18.02.2013 - European researchers have shown that depletion of immunosuppressant T lymphocytes boosts hypercholersterolemia and atherosclerosis in mice.
The findings lay the foundation for cell-based therapies against the fatal disease. Until now, several studies had supported the assumption that FoxP3-positive CD4+CD25+ T cells block the inflammatory processes that lead to the formation of atherosclerotic plaques in the blood vessels, which can cause cardiac infarction and stroke. But the team under Göran Hansson from Swedish Karolinska Institute was the first to demonstrate the effect in genetically engineered DEREG mice. Those mice express the diphteria toxin (DT) under control of a Treg-specific FoxP3 promotor.
Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr–/–) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3+ Tregs. The depletion caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. The mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. The results prove that FOXP3+ Tregs block atherosclerosis by modulating lipoprotein metabolism.
The findings are good news for drug developers, as Milan-based researchers have recently demonstrated that it is feasible to isolate functional Tregs and expand them in vitro. The patent has already been licenced to German T-cell Europe, which will use the technology for inducing immune tolerance after organ transplantation.
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