Cytokine Therapy with IL-2/anti-IL-2mAb Complexes Expands CD4+CD25+Foxp3+ Regulatory T Cells and Attenuates Development and of Developed Atherosclerosis
Background—CD4+CD25+Foxp3+ regulatory T cells (Tregs) attenuate atherosclerosis but their therapeutic application by adoptive transfer is limited by the need for their expansion in vitro and limited purity. Recently, an IL-2/anti-IL-2 neutralizing mAb (IL-2/anti-IL-2 mAb) complex has been shown to expand these Tregs. We examined the capacity of a modified IL-2/anti-IL-2 mAb treatment to expand Tregs and inhibit both the progression and development of developed atherosclerosis.
Methods and Results—Six-week old apolipoprotein-E-deficient mice fed a high fat diet for 8 weeks were administered IL-2/anti-IL-2 mAb commencing 2 weeks after starting the diet. Tregs in the spleen, lymph node and liver were selectively expanded without affecting CD4+, CD8+ or NK cells. Tregs were increased in lesions and lesion size reduced. CD4+ T-cells, macrophages, mature dendritic cells, PCNA+ cells and MCP-1 and VCAM-1 were reduced. In anti-CD3 stimulated splenocytes, proliferation and secretion of Th1, Th2, Th17 (IL-17) cytokines and IL-1β were reduced. To determine whether treatment attenuated progression of developed atherosclerosis, 6-week old apolipoprotein-E-deficient mice were fed a high fat diet for 6 weeks, followed by Il-2/anti-IL-2 mAb treatment for 6 weeks whilst continuing the high fat diet. Treatment also increased Tregs without affecting CD4+, CD8+ or NK cells, suppressed inflammation and greatly attenuated progression of atherosclerosis.
Conclusions—IL-2/anti-IL-2 mAb treatment in vivo attenuates atherosclerosis via selective Tregs expansion. The findings suggest that cytokine-based IL-2/anti-IL-2 mAb complex therapy could represent an attractive approach for treating atherosclerosis, since it markedly attenuates progression as well as development, by modulating its immunoinflammatory component.
- Received February 12, 2012.
- Accepted July 17, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited