Interleukin-2 receptor-specific fusion toxin inhibits barotrauma-induced arterial atherosclerosis

Donald D Miller, Richard G. Bach, Fermin O. Tio, Steven R. Bailey, Cory A. Waters, Thasia G. Woodworth, Jean C. Nichols, Stephen B. Paige, Melody Farrar

Research output: Contribution to journalArticle

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Abstract

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 ~ 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 ± 0.5 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.

Original languageEnglish (US)
Pages (from-to)1-14
Number of pages14
JournalAtherosclerosis
Volume126
Issue number1
DOIs
StatePublished - Sep 27 1996

Fingerprint

Barotrauma
Interleukin-2 Receptors
Interleukin-2
Atherosclerosis
Angioplasty
Mononuclear Leukocytes
Immunotoxins
Vascular Smooth Muscle
Rabbits
Smooth Muscle Myocytes
Placebos
Inhibitory Concentration 50
Blood Vessels
Tunica Intima
Balloon Angioplasty
Muscle Proteins
Concanavalin A
Transaminases
Major Histocompatibility Complex
Leucine

Keywords

  • Angioplasty
  • Atherosclerosis
  • Cytokines
  • Cytotoxic therapy
  • Fusion toxin
  • Interleukin-2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Miller, D. D., Bach, R. G., Tio, F. O., Bailey, S. R., Waters, C. A., Woodworth, T. G., ... Farrar, M. (1996). Interleukin-2 receptor-specific fusion toxin inhibits barotrauma-induced arterial atherosclerosis. Atherosclerosis, 126(1), 1-14. https://doi.org/10.1016/0021-9150(96)05843-1

Interleukin-2 receptor-specific fusion toxin inhibits barotrauma-induced arterial atherosclerosis. / Miller, Donald D; Bach, Richard G.; Tio, Fermin O.; Bailey, Steven R.; Waters, Cory A.; Woodworth, Thasia G.; Nichols, Jean C.; Paige, Stephen B.; Farrar, Melody.

In: Atherosclerosis, Vol. 126, No. 1, 27.09.1996, p. 1-14.

Research output: Contribution to journalArticle

Miller, DD, Bach, RG, Tio, FO, Bailey, SR, Waters, CA, Woodworth, TG, Nichols, JC, Paige, SB & Farrar, M 1996, 'Interleukin-2 receptor-specific fusion toxin inhibits barotrauma-induced arterial atherosclerosis', Atherosclerosis, vol. 126, no. 1, pp. 1-14. https://doi.org/10.1016/0021-9150(96)05843-1
Miller, Donald D ; Bach, Richard G. ; Tio, Fermin O. ; Bailey, Steven R. ; Waters, Cory A. ; Woodworth, Thasia G. ; Nichols, Jean C. ; Paige, Stephen B. ; Farrar, Melody. / Interleukin-2 receptor-specific fusion toxin inhibits barotrauma-induced arterial atherosclerosis. In: Atherosclerosis. 1996 ; Vol. 126, No. 1. pp. 1-14.
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AU - Waters, Cory A.

AU - Woodworth, Thasia G.

AU - Nichols, Jean C.

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N2 - 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 ~ 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 ± 0.5 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.

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