprising:

(a) isolating mammalian Sertoli cells from mammalian tissue;

(b) incubating said isolated mammalian Sertoli cells with a mutagen under conditions sufficient to transform said Sertoli cells; and

(c) collecting said transformed Sertoli cells.

39. The method of claim 37 wherein said virus producing cells are SV40 or polyoma virus.

40. A method of treating an autoimmune disease in a mammal wherein said method comprises transplanting in to said mammal a therapeutically effective amount of isolated Sertoli cells obtained from a cell line to a transplant site in said mammal having said autoimmune disease, wherein said site is other than testes.

41. The method of claim 40 wherein said Sertoli cells are administered in a dosage ranging from 10⁵ to 10¹⁰ cells.

42. The method of claim 40 wherein said Sertoli cells are obtained by the steps comprising:

(a) isolating mammalian Sertoli cells from mammalian tissue;

(b) incubating said isolated mammalian Sertoli cells with virus producing cells under conditions sufficient to transform said Sertoli cells; and

(c) collecting said transformed Sertoli cells from the virus producing cell.

43. The method of claim 40 wherein said Sertoli cells are obtained by the steps comprising:

(a) isolating mammalian Sertoli cells from mammalian tissue;

(b) incubating said isolated mammalian Sertoli cells with a mutagen under conditions sufficient to transform said Sertoli cells; and

(c) isolating said transformed Sertoli cells.

44. The method of claim 42 wherein said virus producing cells are SV40 or polyoma virus.

45. A method of enhancing the recovery and proliferation of ex vivo cells comprising co-culturing said cells with Sertoli cells for a time and under conditions sufficient to achieve said enhanced recovery and proliferation.

46. A method of enhancing the recovery and proliferation of ex vivo cells comprising culturing said cells in a tissue culture medium containing Sertoli cells for a time and under conditions sufficient to achieve said enhanced recovery and proliferation.

47. A method of treating a disease that results from a deficiency of a biological factor in a mammal wherein said method comprises administering Sertoli cells and a therapeutically effective amount of cells that produce said biological factor to a mammal in need of such treatment, wherein said Sertoli cells are administered in an amount effective to create an immunologically privileged site;

and wherein said Sertoli cells and said cells that produce a biological factor are co-localized.

48. The method of claim 47 wherein said biological factor producing cells are co-localized by co-encapsulation.

49. The method of claim 47 or 48 wherein said disease is diabetes mellitus and said biological factor producing cells are islet of Langerhans cells.