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The Use of Rat Heterotopic Heart Transplantation Models to Characterize the Immunosuppressive Activities of Leflunomide

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Organtransplantation in Rats and Mice

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Abstract

Leflunomide [Lef: N-(4-trifluoro-methyphenyl)-5-methylisoxazole-4-carbox-amidel] is a pro-drug with immunomodulatory activities that were initially described in experimental models of autoimmune disease, and subsequently in models of allograft and xenograft rejection (reviewed in [1, 2]). Leflunomide is an isoxazole derivative that is rapidly metabolized to the active metabolite, A77 1726 [2 cyano-3-hydroxy-N-(4-trifluoromethylphenyl)butenamide)], in the intestinal mucosa or liver. A77 1726 belongs to a class of compounds, classified as malononitriloamides, that are structurally unrelated to other known immunosuppressive agents. In vitro studies indicate that A77 1726 inhibits the proliferation of T cells and B cells as well as other cell types [1]. In addition, A77 1726 inhibits the expression of cytotoxic activity by T cells and IgG production by B cells in vitro [3,4]. Biochemical studies have described at least two activities of A77 1726 [4–7]: inhibition of the enzymatic activities of selected protein tyrosine kinases and inhibition of dihydroorotate dehydrogenase, the fourth enzyme in the biosynthesis of pyrimidine nucleotides. Recent studies performed by our group indicate that both these activities should be monitored and that both contribute to the immunosuppressive activity of Lef in vivo [3, 4, 8].

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Authors
  1. A. S.-F. Chong
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  2. J-K. Shen
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  3. D-P. Yin
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  4. J. W. Williams
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Editors and Affiliations

  1. Chirurgische Universitätsklinik und Poliklinik Würzburg, Josef-Schneider-Straße 2, 97080, Würzburg, Germany

    Wolfgang Timmermann , Heinz-Jochen Gassel , Karin Ulrichs  & Arnulf Thiede , ,  & 

  2. Department of Surgery, University of Western Ontario, 339 Windermere Road, N6A 5A5, London, Ontario, Canada

    Robert Zhong

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© 1998 Springer-Verlag Berlin Heidelberg

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Chong, A.SF., Shen, JK., Yin, DP., Williams, J.W. (1998). The Use of Rat Heterotopic Heart Transplantation Models to Characterize the Immunosuppressive Activities of Leflunomide. In: Timmermann, W., Gassel, HJ., Ulrichs, K., Zhong, R., Thiede, A. (eds) Organtransplantation in Rats and Mice. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-72140-3_39

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  • DOI: https://doi.org/10.1007/978-3-642-72140-3_39

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