title: Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis.
abstract: 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 interleukin (IL)-2/anti-IL-2 neutralizing monoclonal antibody (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.
  
  
  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 natural killer cells. Tregs were increased in lesions and lesion size reduced. CD4+ T-cells, macrophages, mature dendritic cells, proliferating cell nuclear antigen+ cells, and monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were reduced. In anti-CD3-stimulated splenocytes, proliferation and secretion of Th1, Th2, and 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 while continuing the high-fat diet. Treatment also increased Tregs without affecting CD4+, CD8+, or natural killer 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, because it markedly attenuates progression as well as development, by modulating its immunoinflammatory component.
authors.affiliation: Vascular Biology and Atherosclerosis Laboratory, BakerIDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Tam Nguyen
authors.initials: TN
authors.lastname: Dinh
authors.forename: Tin Soe
authors.initials: TS
authors.lastname: Kyaw
authors.forename: Peter
authors.initials: P
authors.lastname: Kanellakis
authors.forename: Kelly
authors.initials: K
authors.lastname: To
authors.forename: Peter
authors.initials: P
authors.lastname: Tipping
authors.forename: Ban-Hock
authors.initials: BH
authors.lastname: Toh
authors.forename: Alexander
authors.initials: A
authors.lastname: Bobik
authors.forename: Alex
authors.initials: A
authors.lastname: Agrotis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000276:immunology / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D004306:Dose-Response Relationship, Immunologic; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D001057:Apolipoproteins E; D015415:Biomarkers; D015704:CD4 Antigens; D004041:Dietary Fats; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit