Modulation of in vivo alloreactivity by inhibition of inducible nitric oxide synthase

Neil K. Worrall, W. Douglas Lazenby, Thomas P. Misko, Tien Sung Lin, Charles P. Rodi, Pamela T. Manning, Ronald Tilton, Joseph R. Williamson, T. Bruce Ferguson

Research output: Contribution to journalArticle

191 Citations (Scopus)

Abstract

The role of nitric oxide in the immune response to allogeneic tissue was explored in an in vivo cardiac transplant model in the rat. Nitric oxide production during organ rejection was demonstrated by elevations in systemic serum nitrite/nitrate levels and by electron paramagnetic resonance spectroscopy. Messenger RNA for the inducible nitric oxide synthase enzyme was detected in the rejecting allografted heart, but not in the nonrejecting isografted heart. The enzyme was demonstrated to be biologically active by the in vitro conversion of L-arginine to L-citrulline and was immunohistochemically localized to the infiltrating inflammatory cells. Treatment with aminoguanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, prevented the increased nitric oxide production in the transplanted organ and significantly attenuated the pathogenesis of acute rejection. Aminoguanidine treatment prolonged graft survival, improved graft contractile function, and significantly reduced the histologic grade of rejection. These results suggest an important role for nitric oxide in mediating the immune response to allogeneic tissue. Inhibition of inducible nitric oxide synthase may provide a novel therapeutic modality in the management of acute transplant rejection and of other immune- mediated processes.

Original languageEnglish
Pages (from-to)63-70
Number of pages8
JournalJournal of Experimental Medicine
Volume181
Issue number1
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Nitric Oxide Synthase Type II
Nitric Oxide
Transplants
Citrulline
Electron Spin Resonance Spectroscopy
Graft Rejection
Graft Survival
Enzymes
Nitrites
Nitrates
Arginine
Spectrum Analysis
Protein Isoforms
Messenger RNA
Serum
pimagedine
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Worrall, N. K., Lazenby, W. D., Misko, T. P., Lin, T. S., Rodi, C. P., Manning, P. T., ... Ferguson, T. B. (1995). Modulation of in vivo alloreactivity by inhibition of inducible nitric oxide synthase. Journal of Experimental Medicine, 181(1), 63-70. https://doi.org/10.1084/jem.181.1.63

Modulation of in vivo alloreactivity by inhibition of inducible nitric oxide synthase. / Worrall, Neil K.; Lazenby, W. Douglas; Misko, Thomas P.; Lin, Tien Sung; Rodi, Charles P.; Manning, Pamela T.; Tilton, Ronald; Williamson, Joseph R.; Ferguson, T. Bruce.

In: Journal of Experimental Medicine, Vol. 181, No. 1, 01.01.1995, p. 63-70.

Research output: Contribution to journalArticle

Worrall, NK, Lazenby, WD, Misko, TP, Lin, TS, Rodi, CP, Manning, PT, Tilton, R, Williamson, JR & Ferguson, TB 1995, 'Modulation of in vivo alloreactivity by inhibition of inducible nitric oxide synthase', Journal of Experimental Medicine, vol. 181, no. 1, pp. 63-70. https://doi.org/10.1084/jem.181.1.63
Worrall, Neil K. ; Lazenby, W. Douglas ; Misko, Thomas P. ; Lin, Tien Sung ; Rodi, Charles P. ; Manning, Pamela T. ; Tilton, Ronald ; Williamson, Joseph R. ; Ferguson, T. Bruce. / Modulation of in vivo alloreactivity by inhibition of inducible nitric oxide synthase. In: Journal of Experimental Medicine. 1995 ; Vol. 181, No. 1. pp. 63-70.
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