Interleukin-2 receptor-specific fusion toxin inhibits barotrauma-induced arterial atherosclerosis.
Immunocytochemical analyses of human plaques and experimental arterial lesions have implicated activated lymphocytes and monocytes in the pathogenesis of atherosclerosis, as demonstrated by the expression of interleukin-2 (IL-2) membrane receptors and major histocompatibility complex class II epitopes. The objective is to determine if targeting these cells with an IL-2 receptor-specific chimeric toxin, DAB486-IL-2, can inhibit experimental post-angioplasty vascular neointimal thickening. Twenty-two atherogenically modeled rabbits were treated in vivo with DAB486-IL-2 (0.1 mg/kg per day i.v.; n = 11) or placebo (n = 11) for 10 days following aortic balloon angioplasty (4 atm x 30 s each x 2 dilatations). In vitro 3H-leucine incorporation studies of mononuclear leukocyte and vascular smooth muscle cell protein synthesis inhibition by DAB486-IL-2 were also performed. Angioplasty sites were examined for evidence of hyperproliferative atherosclerotic narrowing by quantitative angiography and histomorphometry of neointimal cross-sectional area at baseline and 6 weeks after injury. In vitro Concanavalin-A stimulated rabbit mononuclear leukocyte protein synthesis was 50% inhibited by DAB486-IL-2 at a concentration (IC50) of 6 x 10(-11) M. Rabbit vascular smooth muscle cells were approximately 150-fold less sensitive to DAB486-IL-2 (IC50 = 10(-8) M). In vivo studies showed no change in angioplasty site angiographic minimum luminal diameter at 6 weeks in DAB486-IL-2 treated animals (from 2.96 +/- 0.52 to 2.96 +/- 0.48 mm; percent cross-sectional area reduction = 1 +/- 10%; P = N.S.). In control animals, luminal diameter decreased from 2.79 +/- 0.4 to 2.32 +/- 0.52 mm at 6 weeks, and percent cross-sectional area was reduced by 34 +/- 14% (P < 0.01 vs. placebo). Quantitative histomorphometric angioplasty segmental intimal cross-sectional area reduction of treated and placebo vessels also differed significantly (19 +/- 16% vs. 31 +/- 21%; P < 0.05). DAB486-IL-2 caused no adverse effects on animal survival, weight or hepatic transaminase levels. We conclude that post-angioplasty administration of the chimeric toxin DAB486-IL-2 inhibits angiographic narrowing and neointimal thickening in the atherogenic rabbit model. Although this IL-2 receptor-specific molecule was cytotoxic in vitro for activated mononuclear leukocytes and vascular smooth muscle cells, systemic toxicity did not occur in vivo at a dose comparable to that evaluated in clinical trials of this agent. Potential anti-proliferative effects of this chimeric toxin may be mediated by direct local inhibition of leukocyte-mediated inflammation, or through the indirect modification of vascular cell mitogenesis and cytokine release.
Miller
D D
DD
Department of Internal Medicine, St. Louis University Medical Center, MO 63110-0250, USA.
Bach
R G
RG
Tio
F O
FO
Bailey
S R
SR
Waters
C A
CA
Woodworth
T G
TG
Nichols
J C
JC
Paige
S B
SB
Farrar
M
M
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001012:Aorta, Abdominal / Q000293:injuries / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology / Q000517:prevention & control* / Q000628:therapy; D003208:Concanavalin A / Q000494:pharmacology; D003603:Cytotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D004036:Diet, Atherogenic; D004167:Diphtheria Toxin / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D007083:Iliac Artery / Q000293:injuries / Q000473:pathology; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011817:Rabbits; D015375:Receptors, Interleukin-2 / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence
D003603:Cytotoxins; C054780:DAB(486)-interleukin 2; D004167:Diphtheria Toxin; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D003208:Concanavalin A