Effect of six virustatic nucleoside analogues on the development of fetal rat thymus in organ culture
- 44 Downloads
The effects of the virustatic agents zidovudine (azidothymidine, AZT) 2′3′-dideoxycytidine (ddC), 2′3′-dideoxyinosine (ddI), acyclovir (ACV), ganciclovir (GCV), and vidarabine phosphate (VP) on the in vitro development of thymic lobes of 17-day-old rat fetuses were tested in an organ culture system. The virustatics were added to the medium for a culture period of 7 days. All nucleoside analogues inhibited the proliferation and differentiation of lymphatic cells. However, differences were observable with respect to the potency of the six drugs to interfere with thymic development. Compared to untreated controls, reduction in the number of thymocytes was significant at concentrations of 30 μM AZT and ddI. In the case of ACV, GCV, VP, and ddC concentrations as low as 10 μM were sufficient to cause a significant reduction, ddC being the most potent derivate. Increasing concentrations of the nucleoside analogues led to a dose-dependent further inhibition of cell proliferation. At a concentration of 30 μM flow cytometry revealed a decrease in the relative number of double positive CD4+ CD8+ and single positive CD4+ CD8− cells but an increase in the relative number of CD4-CD8+ cells. At the same concentration the expression of the CD5 antigen was reduced by the antimetabolites, indicating that maturation of the thymocytes was inhibited. Distribution of the forward light scatter, a cell size-related parameter, showed that the formation of small thymocytes was reduced by the nucleoside analogues. Light and electron microscopic investigations indicated cytotoxic effects of the drugs on the thymocytes, whereas the epithelium was only slightly affected.
Key wordsImmunotoxicity Thymus Organ culture Nucleoside analogues Acyclovir 2′3′-dideoxycytidine 2′3′-dideoxyinosine Ganciclovir Vidarabine phosphate Zidovudine
Unable to display preview. Download preview PDF.
- Descotes J (1988) Antiviral agents. In: Immunotoxicology of drugs and chemicals, 2nd edn. Elsevier, Amsterdam, p 107Google Scholar
- Fischl MA, Richman DD, Greco MH, Gottlieb MS, Volberding PA, Laskin OL, Leedom JM, Groopman JE, Mildvan D, Schooley RT, Jackson GG, Durack DT, King D, AZT Collaborative Working Group (1987) The efficacy of azodothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controled trial. N Engl J Med 317: 185–191PubMedGoogle Scholar
- Groopman JE (1990) Zidovudine intolerance. Rev Infect Dis 12: 500–506Google Scholar
- Hugo P, Waanders GA, Scollay R, Petrie HT, Boyd RL (1991) Characterization of immature CD4+CD8−CD3− thymocytes. Eur J Immunol 211: 835–838Google Scholar
- Jenkinson EJ, Franchi LL, Kingston R, Owen JJT (1983) Effect of deoxyguanosine on lymphopoiesis in the developing thymus rudiment in vitro: application in the production of chimeric thymus rudiments. Eur J Immunol 12: 583–587Google Scholar
- Kampinga J, Aspinall R (1989) Thymocyte differentiation and thymic microenvironment development in the fetal rat thymus: an immunohistological approach. In: Kendall MD, Ritter MA, (eds) Thymus update. Harward, London, vol 2, pp 149–186Google Scholar
- Matthews T, Boehme R (1988) Antiviral activity and mechanism of action of ganciclovir. Rev Infect Dis 10: 490–494Google Scholar
- Polsky B (1989) Antiviral chemotherapy for infection with human immunodeficiency virus. Rev Infect Dis 11: 1648–1663Google Scholar
- Quinn GP, Wolberg G, Medzihtradsky J, Elion GB (1982) Effect of aciclovir on various murine in vivo and in vitro immunologic assay systems. Am J Med [Suppl] 77: 62–66Google Scholar
- Royer HD, Reinherz EL (1987) The human T cell receptor for antigen: structure, ontogeny and gene expression. Behring Inst Mitteilung 81: 1–14Google Scholar
- Stahlmann R, Chahoud I, Korte M, van Loveren H, Voss JG, Foerster M, Merker H-J, Neubert D (1991) Structural anomalies of thymus and other organs and impaired resistance toTrichinella spiralis infection in rats after prenatal exposure to aciclovir. In: Kendall MD, Ritter MA (eds) Thymus update. Harwood, London, vol 4, pp 129–155Google Scholar