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

D. Douglas 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

7 Citations (Scopus)

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
Externally publishedYes

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, D. Douglas; 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, D. Douglas ; 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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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.",
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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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KW - Atherosclerosis

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