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IFN-gamma and Fas/FasL pathways cooperate to induce medial cell loss and neointimal lesion formation in allograft vasculopathy.
- Source :
-
Transplant immunology [Transpl Immunol] 2010 Feb; Vol. 22 (3-4), pp. 157-64. Date of Electronic Publication: 2009 Nov 03. - Publication Year :
- 2010
-
Abstract
- Using a clinically relevant, fully disparate, allogeneic aortic transplant mouse model of allograft vasculopathy, we have demonstrated that neointimal proliferation is dependent on CD8(+) T cell effector pathways in the presence of therapeutic doses of calcineurin inhibitor (CNI) immunosuppression. CD4(+) T cell pathways are ablated by CNI immunosuppression. In the current study, we examined the relationship between CD8(+) T cell activities, medial SMC loss and neointimal hyperplasia. We demonstrate that at 5-6wk post transplantation in a wild type/wild type transplant CD8(+) T cell infiltration, CD8(+) CTL effector cell mediator expression and medial SMC loss all occur within aortic interposition grafts in the face of CNI immunosuppression. Both IFN-gamma and CTL mediated effector function is required for SMC loss and lesion formation under these conditions. Using strain combinations and reconstitution models, we provide data that blockade of the perforin/granzyme pathway does not prevent lesion formation but that blockade of the Fas/FasL pathway of cytotoxicity dramatically reduces SMC loss and prevents neointimal lesion formation. Both of these blockade strategies are in the face of an active IFN-gamma pathway. These data suggest a cooperative role between Fas/FasL and IFN-gamma mediated effector functions in medial SMC loss and neointimal lesion formation.<br /> (Copyright 2009 Elsevier B.V. All rights reserved.)
- Subjects :
- Adaptor Proteins, Signal Transducing
Animals
Aorta drug effects
Aorta pathology
Aorta transplantation
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
CD8-Positive T-Lymphocytes pathology
Calcineurin administration & dosage
Cell Movement
Cytotoxicity, Immunologic drug effects
Graft Occlusion, Vascular drug therapy
Graft Occlusion, Vascular pathology
Graft Occlusion, Vascular physiopathology
Humans
Immunosuppression Therapy
Intracellular Signaling Peptides and Proteins
Lymphocyte Cooperation
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Myocytes, Smooth Muscle drug effects
Myocytes, Smooth Muscle pathology
Phosphoproteins administration & dosage
Tunica Intima drug effects
Tunica Intima immunology
Tunica Intima metabolism
Tunica Intima pathology
Tunica Media immunology
Tunica Media metabolism
Tunica Media pathology
Aorta immunology
Fas Ligand Protein metabolism
Graft Occlusion, Vascular immunology
Interferon-gamma metabolism
fas Receptor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-5492
- Volume :
- 22
- Issue :
- 3-4
- Database :
- MEDLINE
- Journal :
- Transplant immunology
- Publication Type :
- Academic Journal
- Accession number :
- 19895889
- Full Text :
- https://doi.org/10.1016/j.trim.2009.10.004