Abstract 18745: In vivo Expansion of CD4+CD25+Foxp3+ Regulatory T cells with IL-2/anti-IL-2 mAb Complexes Attenuates Development and Progression of Atherosclerosis
Adoptive transfer of CD4+CD25+Foxp3+ Regulatory T cells (Tregs) suppresses development of atherosclerosis. However, the small numbers of cells that can be isolated for adoptive transfer and issues about cell purity greatly limit this approach for the treatment of atherosclerosis. In the present study we examined whether cytokine induced in vivo expansion of Tregs could also suppress atherosclerosis. Six week old ApoE−/− mice were treated 3 times per week 2 weeks after commencing a high fat diet with an IL-2/anti-IL-2 monoclonal antibody (JES6-1) complex (1mcg IL-2/5mcg mAb). Six weeks later treatment did not affect CD8+ T cells, NK or NKT cells but Tregs were increased 3.3, 4.7 and 2.7-fold in spleen, liver and inguinal lymph nodes and were highly effective in suppressing CD4+ T cell proliferation. These effects were associated with a 4-fold increase in Tregs in aortic sinus atherosclerotic lesions and a 53% reduction in lesion size. Macrophage accumulation was also reduced by 55% whilst CD4+ T cell numbers were reduced by 78% and CD83+ dendritic cells by 68%; MCP-1 and VCAM-1 expression were also reduced, by 66 and 65% respectively (all P <0.05). Proliferation of splenocytes from IL-2/anti-IL-2 mAb treated mice was also attenuated, by 36% as was proinflammatory cytokine secretion: IL-1beta (85%), IL-12 (90%), IL-17 (40%) and IFN-gamma (65%) and secretion of chemokines: MCP-1 (68%), RANTES (60%) and MIP-1alpha (50%). IL-2/anti-IL-2 mAb complex treatment was also highly effective in attenuating progression of developed lesions in hyperlipidemic mice, attenuating progression by 45% (P < 0.05). Treatment did not affect plasma LDL- or HDL-cholesterol. We conclude that cytokine induced in vivo expansion of regulatory T cells using IL-1/anti-IL-2 mAb complexes is highly effective in suppressing development and progression of atherosclerosis.
- © 2010 by American Heart Association, Inc.