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. 1988 Mar;63(3):423–429.

Lethal vaccinia infection in cyclophosphamide-suppressed mice is associated with decreased expression of Thy-1, Lyt-2 and L3T4 and diminished IL-2 production in surviving T cells.

Z Tabi 1, J E Allan 1, R Ceredig 1, P C Doherty 1
PMCID: PMC1454773  PMID: 2895062

Abstract

Prior treatment of C57BL/6J mice with 300 mg/kg of cyclophosphamide (Cy) converts a subclinical infection with vaccinia virus to a lethal disease. This is accompanied by a loss of more than 80% of spleen cells and a decreased capacity, on a cell-for-cell basis, to develop virus-immune cytotoxic T lymphocytes (CTL), although the frequency of CTL precursors among surviving T cells is not greatly modified. Phenotypically, the surviving T cells express low levels of cell-surface Thy-1, Lyt-2 and L3T4 and, upon stimulation, are less able to produce IL-2 for more than 1 week following Cy treatment. The defect in capacity to generate CTL effectors both in vitro and in vivo can be corrected by providing an exogenous source of IL-2. These experiments indicate that a single dose of Cy induces changes in T cells that persist throughout the development of an immune response. Such effects are in accordance with the known property of Cy to mediate DNA damage.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allan J. E., Doherty P. C. Consequences of cyclophosphamide treatment in murine lymphocytic choriomeningitis: evidence for cytotoxic T cell replication in vivo. Scand J Immunol. 1985 Oct;22(4):367–374. doi: 10.1111/j.1365-3083.1985.tb01894.x. [DOI] [PubMed] [Google Scholar]
  2. Allan J. E., Doherty P. C. Natural killer cells contribute to inflammation but do not appear to be essential for the induction of clinical lymphocytic choriomeningitis. Scand J Immunol. 1986 Aug;24(2):153–162. doi: 10.1111/j.1365-3083.1986.tb02081.x. [DOI] [PubMed] [Google Scholar]
  3. Ballas Z. K. Lymphokine-activated killer (LAK) cells. I. Differential recovery of LAK, natural killer cells, and cytotoxic T lymphocytes after a sublethal dose of cyclophosphamide. J Immunol. 1986 Oct 1;137(7):2380–2384. [PubMed] [Google Scholar]
  4. Blanden R. V., Bowern N. A., Pang T. E., Gardner I. D., Parish C. R. Effects of thymus-independent (B) cells and the H-2 gene complex on antiviral function of immune thymus-derived (T) cells. Aust J Exp Biol Med Sci. 1975 Jun;53(3):187–195. doi: 10.1038/icb.1975.19. [DOI] [PubMed] [Google Scholar]
  5. Ceredig R., Allan J. E., Tabi Z., Lynch F., Doherty P. C. Phenotypic analysis of the inflammatory exudate in murine lymphocytic choriomeningitis. J Exp Med. 1987 Jun 1;165(6):1539–1551. doi: 10.1084/jem.165.6.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ceredig R. Proliferation in vitro and interleukin production by 14 day fetal and adult Lyt-2-/L3T4- mouse thymocytes. J Immunol. 1986 Oct 1;137(7):2260–2267. [PubMed] [Google Scholar]
  7. Cerottini J. C., Engers H. D., Macdonald H. R., Brunner T. Generation of cytotoxic T lymphocytes in vitro. I. Response of normal and immune mouse spleen cells in mixed leukocyte cultures. J Exp Med. 1974 Sep 1;140(3):703–717. doi: 10.1084/jem.140.3.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Denizot F., Wilson A., Battye F., Berke G., Shortman K. Clonal expansion of T cells: a cytotoxic T-cell response in vivo that involves precursor cell proliferation. Proc Natl Acad Sci U S A. 1986 Aug;83(16):6089–6092. doi: 10.1073/pnas.83.16.6089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Doherty P. C., Allan J. E. Participation of cyclophosphamide-resistant T cells in murine lymphocytic choriomeningitis. Scand J Immunol. 1985 Feb;21(2):127–132. doi: 10.1111/j.1365-3083.1985.tb01411.x. [DOI] [PubMed] [Google Scholar]
  10. Erard F., Nabholz M., Dupuy-D'Angeac A., MacDonald H. R. Differential requirements for the induction of interleukin 2 responsiveness in L3T4+ and Lyt-2+ T cell subsets. J Exp Med. 1985 Nov 1;162(5):1738–1743. doi: 10.1084/jem.162.5.1738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Farrar J. J., Fuller-Farrar J., Simon P. L., Hilfiker M. L., Stadler B. M., Farrar W. L. Thymoma production of T cell growth factor (Interleukin 2). J Immunol. 1980 Dec;125(6):2555–2558. [PubMed] [Google Scholar]
  12. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  13. Heitzmann H., Richards F. M. Use of the avidin-biotin complex for specific staining of biological membranes in electron microscopy. Proc Natl Acad Sci U S A. 1974 Sep;71(9):3537–3541. doi: 10.1073/pnas.71.9.3537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hemminki K. Binding of metabolites of cyclophosphamide to DNA in a rat liver microsomal system and in vivo in mice. Cancer Res. 1985 Sep;45(9):4237–4243. [PubMed] [Google Scholar]
  15. Hurme M., Sihvola M., Bång B. During lymphatic regeneration, precursors for major histocompatibility complex-restricted cytotoxic T cells appear before alloreactive precursors. J Exp Med. 1982 Jan 1;155(1):327–332. doi: 10.1084/jem.155.1.327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Julius M. H., Simpson E., Herzenberg L. A. A rapid method for the isolation of functional thymus-derived murine lymphocytes. Eur J Immunol. 1973 Oct;3(10):645–649. doi: 10.1002/eji.1830031011. [DOI] [PubMed] [Google Scholar]
  17. Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
  18. Merluzzi V. J., Welte K., Mertelsmann R. H., Souza L., Boone T., Last-Barney K. Rescue of anti-influenza A virus cytotoxic T-lymphocyte responses in chemotherapy-suppressed mice. J Virol. 1984 Jul;51(1):20–25. doi: 10.1128/jvi.51.1.20-25.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Merluzzi V. J., Welte K., Savage D. M., Last-Barney K., Mertelsmann R. Expansion of cyclophosphamide-resistant cytotoxic precursors in vitro and in vivo by purified human interleukin 2. J Immunol. 1983 Aug;131(2):806–809. [PubMed] [Google Scholar]
  20. Miller R. A., Reiss C. S. Limiting dilution cultures reveal latent influenza virus-specific helper T cells in virus-primed mice. J Mol Cell Immunol. 1984;1(6):357–368. [PubMed] [Google Scholar]
  21. Mills G. B., Cheung R. K., Grinstein S., Gelfand E. W. Increase in cytosolic free calcium concentration is an intracellular messenger for the production of interleukin 2 but not for expression of the interleukin 2 receptor. J Immunol. 1985 Mar;134(3):1640–1643. [PubMed] [Google Scholar]
  22. Orosz C. G., Scott J. W., Gillis S., Finke J. H. Reversal of phorbol ester-mediated reduction of cloned T lymphocyte cytolysis by interleukin 2. J Immunol. 1985 Jan;134(1):324–329. [PubMed] [Google Scholar]
  23. Pevnitsky L. A., Telegin LYu, Zhirnov G. F., Mazurov A. V., Viktorov V. V. Sensitivity to immunodepressant action of cyclophosphamide: analysis of interstrain differences in mice. Int J Immunopharmacol. 1985;7(6):875–880. doi: 10.1016/0192-0561(85)90050-5. [DOI] [PubMed] [Google Scholar]
  24. Pierres A., Naquet P., Van Agthoven A., Bekkhoucha F., Denizot F., Mishal Z., Schmitt-Verhulst A. M., Pierres M. A rat anti-mouse T4 monoclonal antibody (H129.19) inhibits the proliferation of Ia-reactive T cell clones and delineates two phenotypically distinct (T4+, Lyt-2,3-, and T4-, Lyt-2,3+) subsets among anti-Ia cytolytic T cell clones. J Immunol. 1984 Jun;132(6):2775–2782. [PubMed] [Google Scholar]
  25. Ryser J. E., MacDonald H. R. Limiting dilution analysis of alloantigen-reactive T lymphocytes. I. Comparison of precursor frequencies for proliferative and cytolytic responses. J Immunol. 1979 May;122(5):1691–1696. [PubMed] [Google Scholar]
  26. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  27. Schlick E., Ruffmann R., Chirigos M. A., Welker R. D., Herberman R. B. In vivo modulation of myelopoiesis and immune functions by maleic anhydride divinyl ether copolymer (MVE-2) in tumor-free and MBL-2 tumor-bearing mice treated with cyclophosphamide. Cancer Res. 1985 Mar;45(3):1108–1114. [PubMed] [Google Scholar]
  28. Shand F. L., Howard J. G. Induction in vitro of reversible immunosuppression and inhibition of B cell receptor regeneration by defined metabolites of cyclophosphamide. Eur J Immunol. 1979 Jan;9(1):17–21. doi: 10.1002/eji.1830090105. [DOI] [PubMed] [Google Scholar]
  29. Smith K. A., Cantrell D. A. Interleukin 2 regulates its own receptors. Proc Natl Acad Sci U S A. 1985 Feb;82(3):864–868. doi: 10.1073/pnas.82.3.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Takeshita T., Conner M. K. Accumulation and persistence of cyclophosphamide-induced sister chromatid exchange in murine peripheral blood lymphocytes. Cancer Res. 1984 Sep;44(9):3820–3824. [PubMed] [Google Scholar]
  31. Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed] [Google Scholar]
  32. Taswell C., MacDonald H. R., Cerottini J. C. Limiting dilution analysis of alloantigen-reactive T lymphocytes. II. Effect of cortisone and cyclophosphamide on cytolytic T lymphocyte precursor frequencies in the thymus. Thymus. 1979 Sep;1(1-2):119–131. [PubMed] [Google Scholar]
  33. Turk J. L., Parker D. Effect of cyclophosphamide on immunological control mechanisms. Immunol Rev. 1982;65:99–113. doi: 10.1111/j.1600-065x.1982.tb00429.x. [DOI] [PubMed] [Google Scholar]
  34. Varkila K., Hurme M. The effect of cyclophosphamide on cytotoxic T-lymphocyte responses: inhibition of helper T-cell induction in vitro. Immunology. 1983 Mar;48(3):433–438. [PMC free article] [PubMed] [Google Scholar]
  35. Walker C. M., Paetkau V., Rawls W. E., Rosenthal K. L. Abrogation of anti-Pichinde virus cytotoxic T cell memory by cyclophosphamide and restoration by coinfection or interleukin 2. J Immunol. 1985 Aug;135(2):1401–1407. [PubMed] [Google Scholar]
  36. Wilmer J. L., Erexson G. L., Kligerman A. D. Sister chromatid exchange induction in mouse B- and T-lymphocytes exposed to cyclophosphamide in vitro and in vivo. Cancer Res. 1984 Mar;44(3):880–884. [PubMed] [Google Scholar]

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