This application seeks to address the pathogenesis of chronic rejection in transplantation. The main impediment to long term survival of all solid organ transplants is graft rejection. Currently, transplants are lost in the first year due to acute rejection. Although great strides have been made in the treatment and prevention of acute rejection, chronic rejection has not been amenable to current immunosuppressive therapy. The histological features of chronic rejection are common to all solid organ grafts, and include a vascular lesion associated with the proliferation and migration of smooth muscle cells into the intima, the generation of myofibroblasts, and the synthesis of matrix leading to vessel occlusion. The mechanisms of chronic rejection are poorly understood; however, recent studies have suggested a role for polypeptide growth factors. In particular, PDGF and IGF-I have been implicated as key growth factors supporting proliferation and chemotaxis during fibrotic tissue remodeling in response to injury.
The specific aims of this proposal are: (1) To test the hypothesis that PDGF and IGF-I expression is elevated prior to the development of chronic allograft pathology. These experiments will take advantage of a unique tissue library derived from 71 patients that had serial protocol renal allograft biopsies at 1,2,3,6, and 12 months post-transplant to probe for (a) the expression of PDGF-B and PDGFR, IGF-I and IGF-IR, and (b) PCNA, a marker of proliferation in response to PDGF and IGF-I; (2) To test the hypothesis that IGF-I is a critical component of chronic rejection. These experiments will use (a) transgenic cardiac allografts overexpressing IGF-binding protein 1 compared with wild type, and (b) treatment of recipients of wild type allografts with IGF-IRa Fc fusion protein to compete with cell surface receptors for IGF-I. The data from these experiments will either support or refute the primary hypothesis that PDGF-B and IGF-I are associated with the development of chronic allograft pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI043655-02
Application #
2887834
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Kerr, Lawrence D
Project Start
1998-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Manitoba
Department
Type
DUNS #
207584707
City
Winnipeg
State
MB
Country
Canada
Zip Code
R3 2-N2