title: Autoimmune-mediated vasculopathy.
abstract: The use of the immunosuppressive drug cyclosporine A (CsA) in solid organ transplantation can be associated with the development of vasculopathy as part of the complex immune response involved in chronic rejection, including autoimmune recognition. Although CsA can directly affect endothelial cells, this drug alters the T cell repertoire promoting autoimmune recognition. The present studies evaluated the ability of CsA-induced autoreactive T cells to mediate vascular lesions in syngeneic heart grafts. Graft vasculopathy developed in syngeneic heart grafts following either the primary induction of autoimmunity with CsA or the adoptive transfer of CsA-induced autoreactive T cells. Initially, an inflammatory response occurred in the medial wall of the small arterial vessels, accompanied by a perivascular lymphocytic infiltrate (including a lymphocytic infiltrate into the myocardium), followed by progression of vascular disease with endothelial cell proliferation. The development and progression of vascular disease correlated with the cytokine profile of the infiltrating lymphocytes with type 1 cytokines detected early and type 2 cytokines detected as the disease progressed. Initiation of this response correlated with upregulation of the target antigen recognized by the CsA-induced autoreactive T cells, the MHC class II-invariant chain peptide complex. This antigen complex, when upregulated on endothelial cells by interferon, allowed effective targeting by the autoreactive T lymphocytes. Strategies to inhibit the upregulation of MHC class II antigens by treatment of the recipients with chloroquine truncated the disease process. The results of these studies suggest that CsA-induced autoreactive mechanisms can contribute to the development of graft vasculopathy.
authors: Department of Oncology, The Johns Hopkins University, Baltimore, Maryland 21231, USA.
authors: W
authors: W
authors: Chen
authors: C J
authors: CJ
authors: Thoburn
authors: Y
authors: Y
authors: Miura
authors: M
authors: M
authors: Sommer
authors: R
authors: R
authors: Hruban
authors: Z
authors: Z
authors: Qian
authors: W
authors: W
authors: Baldwin
authors: A D
authors: AD
authors: Hess
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D001161:Arteriosclerosis / Q000209:etiology; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D002738:Chloroquine / Q000627:therapeutic use; D016572:Cyclosporine / Q000633:toxicity*; D003602:Cytotoxicity, Immunologic; D018450:Disease Progression; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008212:Lymphocyte Depletion; D008222:Lymphokines / Q000378:metabolism; D046911:Macromolecular Substances; D011183:Postoperative Complications / Q000209:etiology; D011828:Radiation Chimera; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013934:Thymectomy; D014185:Transplantation, Isogeneic; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology; D014657:Vasculitis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D008222:Lymphokines; D046911:Macromolecular Substances; C045084:invariant chain; D016572:Cyclosporine; D002738:Chloroquine