Invariant natural killer T cells: linking inflammation and neovascularization in human atherosclerosis.

Atherosclerosis, a chronic inflammatory lipid storage disease of large arteries, is complicated by cardiovascular events usually precipitated by plaque rupture or erosion. Inflammation participates in lesion progression and plaque rupture. Identification of leukocyte populations involved in plaque destabilization is important for effective prevention of cardiovascular events. This study investigates CD1d-expressing cells and invariant NKT cells (iNKT) in human arterial tissue, their correlation with disease severity and symptoms, and potential mechanisms for their involvement in plaque formation and/or destabilization. CD1d-expressing cells were present in advanced plaques in patients who suffered from cardiovascular events in the past and were most abundant in plaques with ectopic neovascularization. Confocal microscopy detected iNKT cells in plaques, and plaque-derived iNKT cell lines promptly produced proinflammatory cytokines when stimulated by CD1d-expressing APC-presenting α-galactosylceramide lipid antigen. Furthermore, iNKT cells were diminished in the circulating blood of patients with symptomatic atherosclerosis. Activated iNKT cell-derived culture supernatants showed angiogenic activity in a human microvascular endothelial cell line HMEC-1-spheroid model of in vitro angiogenesis and strongly activated human microvascular endothelial cell line HMEC-1 migration. This functional activity was ascribed to IL-8 released by iNKT cells upon lipid recognition. These findings introduce iNKT cells as novel cellular candidates promoting plaque neovascularization and destabilization in human atherosclerosis.

Requirements for CD8 T-cell migration into the human arterial wall.

Atherosclerotic lesions develop in the arterial intima. Among the leukocytes that accumulate in advanced atherosclerotic plaques, CD8 T cells play a quantitatively important role. They may be involved in disease progression and plaque destabilization, leading to plaque rupture or erosion. These events finally precipitate cardiovascular events. Therefore, we wished to determine the accessibility of the human arterial wall, particularly the arterial intima, for CD8-positive, cytotoxic T lymphocytes. We quantified the number of CD8-positive T cells in the arterial wall using human arterial tissue microarrays. The conditions for efficient cytotoxic T-lymphocyte migration into the arterial wall were determined in an in vitro tissue invasion assay. The invasion pattern of resting or activated cytotoxic T-lymphocyte clones was morphometrically analyzed by confocal microscopy. CD8 T cells represented up to 50% of the lymphocytes in advanced atherosclerotic lesions. Resting CD8-positive cytotoxic T lymphocytes were able to migrate into the arterial intima when it was affected by advanced lesions but not at the earliest stages of the disease. After T-cell receptor and/or proinflammatory cytokine activation, cytotoxic T lymphocytes migrated efficiently into the arterial intima, even in the healthy or mildly affected sites. This in vitro tissue invasion assay mimics conditions under which effector cytotoxic T lymphocytes migrate into the arterial wall to reach similar cell densities as observed in arterial tissue sections from autopsies. Interference with T-cell activation may be important to inhibit cytotoxic T-lymphocyte invasion into the unaffected, healthy artery but may not prevent cytotoxic T-lymphocyte invasion into arteries that are severely affected by atherosclerotic lesions.

Major vascular resection and prosthetic replacement for retroperitoneal tumors.

INTRODUCTION: Involvement of major vascular structures has been considered a limiting factor for resecting advanced tumors. The objective of this study was to evaluate the outcome after concomitant retroperitoneal tumor and vascular resection with prosthetic replacement of the aorta/vena cava. METHODS: The authors reviewed a 5-year series of eight patients with a median age of 50 years (range 11-68 years) who had undergone resection of a retroperitoneal tumor and concomitant resection and replacement of the abdominal aorta, inferior vena cava, or both. The histologic diagnoses were sarcoma (five patients), teratoma (one), transitional cell carcinoma (one), and ganglioneuroma (one). The main outcome measures were early (<30 days) and late (>or=30 days) surgical morbidity and mortality. Secondary endpoints were vascular graft patency and tumor-free survival. Two patients underwent combined graft replacement of the aorta and vena cava. Single aortic and vena cava graft replacement were each done in three patients. RESULTS: Two patients showed early surgical morbidity necessitating reoperation for a thrombotic graft occlusion. No patient died during the early course of the follow-up. During a median follow-up of 14 months (range 1-56 months), two patients had late surgical morbidity. The median tumor-free survival for patients with malignancy was 14 months (range 1-54 months). One patient developed locoregional tumor recurrence, and two developed distant metastases. The median survival for patients with malignancy was 14 months (range 1-60 months). CONCLUSIONS: An aggressive surgical approach for otherwise unresectable retroperitoneal tumors with vascular resection and prosthetic vascular replacement is justified in selected cases and has acceptable morbidity and mortality.