Cardiac Allograft Vasculopathy

Abstract

We have previously reported that cell-mediated immunity to vascular endothelium is associated with the development of cardiac allograft vasculopathy (CAV). The mechanism by which a cell-mediated immune response to the coronary vascular is translated into the development of CAV is, however unknown. Peripheral blood mononuclear cells (PBMCs) obtained serially following cardiac transplantation were cocultured with donor-specific human aortic endothelial cells (HAECs) in 47 allograft recipients, 9 of whom had CAV (CAV+) at 1 year by angiography. At 20 hr following coculture, HAEC poly (A+) RNA was isolated, reverse-transcribed, and the cDNA-amplified (PCR) for a panel of growth factors (GFs) known to alter smooth muscle cell proliferation or migration. Relative quantitation of PCR product was performed using high-pressure liquid chromatography (HPLC). Three patterns of GF regulation were observed depending on the GF, the time posttransplant, and whether the patient had CAV: (1) no regulation (TGF-beta, PDGF-A early post-tx); (2) upregulation irrespective of CAV (bFGF, PDGF-B, TGF-alpha early post-tx); and (3) preferential or exclusive upregulation by CAV+ patients (PDGF-A and TGF-alpha late post-tx, HB-EGF early and late post-tx). For example, using PBMCs as stimulators, obtained 6 months posttransplant from CAV+ patients, increases in HAEC-derived PDGF-A chain (31 +/- 7 to 69 +/- 11), TGF-alpha (97 +/- 27 to 201 +/- 23), and HB-EGF (78 +/- 16 to 173 +/- 27) mRNA were demonstrated (all P<0.05 or greater using HPLC peak area as units). These data demonstrate that cell-mediated activation of vascular endothelial cells in patients with CAV results in preferential upregulation of certain endothelial-derived mesenchymal growth factors capable of stimulating smooth muscle cell proliferation and migration.

The link between major histocompatibility complex antibodies and cell proliferation

“…Expression of proliferating cell nuclear antigen (PCNA) is elevated in grafts with TV (10, 11). Further, increased expression of mitogenic factors, such as PDGF, TGFalpha (12), and TGFbeta (13), is observed. Chronically rejected allografts also have an increase in vascular endothelial growth factor (VEGF), an essential soluble factor which regulates angiogenesis and inflammation and is highly proliferative for vascular cells (14).…”

Cardiac retransplantation

“…Presently, it is known as the major limitation of truly long-term survival. It can develop as early as 3 months after CTx [24], and has become the leading cause of death after the first posttransplant year [20,144,237]. The incidence is angiographically detectable in 30% -50% of recipients by 5 years after CTx [238].…”

“…The limited involvement of the allograft vasculature with sparing of the recipient's native vessels suggests processes that specifically target the allograft and produce endothelial injury and/or derangement in regulation of the smooth muscle cell growth. Immuno-histochemical studies of allograft vasculopathy demonstrated endothelial expression of the MHC I and II antigens as well as adhesion molecules, such as: vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and ELAM (E-selectin) which make the vascular endothelium susceptible to be attacked by the immune system via a cellular or humoral mechanism [3,7,27,144,207].…”

HLA Class I: An unexpected role in integrin β4 signaling in endothelial cells

“…Histologically, the vessels of the graft show perivascular fibrosis, smooth muscle cell proliferation accompanied by subendothelial lymphocytes and macrophages [14, 15]. Proliferation is a central feature of transplant vasculopathy lesions and grafts show increased expression of mitogenic factors, such as PDGF, TGFα and TGFβ, and vascular endothelial growth factor, an essential soluble factor which regulates angiogenesis [16-18]. …”