Rapamycin completely remodeled the immune environment of atherosclerotic plaques in aged mice, suppressing inflammatory cells and nearly eliminating germinal centers in lymph nodes near the heart, while plaque size remained unchanged and cholesterol rose by a quarter
Rapamycin completely remodeled the immune environment of atherosclerotic plaques in aged mice, suppressing inflammatory cells and nearly eliminating germinal centers in lymph nodes near the heart, while plaque size remained unchanged and cholesterol rose by a quarter
On September 23, a team from Leiden University and the Medical University of Vienna published a study in Aging Cell. For eight weeks, rapamycin was given to aged mice with established atherosclerosis, a model that approximates an actual elderly patient rather than the young animals on accelerated atherogenic diets used in most prior experiments.
The mice were maintained on standard chow until 80 to 90 weeks of age, roughly 55 to 65 in human years. Lacking the receptor that clears "bad" cholesterol from the bloodstream, their arteries accumulate mature plaques on their own. Half received rapamycin injections; half received vehicle.
Rapamycin blocks mTOR, an intracellular switch that drives cell growth and division. Most immune cells stop proliferating when mTOR is inhibited, but regulatory T-cells (Treg), which suppress inflammation rather than attack tissue, bypass the block through alternative signaling pathways and consequently expand relative to their suppressed neighbors.
The plaque itself did not change: its size, volume, collagen content, and necrotic core (the most dangerous component, prone to rupture) all remained the same. What changed was the cellular composition. Macrophage numbers fell by 23%. These are the scavenger cells that in aged plaques often become trapped in inflammatory senescence and stop clearing cellular debris, instead engulfing cholesterol and swelling the plaque from within. Neutrophils and cytotoxic CD8 T-cells declined two to threefold. The share of regulatory T-cells among CD4 T-cells rose from 57% to 71%. The authors attribute this shift to Treg activity: Tregs suppress the macrophage signals that recruit fresh monocytes from the blood into the plaque, so a larger Treg population means fewer new macrophages replenishing it.
The same Treg shift appeared in the spleen and, most dramatically, in the lymph nodes adjacent to the heart and aorta. There, total immune cell numbers fell nearly sixfold, and germinal centers (the sites within lymph nodes where B-cells learn to produce high-affinity antibodies) virtually disappeared, dropping from 1.16% to 0.04% of cells. Antibody levels collapsed in parallel: IgM fell by roughly 61%, several IgG subclasses by 37 to 48%. Antibodies against oxidized cholesterol, the very material from which plaques are built, also declined.
This remodeling comes at a cost. Cholesterol rose by a quarter, from 258 to 323 mg/dL, a known side effect of rapamycin already documented in human organ transplant recipients. Normally, rising cholesterol accelerates plaque growth, but here the plaques did not enlarge: the authors propose that rapamycin's anti-inflammatory effect counterbalanced this harm. The weakened immune response carries a similar cost: organ transplant patients on mTOR inhibitors respond more poorly to vaccines and suffer more severe infections. Cellular senescence shifted partially as well: in splenic immune cells, the markers p16 and Btg2 decreased, while p21 and p53 remained unchanged.
This points to a practical next step, one the authors themselves suggest: combining rapamycin with statins in atherosclerosis, capturing the immune benefit without paying the vascular price of elevated cholesterol.
For this laboratory, the result closes a question the group raised in earlier work. They were the first to characterize which age-related immune cells colonize old plaques; now they have tested whether a known drug can shift that picture. The effect had already been hinted at in humans: rapamycin-eluting coronary stents in patients with ischemic heart disease were previously shown to increase circulating Treg numbers. The present study is the first to reveal the mechanism behind this shift in an aged organism.