Related Experiment Video
Updated: Aug 21, 2026
Mouse Model of Alloimmune-induced Vascular Rejection and Transplant Arteriosclerosis
Published on: May 17, 2015
Inhibition of graft coronary arteriosclerosis after heart transplantation
Harmik J Soukiasian1, Lawrence S C Czer, Hai-Mei Wang
1Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Insights
Cyclosporine (CsA) prevents graft coronary arteriosclerosis (GCA) in heart transplant recipients. Higher CsA doses significantly inhibit immune-mediated injury and vascular changes, improving graft survival.
Area of Science:
- Cardiovascular Surgery
- Immunology
- Transplantation Medicine
Background:
- Graft coronary arteriosclerosis (GCA) is a primary cause of mortality post-heart transplantation (HTx).
- Immune-mediated injury significantly contributes to GCA development.
- Effective immunosuppression is crucial for long-term allograft survival.
Purpose of the Study:
- To investigate the protective effects of cyclosporine (CsA) against GCA in a rat heart transplant model.
- To determine the dose-dependent efficacy of CsA in preventing immune-mediated vascular injury.
Main Methods:
- ACI-to-Lewis rat allografts and Lewis-Lewis isografts were used.
- Rats received varying doses of CsA (2.5-20 mg/kg/day) or olive oil for 3 months.
- Histology, immunohistochemistry, and computerized image morphometry assessed vascular changes and immune cell infiltration.
Main Results:
- Low-dose CsA (2.5 mg/kg/day) resulted in severe rejection and no graft survival.
- Moderate CsA dose (5 mg/kg/day) showed reduced rejection but significant intimal/medial proliferation.
- High-dose CsA (10-20 mg/kg/day) mirrored isograft outcomes, inhibiting GCA and vascular changes (P < 0.001).
Conclusions:
- Inadequate immunosuppression with CsA promotes immune-mediated vasculopathy and GCA.
- CsA effectively prevents GCA in a dose-dependent manner in this rat model.
- GCA affects both epicardial arteries and intramyocardial arterioles.
Abstract:
Graft coronary arteriosclerosis (GCA) is the leading cause of long-term mortality after heart transplantation (HTx). The goal of this study was to demonstrate that inhibition of immunemediated injury by cyclosporine (CsA) protects the allograft from GCA. ACI-to-Lewis rat allografts were disparate in major and nonmajor histocompatibility loci. Isografts (Lewis-Lewis) were controls. Treatment groups received either olive oil or CsA at 2.5, 5, 10, or 20 mg/kg/day for 3 months. Histology (elastin) and immunohistochemistry using monoclonal antibodies to CD4, CD8, CD45R, RT1B, CD11b/c, CD25, and alpha-actin was performed to examine the epicardial and intramyocardial coronary arteries. Computerized image morphometry was utilized to measure intimal and medial thickness and area. Rats receiving olive oil or CsA at 2.5 mg/kg/day had severe rejection and no graft survival. CsA at 5 mg/kg/day resulted in less severe rejection with significant intimal and medial proliferation (P < 0.001). CsA at 10-20 mg/kg/day paralleled Lewis-Lewis isograft outcomes and inhibited arteriosclerotic vascular changes in the allograft (P < 0.001). Perivascular T-helper cells and macrophages were a characteristic finding with low-dose CsA but rare with higher CsA doses. In this new model of accelerated GCA in rats, immune-mediated antigen-dependent vasculopathy as a result of inadequate immunosuppresion is fundamental in the development of GCA, which appeared equally in epicardial arteries and intramyocardial arterioles. CsA prevents GCA in a dose-dependent fashion in the rat allograft.
