Cellular basis of vascular-graft stenosis

• US 6,248,933 B1
• Filed: 11/06/1998
• Issued: 06/19/2001
• Est. Priority Date: 11/07/1997
• Status: Expired due to Fees

• Current Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Haber, Edgar, Shi, Chengwei, Sibinga, Nicholas E. S.
• Primary Examiner(s): Clark, Deborah J. R.
• Assistant Examiner(s): STROUP, CARRIE M
• Application Number:
  US09/188,081
• Time in Patent Office: 956 Days
• Field of Search: 800/9, 800/18, 800/2, 800/3, 800/8, 800/13, 800/21, 800/14, 514/44, 435/1.1, 435/1.2, 435/320.1, 424/422, 424/423, 424/9.2, 424/569, 600/36
• US Class Current: 800/18
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 67/0271 Chimeric vertebrates, e.g. comprising exogenous cells
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure

Abstract

A mouse model for vein graft stenosis useful for identifying compounds which reduce or prevent such stenosis, consisting of a mouse engrafted with an autogenous vein which exhibits detectable stenosis within 30 days of transplantation. Also disclosed are therapeutic methods for inhibiting the development of vein graft stenosis.

Claims

1. A mouse model for vein graft stenosis, said model comprising a recipient mouse comprising a vein patch surgically transplanted from a histocompatible donor mouse into a defect in an artery of said recipient mouse, wherein graft stenosis occurs within 30 days of transplantation.

2. The model of claim 1, wherein said vein patch is autologous.

3. The model of claim 1, wherein said vein patch is derived from a jugular vein.

4. The model of claim 1, wherein said artery is a carotid artery.

5. The model of claim 1, wherein said mouse is of the C57BL/6J strain.

6. The model of claim 1, wherein said recipient mouse has a knockout mutation in the gene encoding plasminogen.

7. An in vivo screening assay to determine whether a compound reduces vein graft stenosis, comprising:

(a) providing a first mouse comprising a first vein patch autogenously transplanted into an artery of said mouse;

(b) providing a second mouse histocompatible with said first mouse, said second mouse comprising a second vein patch autogenously transplanted into an artery of said second mouse;

(c) contacting said artery of said first mouse with a candidate compound either before or after autogenous transplantation of said first vein patch; and

(d) comparing (1) the degree of vein graft stenosis in said artery of said first mouse which occurs within 30 days after transplantation of said artery, with (2) the degree of vein graft stenosis in said artery of said second mouse which occurs within 30 days after transplantation of said second artery, wherein a lesser degree of vein graft stenosis in said first artery compared to said second artery is an indication that said candidate compound reduces vein graft stenosis.

8. The screening assay of claim 7, wherein said candidate compound is an inhibitor of macrophage activity.

9. The screening assay of claim 7, wherein said candidate compound is an inhibitor of CD4-positive T cell activity.

10. The screening assay of claim 7, wherein said candidate compound is an inhibitor of B cell activity.

11. The screening assay of claim 7, wherein said candidate compound inhibits vascular smooth muscle cell proliferation.

12. The screening assay of claim 7, wherein said vein is a jugular vein and said artery is a carotid artery.

13. An in vivo screening assay to determine whether a plasminogen gene encodes a gene product that decreases vein graft stenosis, comprising:

(a) providing a first mouse and a second mouse, wherein said first mouse lacks a functional copy of said gene and said second mouse comprises at least one functional copy of said gene, said first mouse further comprising a vein patch autogenously transplanted into an artery of said first mouse and said second mouse further comprising a second vein patch autogenously transplanted into an artery of said second mouse;

(b) comparing the degree of vein graft stenosis in the transplanted artery in said first mouse and second mouse, wherein an increase in vein graft stenosis in said first mouse compared to said second mouse indicates that the gene product decreases vein graft stenosis.

14. An in vivo screening assay to determine whether a plasminogen gene encodes a gene product that increases vein graft stenosis, comprising:

(a) providing a first mouse and a second mouse, wherein said first mouse lacks a functional copy of said gene and said second mouse comprises at least one functional copy of said gene, said first mouse further comprising a vein patch autogenously transplanted into an artery of said first mouse and said second mouse further comprising a second vein patch autogenously transplanted into an artery of said second mouse;

(b) comparing the degree of vein graft stenosis in the transplanted artery in said first mouse and second mouse, wherein an increase in vein graft stenosis in said first mouse compared to said second mouse indicates that the gene product decreases vein graft stenosis.

15. An in vivo screening assay to determine whether a compound reduces vein graft stenosis, comprising:

(a) providing a first mouse comprising a first vein patch autogenously transplanted into an artery of said mouse;

(b) providing a second mouse histocompatible with said first mouse, said second mouse comprising a second vein patch autogenously transplanted into an artery of said second mouse;

(c) contacting said artery of said first mouse with a candidate compound either before or after autogenous transplantation of said first vein patch; and

(d) comparing (1) the degree of vein graft stenosis in said first artery of said mouse which occurs within 30 days after transplantation of said artery, with (2) the degree of vein graft stenosis in said second artery of said second mouse which occurs within 30 days after transplantation of said second artery, wherein a lesser degree of vein graft stenosis in said first artery compared to said second artery is an indication that said candidate compound reduces vein graft stenosis.

16. A method of making a mouse comprising a vein graft stenosis, said method comprising

(a) providing a recipient mouse;

and

(b) engrafting a vein patch from a histocompatible donor mouse into an artery of said recipient mouse, wherein graft stenosis occurs within 30 days of transplantation.

17. The method of claim 16, wherein said vein patch is derived from a jugular vein and said artery is a carotid artery.

18. The method claim 16, wherein said artery is a carotid artery.

19. The method of claim 16, wherein said vein patch is derived from a jugular vein.