We have hypothesized that transplantation-associated arteriosclerosis (TxAA) is a fibroproliferative response of donor vascular smooth muscle cells (SMC) caused in large part by a chronic delayed hypersensitivity response of host T cells to donor endothelial cells (BC), distinct from the cytolytic response of acute rejection. This chronic delayed hypersensitivity response differs from acute rejection in that it persists because it does not effectively eliminate the foreign antigen and because it produces fibroplasia rather than necrosis. We will test critically this central hypothesis and its corollaries. TxAA commonly occurs despite administration of sufficient Cyclosporine A (CyC) to suppress acute myocardial rejection. We have found that CyA inhibits incompletely the response of T cells to allogeneic BC, and will also test the hypothesis that alternative immunosuppressive regimens that effectively inhibit this response will prevent TxAA. Specifically: 1) We will test the hypotheses that (a) vascular SMC elaborate mediators that promote the T cells activated by BC to adopt a chronic fibrogenic rather than an acutely cytolytic phenotype and (b) that T cell interactions with allogeneic BC. produce factors that promote migration, proliferation of SMC, and their production of extracellular matrix (ECM). 2) We will test the hypothesis that TxAA, like other ineffective immune responses, results from a perturbation of the cytokine network that regulates effective immune responses such as acute rejection. Specifically, (a) we will test in a mouse model of heterotopic allogeneic heart transplantation whether the cytokine network differs between TxAA and acute rejection. We will also (b) determine whether genetic alterations (""""""""knock-out"""""""" or transgenic) in mice will produce different effects on acute rejection vs. TxAA, and test the causal roles of IFN- gamma, TNF-alpha:, IL-1 perforin and antibody in these processes. 3) We will test the hypothesis that immunosuppression with CyA alone will still allow T cells interacting with allogeneic BC to elaborate mediators that promote migration and proliferation of SMC, while other immunosuppressive agents (e.g. rapamycin) alone or combined with CyA will attenuate mediator production in vitro and retard fibroproliferative lesion development in transplanted arteries. Our model for the pathogenesis of TxAA predicts that pharmacologic interruption of the allogeneic response to donor BC should retard the disease. Testing of this hypothesis should yield information applicable to the management of human patients at risk for TxAA.
| Shimizu, Koichi; Libby, Peter; Rocha, Viviane Z et al. (2011) Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection. Circulation 124:2920-32 |
| Shimizu, Koichi; Minami, Manabu; Shubiki, Rica et al. (2009) CC chemokine receptor-1 activates intimal smooth muscle-like cells in graft arterial disease. Circulation 120:1800-13 |
| Mitchell, Richard N (2009) Graft vascular disease: immune response meets the vessel wall. Annu Rev Pathol 4:19-47 |
| Okamoto, Yoshihisa; Christen, Thomas; Shimizu, Koichi et al. (2009) Adiponectin inhibits allograft rejection in murine cardiac transplantation. Transplantation 88:879-83 |
| Shimizu, Koichi; Libby, Peter; Shubiki, Rica et al. (2008) Leukocyte integrin Mac-1 promotes acute cardiac allograft rejection. Circulation 117:1997-2008 |
| Mitchell, Richard N; Libby, Peter (2007) Vascular remodeling in transplant vasculopathy. Circ Res 100:967-78 |
| Sugiyama, Seigo; Kugiyama, Kiyotaka; Nakamura, Shinichi et al. (2006) Characterization of smooth muscle-like cells in circulating human peripheral blood. Atherosclerosis 187:351-62 |
| Shimizu, Koichi; Mitchell, Richard N; Libby, Peter (2006) Inflammation and cellular immune responses in abdominal aortic aneurysms. Arterioscler Thromb Vasc Biol 26:987-94 |
| Taqueti, Viviany R; Mitchell, Richard N; Lichtman, Andrew H (2006) Protecting the pump: controlling myocardial inflammatory responses. Annu Rev Physiol 68:67-95 |
| Shimizu, Koichi; Libby, Peter; Mitchell, Richard N (2005) Local cytokine environments drive aneurysm formation in allografted aortas. Trends Cardiovasc Med 15:142-8 |
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