This proposal addresses the molecular mechanisms of transplant arteriosclerosis in long term survival of heart transplantation. Transplant arteriosclerosis is characterized by widespread, often obliterative intimal thickening which is rich in macrophages and smooth muscle cells. The applicants propose to study the function of three macrophage derived molecules and determine if they are essential components of the immune response that mediates intimal smooth muscle in transplant arteriosclerosis. First, they plan to establish a temporal pattern of expression of these genes in Lewis to F344 rat cardiac allografts at distinct stages of transplant arteriosclerosis. They will also evaluate the effect of various immunosuppressive drugs on this expression. Second, they will identify cytokines that regulate the expression of these three genes in macrophages. They propose to generate recombinant versions of these three genes and a panel of antibodies against the gene products. They will use both of these to evaluate the activity of the three gene products in chemotaxis assays and adhesive properties of cardiac allografts. Third, they will explore manipulations that modulate levels of the macrophage derived proteins to determine if they will ameliorate arteriosclerosis. They propose to develop a model of transplant arteriosclerosis in """"""""gene knockout"""""""" mice with which to study the arteriosclerotic development in recipients that are deficient in the factors that have isolated.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29HL054897-01
Application #
2233397
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1995-09-22
Project End
1999-08-31
Budget Start
1995-09-22
Budget End
1996-08-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Harvard University
Department
Type
Schools of Public Health
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Russell, M E (2000) Cardiac allograft vasculopathy--a changing perspective. Z Kardiol 89 Suppl 9:IX/6-10
Grimm, P C; McKenna, R; Nickerson, P et al. (1999) Clinical rejection is distinguished from subclinical rejection by increased infiltration by a population of activated macrophages. J Am Soc Nephrol 10:1582-9
Raisanen-Sokolowski, A; Glysing-Jensen, T; Russell, M E (1999) Donor and recipient contributions of ICAM-1 and P-selectin in parenchymal rejection and graft arteriosclerosis: insights from double knockout mice. J Heart Lung Transplant 18:735-43
Glysing-Jensen, T; Raisanen-Sokolowski, A; Sayegh, M H et al. (1997) Chronic blockade of CD28-B7-mediated T-cell costimulation by CTLA4Ig reduces intimal thickening in MHC class I and II incompatible mouse heart allografts. Transplantation 64:1641-5
Raisanen-Sokolowski, A; Glysing-Jensen, T; Mottram, P L et al. (1997) Sustained anti-CD4/CD8 treatment blocks inflammatory activation and intimal thickening in mouse heart allografts. Arterioscler Thromb Vasc Biol 17:2115-22
Russell, M E; Raisanen-Sokolowski, A; Mottram, P et al. (1997) Knockout models of chronic cardiac rejection and graft arteriosclerosis: intimal thickening develops independent of Th1 and Th2 cytokines. Transplant Proc 29:2531-2
Raisanen-Sokolowski, A; Mottram, P L; Glysing-Jensen, T et al. (1997) Heart transplants in interferon-gamma, interleukin 4, and interleukin 10 knockout mice. Recipient environment alters graft rejection. J Clin Invest 100:2449-56