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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Aug;90(2):679–683. doi: 10.1172/JCI115911

Nitric oxide production in host-versus-graft and graft-versus-host reactions in the rat.

J M Langrehr 1, N Murase 1, P M Markus 1, X Cai 1, P Neuhaus 1, W Schraut 1, R L Simmons 1, R A Hoffman 1
PMCID: PMC443151  PMID: 1379617

Abstract

The present study was designed to determine whether .N = O produced in vivo during the rejection of histoincompatible tissues might permit serum NO2-/NO3- levels to serve as markers of a rejection reaction. Rat syngeneic and allogeneic liver, heart, bone marrow/spleen cell, small bowel, skin, and sponge matrix grafts were performed and the stable end-products of .N = O, NO2-/NO3-, were serially assayed in the serum of the grafted animals. A significant rise of serum NO2-/NO3- levels in the allografted animals preceded the onset of clinical signs of rejection or graft-versus-host disease, with the exception of the skin and sponge matrix graft models, where elevated serum NO2-/NO3- levels were never observed. In all transplant models, normal serum NO2-/NO3- levels were observed at all times in animals that received syngeneic grafts. Furthermore, treatment of allograft recipients with the immunosuppressive agents FK 506 or cyclosporine A inhibited .N = O production. Determination of serum creatinine levels demonstrated that the elevated serum NO2-/NO3- levels were not caused by kidney dysfunction. Serum NO2-/NO3- levels might be useful early serum markers of the initiation of a rejection reaction or graft-versus-host disease when functional markers of graft dysfunction are not apparent.

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Selected References

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  1. Albina J. E., Abate J. A., Henry W. L., Jr Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway. J Immunol. 1991 Jul 1;147(1):144–148. [PubMed] [Google Scholar]
  2. Araujo J. L., Kupiec-Weglinski J. W., Araneda D., Towpik E., Heidecke C. D., Williams J. M., Tilney N. L. Phenotype, activation status, and suppressor activity of host lymphocytes during acute rejection and after cyclosporine-induced unresponsiveness of rat cardiac allografts. Transplantation. 1985 Sep;40(3):278–284. doi: 10.1097/00007890-198509000-00012. [DOI] [PubMed] [Google Scholar]
  3. Drapier J. C., Pellat C., Henry Y. Generation of EPR-detectable nitrosyl-iron complexes in tumor target cells cocultured with activated macrophages. J Biol Chem. 1991 Jun 5;266(16):10162–10167. [PubMed] [Google Scholar]
  4. Efron D. T., Kirk S. J., Regan M. C., Wasserkrug H. L., Barbul A. Nitric oxide generation from L-arginine is required for optimal human peripheral blood lymphocyte DNA synthesis. Surgery. 1991 Aug;110(2):327–334. [PubMed] [Google Scholar]
  5. Gill T. J., 3rd, Kunz H. W., Misra D. N., Hassett A. L. The major histocompatibility complex of the rat. Transplantation. 1987 Jun;43(6):773–785. [PubMed] [Google Scholar]
  6. Green L. C., Wagner D. A., Glogowski J., Skipper P. L., Wishnok J. S., Tannenbaum S. R. Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. 1982 Oct;126(1):131–138. doi: 10.1016/0003-2697(82)90118-x. [DOI] [PubMed] [Google Scholar]
  7. Hoffman R. A., Langrehr J. M., Billiar T. R., Curran R. D., Simmons R. L. Alloantigen-induced activation of rat splenocytes is regulated by the oxidative metabolism of L-arginine. J Immunol. 1990 Oct 1;145(7):2220–2226. [PubMed] [Google Scholar]
  8. Ignarro L. J. Biosynthesis and metabolism of endothelium-derived nitric oxide. Annu Rev Pharmacol Toxicol. 1990;30:535–560. doi: 10.1146/annurev.pa.30.040190.002535. [DOI] [PubMed] [Google Scholar]
  9. Ildstad S. T., Wren S. M., Sharrow S. O., Stephany D., Sachs D. H. In vivo and in vitro characterization of specific hyporeactivity to skin xenografts in mixed xenogeneically reconstituted mice (B10 + F344 rat----B10). J Exp Med. 1984 Dec 1;160(6):1820–1835. doi: 10.1084/jem.160.6.1820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lancaster J. R., Jr, Hibbs J. B., Jr EPR demonstration of iron-nitrosyl complex formation by cytotoxic activated macrophages. Proc Natl Acad Sci U S A. 1990 Feb;87(3):1223–1227. doi: 10.1073/pnas.87.3.1223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lancaster J. R., Jr, Langrehr J. M., Bergonia H. A., Murase N., Simmons R. L., Hoffman R. A. EPR detection of heme and nonheme iron-containing protein nitrosylation by nitric oxide during rejection of rat heart allograft. J Biol Chem. 1992 Jun 5;267(16):10994–10998. [PubMed] [Google Scholar]
  12. Langrehr J. M., Dull K. E., Ochoa J. B., Billiar T. R., Ildstad S. T., Schraut W. H., Simmons R. L., Hoffman R. A. Evidence that nitric oxide production by in vivo allosensitized cells inhibits the development of allospecific CTL. Transplantation. 1992 Mar;53(3):632–640. doi: 10.1097/00007890-199203000-00027. [DOI] [PubMed] [Google Scholar]
  13. Langrehr J. M., Hoffman R. A., Billiar T. R., Lee K. K., Schraut W. H., Simmons R. L. Nitric oxide synthesis in the in vivo allograft response: a possible regulatory mechanism. Surgery. 1991 Aug;110(2):335–342. [PubMed] [Google Scholar]
  14. Langrehr J. M., Lee K. K., Wachs M. E., Lee T. K., Stangl M. J., Venkataramanan R., Kunz H. W., Schraut W. H. Comparison of the effectiveness of cyclosporine A in small-bowel transplantation using different rat strain combinations. Transplant Proc. 1990 Dec;22(6):2533–2535. [PubMed] [Google Scholar]
  15. Markus P. M., Cai X., Ming W., Demetris A. J., Fung J. J., Starzl T. E. FK 506 reverses acute graft-versus-host disease after allogeneic bone marrow transplantation in rats. Surgery. 1991 Aug;110(2):357–364. [PMC free article] [PubMed] [Google Scholar]
  16. Mills C. D. Molecular basis of "suppressor" macrophages. Arginine metabolism via the nitric oxide synthetase pathway. J Immunol. 1991 Apr 15;146(8):2719–2723. [PubMed] [Google Scholar]
  17. Murase N., Kim D. G., Todo S., Cramer D. V., Fung J. J., Starzl T. E. Suppression of allograft rejection with FK506. I. Prolonged cardiac and liver survival in rats following short-course therapy. Transplantation. 1990 Aug;50(2):186–189. doi: 10.1097/00007890-199008000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nathan C. F., Hibbs J. B., Jr Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol. 1991 Feb;3(1):65–70. doi: 10.1016/0952-7915(91)90079-g. [DOI] [PubMed] [Google Scholar]
  19. Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Wachter H., Fuchs D., Hausen A., Reibnegger G., Werner E. R. Neopterin as marker for activation of cellular immunity: immunologic basis and clinical application. Adv Clin Chem. 1989;27:81–141. doi: 10.1016/s0065-2423(08)60182-1. [DOI] [PubMed] [Google Scholar]
  21. Wagner D. A., Schultz D. S., Deen W. M., Young V. R., Tannenbaum S. R. Metabolic fate of an oral dose of 15N-labeled nitrate in humans: effect of diet supplementation with ascorbic acid. Cancer Res. 1983 Apr;43(4):1921–1925. [PubMed] [Google Scholar]
  22. Wagner D. A., Young V. R., Tannenbaum S. R. Mammalian nitrate biosynthesis: incorporation of 15NH3 into nitrate is enhanced by endotoxin treatment. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4518–4521. doi: 10.1073/pnas.80.14.4518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Werner-Felmayer G., Werner E. R., Fuchs D., Hausen A., Reibnegger G., Wachter H. Tetrahydrobiopterin-dependent formation of nitrite and nitrate in murine fibroblasts. J Exp Med. 1990 Dec 1;172(6):1599–1607. doi: 10.1084/jem.172.6.1599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Zimmermann F. A., Davies H. S., Knoll P. P., Gokel J. M., Schmidt T. Orthotopic liver allografts in the rat. The influence of strain combination on the fate of the graft. Transplantation. 1984 Apr;37(4):406–410. doi: 10.1097/00007890-198404000-00019. [DOI] [PubMed] [Google Scholar]

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