Recent advances in cardiac transplantation have led to wider use of this procedure, but the frequent development of accelerated arteriosclerosis (TxAA) by the coronary arteries of the engrafted heart often limits long term success. Recent studies have disclosed that vascular endothelial (EC) and smooth muscle cells (SMC) can participate actively in immune and inflammatory responses and elaborate growth modulators that might contribute to TxAA. We will explore whether immune phenomena may injure directly or activate potentially deleterious functions of vascular cells within the coronary arteries of allografted hearts by testing the following hypotheses in human cells and tissue in vitro. Hypothesis I: Cell-mediated immune reactions such as delayed hypersensitivity or chronic rejection contribute to the development of TxAA coronary lesions. a) We will use immunohistochemistry to identify cells found in human TxAA lesions. Selective reagents will characterize EC, SMC, mononuclear phagocytes, and lymphocyte subsets in these lesions. b) We will test whether vascular cells or leukocytes within TxAA lesions exhibit markers of immune or inflammatory activation including class II major histocompatibility antigens (HLA), specific leukocyte adhesion molecules, arid genes for various cytokines. These studies will use immunohistochemistry, in situ hybridization and polymerase chain reaction (PCR) technology. c) We will examine lymphocytes isolated from coronary artery lesions, from myocardium, and from peripheral blood for frequency of various lymphocyte populations (judged by surface phenotype), for specific effector functions (judged by biochemical and biological assays), and for T-cell antigen receptor gene usage by PCR. d) We will test for the presence of T cells within the coronary artery lesions of allografted hearts and in the peripheral blood of recipients reactive with class II+ donor vascular cells, measured by mitogenic responses and cytolytic activity. e) We will develop long term T lymphocyte lines and clones of alloreactive lesion-derived T cells for further characterization. Hypothesis II: Humorally-mediated immunologic injury to vascular EC and/or SMC contributes to the development of TxAA following cardiac transplantation. a) We will use immunohistochemical methods to seek evidence for serological reactions in situ as well as for assembly of the complement membrane attack complex. b) We will examine sera and vessels from transplant recipients for the presence of antibodies reactive with EC and SMC. We will assay recipient sera and lesion eluates for Igs that bind to, activate, or (in the presence of complement) lyse vascular cells. We will further characterize any antigens identified by immuno- and biochemical and molecular techniques. Finally, we will correlate results of these immunologic studies with angiographic evidence of vascular dysfunction or injury determined at the time of flood drawing in the same patients.
| 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 |
Showing the most recent 10 out of 75 publications
