COMPOSITIONS AND METHODS FOR INHIBITING ADVERSE IMMUNE RESPONSE IN HISTOCOMPATIBILITY-MISMATCHED TRANSPLANTATION

• US 20070264269A1
• Filed: 12/15/2006
• Published: 11/15/2007
• Est. Priority Date: 12/16/2005
• Status: Active Grant

• Current Assignee: Depuy Synthes Products Incorporated (Johnson & Johnson)
• Original Assignee: Ethicon Incorporated (Johnson & Johnson)
• Inventors: Davis, Janet, Harmon, Alexander
• Granted Patent: US 9,175,261 B2
• Time in Patent Office: Days
• US Class Current: 424/184.100
• CPC Class Codes: A61K 2035/122 for inducing tolerance or supression of immune responses
• CPC Class Codes: A61K 35/51 Umbilical cord; Umbilical cord blood; Umbilical stem cells
• 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 37/02 Immunomodulators
• 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: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C12N 5/0605 Cells from extra-embryonic tissues, e.g. placenta, amnion, yolk sac, Wharton's jelly

Abstract

Cell-based compositions and methods of their use to inhibit an adverse immune response such as graft versus host disease or rejection of transplanted tissue in a transplant recipient that is histocompatibility mismatched to the transplant donor are disclosed. The compositions and methods utilize postpartum-derived cells, such as cells derived from the placenta or umbilicus.

Claims

1. A method for inhibiting an adverse immune response in a transplant recipient that is histocompatibility-mismatched to the transplant donor, comprising administering a cell composition to the transplant recipient in an amount effective for inhibiting the adverse immune response, wherein the cell composition comprises a pharmaceutically acceptable carrier and postpartum-derived cells derived from human postpartum tissue substantially free of blood, said cells being capable of self-renewal and expansion in culture, wherein the cells require L-Valine for growth and are capable of growth in an atmosphere containing oxygen from about 5% to at least about 20%, and wherein the cells comprise at least one of the following characteristics:

a) potential for at least about 40 doublings in culture;

b) attachment and expansion on a coated or uncoated tissue culture vessel, wherein a coated tissue culture vessel comprises a coating of gelatin, laminin, collagen, polyornithine, vitronectin, or fibronectin;

c) production of at least one of tissue factor, vimentin, and alpha-smooth muscle actin;

d) production of at least one of CD10, CD13, CD44, CD73, CD90, PDGFr-alpha, PD-L2 and HLA-A, B, C;

e) lack of production of at least one of CD31, CD34, CD45, CD80, CD86, CD117, CD141, CD178, B7-H2, HLA-G, and HLA-DR, DP, DQ, as detected by flow cytometry;

f) expression of at least one of interleukin 8;

reticulon 1;

chemokine (C—

X—

C motif) ligand 1 (melanoma growth stimulating activity, alpha);

chemokine (C—

X—

C motif) ligand 6 (granulocyte chemotactic protein

     2);

chemokine (C—

X—

C motif) ligand 3; and

tumor necrosis factor, alpha-induced protein 3;

g) expression of at least one of C-type (calcium dependent, carbohydrate-recognition domain) lectin, superfamily member 2 (activation-induced);

Wilms tumor 1;

aldehyde dehydrogenase 1 family, member A2; and

renin;

oxidized low density lipoprotein (lectin-like) receptor 1;

Homo sapiens, clone IMAGE;

4179671, mRNA, partial cds;

protein kinase C, zeta;

hypothetical protein DKFZp564F013;

downregulated in ovarian cancer 1;

Homo sapiens mRNA; and

cDNA DKFZp547K1113 (from clone DKFZp547K1113);

h) expression of a gene, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is reduced for at least one of;

short stature homeobox 2;

heat shock 27 kDa protein 2;

chemokine (C—

X—

C motif) ligand 12 (stromal cell-derived factor

     1);

elastin (supravalvular aortic stenosis, Williams-Beuren syndrome);

Homo sapiens mRNA;

cDNA DKFZp586M2022 (from clone DKFZp586M2022);

mesenchyme homeobox 2 (growth arrest-specific homeobox);

sine oculis homeobox homolog 1 (Drosophila);

crystallin, alpha B;

dishevelled associated activator of morphogenesis 2;

DKFZP586B2420 protein;

similar to neuralin 1;

tetranectin (plasminogen binding protein);

src homology three (SH3) and cysteine rich domain;

B-cell translocation gene 1, anti-proliferative;

cholesterol 25-hydroxylase;

runt-related transcription factor 3;

hypothetical protein FLJ23191;

interleukin 11 receptor, alpha;

procollagen C-endopeptidase enhancer;

frizzled homolog 7 (Drosophila);

hypothetical gene BC008967;

collagen, type VIII, alpha 1;

tenascin C (hexabrachion);

iroquois homeobox protein 5;

hephaestin;

integrin, beta 8;

synaptic vesicle glycoprotein 2;

Homo sapiens cDNA FLJ12280 fis, clone MAMMA1001744;

cytokine receptor-like factor 1;

potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4;

integrin, alpha 7;

DKFZP586L151 protein;

transcriptional co-activator with PDZ-binding motif (TAZ);

sine oculis homeobox homolog 2 (Drosophila);

KIAA1034 protein;

early growth response 3;

distal-less homeobox 5;

hypothetical protein FLJ20373;

aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II);

biglycan;

fibronectin 1;

proenkephalin;

integrin, beta-like 1 (with EGF-like repeat domains);

Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 1968422;

EphA3;

KIAA0367 protein;

natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C);

hypothetical protein FLJ14054;

Homo sapiens mRNA;

cDNA DKFZp564B222 (from clone DKFZp564B222);

vesicle-associated membrane protein 5 (myobrevin);

EGF-containing fibulin-like extracellular matrix protein 1;

BCL2/adenovirus EIB 19 kDa interacting protein 3-like;

AE binding protein 1;

cytochrome c oxidase subunit VIIa polypeptide 1 (muscle);

neuroblastoma, suppression of tumorigenicity 1;

insulin-like growth factor binding protein 2, 36 kDa;

i) secretion of at least one of MCP-1, IL-6, IL-8, GCP-2, HGF, KGF, FGF, HB-EGF, BDNF, TPO, MIP1a, RANTES, and TIMP1; and

j) lack of secretion of at least one of TGF-beta2, ANG2, PDGFbb, MIP1b, 1309, MDC, and VEGF, as detected by ELISA.

2. The method of claim 1, wherein the adverse immune response is graft versus host disease.

3. The method of claim 1, wherein the adverse immune response is rejection of the transplanted tissue.

4. The method of claim 1, wherein the postpartum derived cells are placenta-derived cells, umbilicus-derived cells, or a combination of placenta-derived cells and umbilicus-derived cells.

5. The method of claim 1 wherein the cell composition is administered by injection or infusion.

6. The method of claim 1, wherein the cell composition is administered by implantation of a device, scaffold or matrix implanted in the transplant recipient.

7. The method of claim 1, wherein the cell composition comprises at least about 50% postpartum-derived cells.

8. The method of claim 1, wherein the cell composition comprises a substantially homogeneous population of postpartum-derived cells.

9. The method of claim 1, wherein the cells are administered with at least one other cell type.

10. The method of claim 9, wherein the at least one other cell type is administered simultaneously with, or before, or after, the postpartum-derived cells.

11. The method of claim 1, wherein the cells are administered with at least one other agent for treating the adverse immune response.

12. The method of claim 11, wherein the at least one other agent is administered simultaneously with, or before, or after, the postpartum-derived cells.

13. The method of claim 11, wherein the at least one other agent is one or more of an antithrombogenic agent, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, or an antiapoptotic agent.

14. A pharmaceutical composition for inhibiting an adverse immune response in a transplant recipient that is histocompatibility-mismatched to the transplant donor, comprising a pharmaceutically acceptable carrier and an amount of the postpartum-derived cells of claim 1 effective to inhibit the adverse immune response in a transplant recipient that is histocompatibility-mismatched to the transplant donor.

15. The pharmaceutical composition of claim 14, wherein the adverse immune response is graft versus host disease.

16. The pharmaceutical composition of claim 14, wherein the adverse immune response is rejection of the transplanted tissue.

17. The pharmaceutical composition of claim 14, wherein the postpartum derived cells are placenta-derived cells, umbilicus-derived cells, or a combination of placenta-derived cells and umbilicus-derived cells.

18. The pharmaceutical composition of claim 14, formulated for administration by injection or infusion.

19. The pharmaceutical composition of claim 14, formulated for administration by implantation of a device, scaffold or matrix implanted in the transplant recipient.

20. The pharmaceutical composition of claim 14, comprising at least about 50% postpartum-derived cells.

21. The pharmaceutical composition of claim 14, comprising a substantially homogeneous population of postpartum-derived cells.

22. The pharmaceutical composition of claim 14, comprising at least one other cell type.

23. The pharmaceutical composition of claim 14, comprising at least one other agent for treating the adverse immune response.

24. The pharmaceutical composition of claim 23, wherein the at least one other agent is one or more of an antithrombogenic agent, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, or an antiapoptotic agent.

25. A kit for inhibiting an adverse immune response in a transplant recipient that is histocompatibility-mismatched to the transplant donor, comprising a pharmaceutically acceptable carrier, a population of the postpartum-derived cells of claim 1, and instructions for using the kit in a method for inhibiting the adverse immune response.

26. The kit of claim 25, which further comprises at least one reagent and instructions for culturing the postpartum-derived cells.

27. The kit of claim 25, which further comprises a population of at least one other cell type.

28. The kit of claim 25, which further comprises at least one other agent for inhibiting the adverse immune response.

29. A method for inhibiting an adverse immune response in a transplant recipient that is histocompatibility-mismatched to the transplant donor comprising administering to the patient a composition comprising one or more of a conditioned medium generated by postpartum-derived cells, a cell lysate generated from postpartum-derived cells, a soluble cell fraction generated from postpartum-derived cells, or an extracellular matrix containing postpartum-derived cells, wherein the postpartum-derived cells are derived from human postpartum tissue substantially free of blood and capable of self-renewal and expansion in culture, wherein the cells require L-Valine for growth and are capable of growth in an atmosphere containing oxygen from about 5% to at least about 20%, and wherein the cells comprise at least one of the following characteristics:

a) potential for at least about 40 doublings in culture;

b) attachment and expansion on a coated or uncoated tissue culture vessel, wherein a coated tissue culture vessel comprises a coating of gelatin, laminin, collagen, polyornithine, vitronectin, or fibronectin;

c) production of at least one of tissue factor, vimentin, and alpha-smooth muscle actin;

d) production of at least one of CD10, CD13, CD44, CD73, CD90, PDGFr-alpha, PD-L2 and HLA-A, B, C;

e) lack of production of at least one of CD31, CD34, CD45, CD80, CD86, CD117, CD141, CD178, B7-H2, HLA-G, and HLA-DR, DP, DQ, as detected by flow cytometry;

f) expression of at least one of interleukin 8;

reticulon 1;

chemokine (C—

X—

C motif) ligand 1 (melanoma growth stimulating activity, alpha);

chemokine (C—

X—

C motif) ligand 6 (granulocyte chemotactic protein

     2);

chemokine (C—

X—

C motif) ligand 3; and

tumor necrosis factor, alpha-induced protein 3;

g) expression of at least one of C-type (calcium dependent, carbohydrate-recognition domain) lectin, superfamily member 2 (activation-induced);

Wilms tumor 1;

aldehyde dehydrogenase 1 family, member A2; and

renin;

oxidized low density lipoprotein (lectin-like) receptor 1;

Homo sapiens, clone IMAGE;

4179671, mRNA, partial cds;

protein kinase C, zeta;

hypothetical protein DKFZp564F013;

downregulated in ovarian cancer 1;

Homo sapiens mRNA; and

cDNA DKFZp547K1113 (from clone DKFZp547K1113);

h) expression of a gene, which relative to a human cell that is a fibroblast, a mesenchymal stem cell, or an ileac crest bone marrow cell, is reduced for at least one of;

short stature homeobox 2;

heat shock 27 kDa protein 2;

chemokine (C—

X—

C motif) ligand 12 (stromal cell-derived factor

     1);

elastin (supravalvular aortic stenosis, Williams-Beuren syndrome);

Homo sapiens mRNA;

cDNA DKFZp586M2022 (from clone DKFZp586M2022);

mesenchyme homeobox 2 (growth arrest-specific homeobox);

sine oculis homeobox homolog 1 (Drosophila);

crystallin, alpha B;

dishevelled associated activator of morphogenesis 2;

DKFZP586B2420 protein;

similar to neuralin 1;

tetranectin (plasminogen binding protein);

src homology three (SH3) and cysteine rich domain;

B-cell translocation gene 1, anti-proliferative;

cholesterol 25-hydroxylase;

runt-related transcription factor 3;

hypothetical protein FLJ23191;

interleukin 11 receptor, alpha;

procollagen C-endopeptidase enhancer;

frizzled homolog 7 (Drosophila);

hypothetical gene BC008967;

collagen, type VIII, alpha 1;

tenascin C (hexabrachion);

iroquois homeobox protein 5;

hephaestin;

integrin, beta 8;

synaptic vesicle glycoprotein 2;

Homo sapiens cDNA FLJ12280 fis, clone MAMMA1001744;

cytokine receptor-like factor 1;

potassium intermediate/small conductance calcium-activated channel, subfamily N, member 4;

integrin, alpha 7;

DKFZP586L151 protein;

transcriptional co-activator with PDZ-binding motif (TAZ);

sine oculis homeobox homolog 2 (Drosophila);

KIAA1034 protein;

early growth response 3;

distal-less homeobox 5;

hypothetical protein FLJ20373;

aldo-keto reductase family 1, member C3 (3-alpha hydroxysteroid dehydrogenase, type II);

biglycan;

fibronectin 1;

proenkephalin;

integrin, beta-like 1 (with EGF-like repeat domains);

Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 1968422;

EphA3;

KIAA0367 protein;

natriuretic peptide receptor C/guanylate cyclase C (atrionatriuretic peptide receptor C);

hypothetical protein FLJ14054;

Homo sapiens mRNA;

cDNA DKFZp564B222 (from clone DKFZp564B222);

vesicle-associated membrane protein 5 (myobrevin);

EGF-containing fibulin-like extracellular matrix protein 1;

BCL2/adenovirus EIB 19 kDa interacting protein 3-like;

AE binding protein 1;

cytochrome c oxidase subunit VIIa polypeptide 1 (muscle);

neuroblastoma, suppression of tumorigenicity 1;

insulin-like growth factor binding protein 2, 36 kDa;

i) secretion of at least one of MCP-1, IL-6, IL-8, GCP-2, HGF, KGF, FGF, HB-EGF, BDNF, TPO, MIP1a, RANTES, and TIMP1; and

j) lack of secretion of at least one of TGF-beta2, ANG2, PDGFbb, MIP1b, 1309, MDC, and VEGF, as detected by ELISA.

30. The method of claim 29, wherein the adverse immune response is graft versus host disease.

31. The method of claim 29, wherein the adverse immune response is rejection of the transplanted tissue.

32. The method of claim 29, wherein the postpartum derived cells are placenta-derived cells, umbilicus-derived cells, or a combination of placenta-derived cells and umbilicus-derived cells.

33. The method of claim 29, wherein the composition is administered by injection or infusion.

34. The method of claim 29, wherein the composition is administered by implantation of a device, scaffold or matrix in the transplant recipient.

35. The method of claim 29, wherein the composition is administered with at least one other agent for treating the adverse immune response.

36. The method of claim 35, wherein the at least one other agent is administered simultaneously with, or before, or after, the composition.

37. The method of claim 35, wherein the at least one other agent is one or more of an antithrombogenic agent, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, or an antiapoptotic agent.

38. A pharmaceutical composition for inhibiting an adverse immune response in a transplant recipient that is histocompatibility-mismatched to the transplant donor, comprising a pharmaceutically acceptable carrier and an amount of the composition of claim 29 effective to inhibit the adverse immune response in a transplant recipient that is histocompatibility-mismatched to the transplant donor.

39. The pharmaceutical composition of claim 38, wherein the adverse immune response is graft versus host disease.

40. The pharmaceutical composition of claim 38, wherein the adverse immune response is rejection of the transplanted tissue.

41. The pharmaceutical composition of claim 38, wherein the postpartum derived cells are placenta-derived cells, umbilicus-derived cells, or a combination of placenta-derived cells and umbilicus-derived cells.

42. The pharmaceutical composition of claim 38, formulated for administration by injection or infusion.

43. The pharmaceutical composition of claim 38, formulated for administration by implantation of a device, scaffold or matrix implanted in the transplant recipient.

44. The pharmaceutical composition of claim 38, comprising at least one other agent for treating the adverse immune response.

45. The pharmaceutical composition of claim 44, wherein the at least one other agent is one or more of an antithrombogenic agent, an anti-inflammatory agent, an immunosuppressive agent, an immunomodulatory agent, or an antiapoptotic agent.

46. A kit for inhibiting an adverse immune response in a transplant recipient that is histocompatibility-mismatched to the transplant donor, comprising a pharmaceutically acceptable carrier, the composition of claim 29, and instructions for using the kit in a method for inhibiting the adverse immune response.

47. The kit of claim 46, which further comprises at least one other agent for inhibiting the adverse immune response.