Diagnosis and therapy of antibody-mediated inflammatory autoimmune disorders

• US 20030021780A1
• Filed: 05/06/2002
• Published: 01/30/2003
• Est. Priority Date: 10/06/2000
• Status: Active Grant

• Current Assignee: Trustees of Boston University, Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center (University of California)
• Original Assignee: Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center (University of California)
• Inventors: Cruikshank, William W., Smith, Terry J.
• Granted Patent: US 8,153,121 B2
• Time in Patent Office: Days
• US Class Current: 424/131.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: C07K 16/244 Interleukins [IL]
• CPC Class Codes: C07K 16/2869 against hormone receptors for antibodies against neuromediator receptors C07K16/286

Abstract

The invention provides a method of reducing the severity of an autoimmune condition associated with T-lymphocyte infiltration. The invention also provides a method of diagnosing or predicting the susceptibility to an autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration. Methods of identifying a substance capable of modulating T-lymphocyte recruitment associated with an autoimmune condition also are provided.

Claims

1. A method of reducing the severity of a condition associated with fibroblast mediated T-lymphocyte infiltration comprising administering an effective amount of at least one substance to a individual, wherein said substance inhibits the interaction between a receptor autoantigen and an endogenous immunoglobulin.

2. The method of claim 1, wherein said autoantigen receptor is Insulin Like Growth Factor-1 Receptor (IGF-1R).

3. The method of claim 1, wherein said immunoglobulin is IgG.

4. The method of claim 1, wherein said condition is an autoimmune disease.

5. The method of claim 4, wherein said autoimmune disease is Graves'"'"' disease (GD) .

6. The method of claim 1, wherein said condition is a manifestation of Graves, disease (GD)

7. The method of claim 6, wherein said manifestation of Graves'"'"' disease (GD) is associated with connective tissue remodeling.

9. The method of claim 4, wherein said autoimmune disease is Rheumatoid Arthritis.

10. The method of claim 4, wherein said condition further is associated with neuroinflammation.

11. A method of reducing the severity of a condition associated with fibroblast mediated T-lymphocyte infiltration comprising administering an effective amount of at least one substance to a individual, wherein said substance inhibits the interaction between IGF-1R and an endogenous immunoglobulin G.

12. The method of claim 11, wherein said condition is an autoimmune disease.

13. The method of claim 12, wherein said autoimmune disease is Graves'"'"' disease (GD).

14. The method of claim 11, wherein said condition is a manifestation of Graves'"'"' disease (GD).

15. The method of claim 14, wherein said manifestation of Graves'"'"' disease (GD) is associated with connective tissue remodeling.

16. The method of claim 15, wherein said manifestation of Graves'"'"' disease (GD) is selected from the group consisting of Thyroid-associated opthalmopathy (TAO) and dermopathy.

17. The method of claim 12, wherein said autoimmune disease is Rheumatoid Arthritis.

18. The method of claim 12, wherein said condition further is associated with neuroinflammation.

19. A method of reducing the severity of a condition associated with fibroblast mediated T-lymphocyte infiltration comprising administering an effective amount of at least one substance to a individual, wherein said substance prevents the influx of immunocompetent cells to affected tissues by reducing the release by fibroblasts of at least one type of chemoattractant molecule that attracts said immunocompetent cells.

20. The method of claim 19, wherein said reduction is the result of inhibiting the interaction between a receptor autoantigen and an endogenous immunoglobulin.

21. The method of claim 20, wherein said receptor autoantigen is IGF-1R.

22. The method of claim 20, wherein said immunoglobulin is IgG.

23. The method of claim 19, wherein said type of chemoattractant molecule is a chemokine.

24. The method of claim 23, wherein said chemokine is a C-C chemokine.

25. The method of claim 24, wherein said C-C chemokine is RANTES.

26. The method of claim 19, wherein said type of chemoattractant molecule is a cytokine.

27. The method of claim 26, wherein said cytokine is a specific CD4+ ligand.

28. The method of claim 27, wherein said cytokine is IL-16.

29. A method of reducing the severity of a condition associated with fibroblast mediated T-lymphocyte infiltration comprising administering an effective amount of at least one substance to a individual, wherein said substance prevents the influx of immunocompetent cells to affected tissues by neutralizing the activity of at least one type of chemoattractant molecule, wherein said chemoattractant molecule is normally released by fibroblasts and attracts said immunocompetent cells in the absence of said substance.

30. The method of claim 29, wherein said type of chemoattractant molecule is a chemokine.

31. The method of claim 30, wherein said neutralization is achieved by inhibiting the interaction between said chemokine and a chemokine receptor.

32. The method of claim 30, wherein said chemokine is a C-C chemokine.

33. The method of claim 32, wherein said C-C chemokine is RANTES.

34. The method of claim 30, wherein said substance is selected from the group consisting of a modified chemokine, an antibody or fragment thereof that specifically binds to said chemokine, an antisense polynucleotide directed to a polynucleotide encoding said chemokine, a nucleotide aptamer that affects the binding of said chemokine to at least one chemokine receptor, a peptide aptamer that affects the binding of said chemokine to at least one chemokine receptor, and a small molecule that affects the binding of said chemokine to at least one chemokine receptor.

35. The method of claim 34, wherein said substance is a modified RANTES molecule.

36. The method of claim 29, wherein said type of chemoattractant molecule is a cytokine.

37. The method of claim 36, wherein said neutralization is achieved by inhibiting the interaction between said cytokine and a cytokine receptor.

38. The method of claim 36, wherein said cytokine is a specific CD4+ ligand.

39. The method of claim 38, wherein said cytokine is IL-16.

40. The method of claim 36, wherein said substance is selected from the group consisting of a modified cytokine, an antibody or fragment thereof that specifically binds to said cytokine, an antisense polynucleotide directed to a polynucleotide encoding said cytokine, a nucleotide aptamer that affects the binding of said cytokine to at least one cytokine receptor, a peptide aptamer that affects the binding of said cytokine to at least one cytokine receptor, and a small molecule that affects the binding of said cytokine to at least one cytokine receptor.

41. The method of claim 40, wherein said substance is a modified IL-16 molecule.

42. A method of diagnosing or predicting the susceptibility to an autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration in an individual suspected of having a such a disease, said method comprising the steps of:

a. obtaining a test tissue sample of the individual;

b. measuring the level of antibodies specific for IGF-1R, and

c. comparing said measured expression levels of antibodies to levels of antibodies from a control tissue sample, wherein a 2-fold or more increase of antibody levels in said test sample compared to said control sample indicates the presence of an autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration.

51. The method of claim 42, 43 or 50, wherein said tissue sample further comprises fibroblasts.

52. The method of claim 51, wherein said tissue sample further comprises serum.

53. The method of claim 52, further comprising the step of establishing a culture of said fibroblasts prior to comparing said measured expression levels.

54. The method of claim 42, 43 or 50, wherein said autoimmune disease is Graves'"'"' disease (GD).

55. The method of claim 42, 43 or 50, wherein said condition is a manifestation of Graves'"'"' disease (GD).

56. The method of claim 55, wherein said manifestation of Graves'"'"' disease (GD) is associated with connective tissue remodeling.

57. The method of claim 56, wherein said manifestation of Graves'"'"' disease (GD) is selected from the group consisting of Thyroid-associated opthalmopathy (TAO) and dermopathy.

58. The method of claim 42, 43 or 50, wherein said autoimmune disease is Rheumatoid Arthritis.

59. The method of claim 58, wherein said autoimmune disease further is associated with neuroinflammation.

43. A method of diagnosing or predicting the susceptibility to an autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration in an individual suspected of having such a disease, said method comprising the steps of:

a. obtaining a test tissue sample of the individual;

b. measuring the level of at least one type of chemoattractant molecule capable of recruiting T-lymphocytes, and

c. comparing said measured expression levels of said type of chemoattractant molecule to levels of chemoattractant molecules from a control tissue sample, wherein a 2-fold or more increase in the measured level of said type of chemoattractant molecule in said test sample compared to said control sample indicates the presence of an autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration.

44. The method of claim 43, wherein said type of chemoattractant molecule is a chemokine.

45. The method of claim 43, wherein said chemokine is a C-C chemokine.

46. The method of claim 45, wherein said C-C chemokine is RANTES.

47. The method of claim 43, wherein said type of chemoattractant molecule is a cytokine.

48. The method of claim 47, wherein said cytokine is a specific CD4+ ligand.

49. The method of claim 48, wherein said cytokine is IL-16.

50. A method of diagnosing or predicting the susceptibility to an autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration in an individual suspected of hav ing such a disease associated with f ibroblast mediated T-lymphocyte infiltration, comprising, said method comprising the steps of:

a. obtaining a test tissue sample of the individual;

b. measuring the level of antibodies specific for IGF-1R, and

c. comparing said measured expression levels of antibodies to levels of antibodies from a control tissue sample, wherein a 2-fold or more increase of antibody levels in said test sample compared to said control sample of antibodies indicates the presence of an autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration.

60. A method of identifying a substance that modulates fibroblast mediated T-lymphocyte infiltration, said method comprising the steps of:

a. inducing fibroblast mediated T-lymphocyte infiltration in a population of cells;

b. contacting a first sub-population of said cells with a test substance, and a second subpopulation of said cells with a control substance, and

c. comparing the amount of fibroblast mediated T-lymphocyte infiltration between said first and second sub-populations of cells,

wherein a difference in the amount of fibroblast mediated T-lymphocyte infiltration between said first and second sub-populations of cells indicates that said test substance modulates fibroblast mediated T-lymphocyte infiltration.

61. The method of claim 60, wherein said fibroblast mediated T-lymphocyte infiltration is induced by antibodies specific for the IGF-1R.

62. The method of claim 60, wherein said cells express the IGF-1R.

63. The method of claim 62, wherein said cells comprise fibroblasts.

64. The method of claim 60, wherein said test-substance is a nucleic acid.

65. The method of claim 60, wherein said test-substance is a small organic molecule.

66. The method of claim 64 or 65, wherein said test-substance modulates the FRAP/mTOR pathway.

67. The method of claim 66, wherein said pathway is rapamycin-sensitive.

68. The method of claim 64 or 65, wherein said test-substance modulates a caspase-3 dependent pathway.

69. A method of identifying a substance capable of modulating the interaction between an IGF-1R and an endogenous immunoglobulin, said method I comprising the steps of:

a. contacting a sample containing IGF-1R and an endogenous immunoglobulin with a test substance under conditions that allow for the interaction between said IGF-1R and said endogenous immunoglobulin, and

b. measuring the interaction between said IGF-1R and said endogenous immunoglobulin, wherein a decrease in the amount of interaction between said IGF-1R and said endogenous immunoglobulin in the presence of said test substance compared to the absence of said test substance indicates that said substance is capable of modulating the interaction between said IGF-1R and said endogenous immunoglobulin.

70. The method of claim 69, wherein said substance capable of modulating the interaction between said IGF-1R and said endogenous immunoglobulin decreases the amount of interaction.

73. The method of claim 69 or 71, wherein said absence of said test substance further comprises the presence of a control substance.

74. The method of claim 69 or 71, wherein the source of said fibroblast cell sample is an individual afflicted with an autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration.

76. The method of claim 69 or 71, wherein said autoimmune disease is Graves'"'"' disease (GD).

77. The method of claim 69 or 71, wherein said condition is a manifestation of Graves'"'"' disease (GD).

78. The method of claim 77, wherein said manifestation of Graves'"'"' disease (GD) is associated with connective tissue remodeling.

79. The method of claim 78, wherein said manifestation of Graves'"'"' disease (GD) is selected from the group consisting of Thyroid-associated opthalmopathy (TAO) and dermopathy.

80. The method of claim 69 or 71, wherein said autoimmune disease is Rheumatoid Arthritis.

81. The method of claim 69 or 71, wherein said autoimmune disease further is associated with neuroinflammation.

71. A method of identifying a substance capable of inhibiting the release of at least one type of chemottractant molecule from fibroblasts, said method comprising the steps of:

a. contacting a fibroblast cell sample with a test substance under conditions that are associated with the release of said chemoattractant, and

b. measuring the amount of said chemottractant that is released from said fibroblast cell sample, wherein a decrease in the amount of said chemottractant that is released from said sample in the presence of said test substance compared to the absence of said test substance indicates that said substance is capable of inhibiting the release of said type of chemottractant molecule from fibroblasts.

8. The method of claim 71, wherein said manifestation of Graves'"'"' disease (GD) is selected from the group consisting of Thyroid-associated opthalmopathy (TAO) and dermopathy.

72. The method of claim 71, further comprising the step of contacting a fibroblast cell sample with a control substance under conditions that are associated with the release of said type of chemoattractant molecule.

75. The method of claim 72, wherein said conditions that are associated with the release of said type of chemoattractant molecule comprise exposing said fibroblast cell sample to an immunoglobulin obtained from an individual afflicted with said autoimmune disease associated with fibroblast mediated T-lymphocyte infiltration.

82. The method of claim 71, wherein said type of chemoattractant molecule is a chemokine.

83. The method of claim 82, wherein said chemokine is a C-C chemokine.

84. The method of claim 83, wherein said C-C chemokine is RANTES.

85. The method of claim 71, wherein said type of chemoattractant molecule is a cytokine.

86. The method of claim 85, wherein said cytokine is a specific CD4+ ligand.

87. The method of claim 86, wherein said cytokine is IL-16.