Journal of Clinical Immunology

, Volume 7, Issue 2, pp 107–113 | Cite as

Increased spontaneous immunoglobulin secretion associated with cyclophosphamide-induced immune suppression

  • Otoniel Martínez-Maza
  • Dewey J. Moody
  • Ali R. Rezal
  • George W. Ellison
  • Lawrence W. Myers
  • Wallace W. Tourtellotte
  • John L. Fahey
Original Articles


Spontaneous immunoglobulin (Ig) secretion by cells from multiple sclerosis (MS) patients (in the progressive phase) treated with monthly pulse doses of cyclophosphamide (CY) (1000–1600 mg/M2) was measured using the protein A plaque assay, to evaluate the effect of CY treatment on B-cell function. Surprisingly, an increase, rather than a decrease, in Ig-secreting cells was seen following CY treatment. CY-treated MS patients averaged 1380±535 spontaneous total (IgM+G+A) Ig plaque-forming cells (PFC) per 1×106 peripheral blood mononuclear cells (MNC), measured at 15–22 days after monthly CY administration, while healthy adults had 280±47 Ig PFC/106 MNC, and MS patients not treated with CY had 300±43 Ig PFC/106 MNC. The observed increase was due to an increase in IgG and IgA PFC. PFC levels remained elevated for 4 weeks following CY treatment, decreasing to control levels by 7–8 weeks post-CY. A small increase in serum IgG level was noted after >12 months of pulse CY therapy; no increase was seen in CSF IgG levels. A preferential decrease in the number of CD4+ T cells was also seen in the CY-treated MS patients. We propose that the observed increase in the number of spontaneous Ig PFC was due to the CY-induced disruption of the CD4+ T cell-mediated control ofin vivo activated B cells.

Key words

Cyclophosphamide immunoglobulin immune suppression immune regulation multiple sclerosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Braun DP, Harris JE: Modulation of the immune response by chemotherapy. Pharm Ther 14:89–122, 1981Google Scholar
  2. 2.
    Hengst JC, Kempf RA: Immunomodulation by cyclophosphamide. Clin Immunol Allergy 4:199–216, 1984Google Scholar
  3. 3.
    Gonsette RE, Demonty L, Delmotte P: Intensive immunosuppression with cyclophosphamide in multiple sclerosis. J Neurol 214:173–181, 1977Google Scholar
  4. 4.
    Hommes OR, Prick JJG, Lamers KJB: Treatment of the chronic progressive from of multiple sclerosis with a combination of cyclophosphamide and prednisone. Clin Neurol Neurosurg 78:59–72, 1975Google Scholar
  5. 5.
    Hauser SL, Davidson DM, Lehrich JR, Beal F, Kevy SV, Propper RD, Mills JA, Weiner HL: Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange and ACTH. N Engl J Med 308:173–180, 1983Google Scholar
  6. 6.
    Shih WWH, Baumhefner RW, Tourtellotte WW, Haskell CM, Korn EL, Fahey JL: Difference in effect of single immunosuppressive agents (cyclophosphamide, CCNU, 5-FU) on peripheral blood immune cell parameters and central nervous system immunoglobulin synthesis rate in patients with multiple sclerosis. Clin Exp Immunol 53:122–132, 1983Google Scholar
  7. 7.
    Ten Berge RJM, Van Walbeek HK, Schellekens PThA: Evaluation of the immunosuppressive effects of cyclophosphamide in patients with multiple sclerosis. Clin Exp Immunol 50:495–502, 1982Google Scholar
  8. 8.
    Cupps TR, Edgar LC, Fauci AS: Suppression of human B lymphocyte function by cyclophosphamide. J Immunol 128:2453–2457, 1982Google Scholar
  9. 9.
    Stevenson HC, Fauci AS: Activation of human B lymphocytes. XII. Differential effects ofin vitro cyclophosphamide on human lymphocyte subpopulations involved in B-cell activation. Immunology 39:391–397, 1980Google Scholar
  10. 10.
    Gronowicz E, Coutinho A, Melchers F: A plaque assay for all cells secreting Ig of a given type or class. Eur J Immunol 6:588–590, 1976Google Scholar
  11. 11.
    Bird G, Britton S: A new approach to the study of human B lymphocyte function using an indirect plaque assay and a direct B cell activator. Immunol Rev 45:41–45, 1979Google Scholar
  12. 12.
    Bird G, Britton S, Ernberg I, Nilsson K: Characteristics of Epstein-Barr virus activation of human B lymphocytes. J Exp Med 154:832–839, 1981Google Scholar
  13. 13.
    Fahey JL, Prince H, Weaver M, Groopman J, Visscher B, Schwartz K, Detels R: Quantitative changes in T helper or T suppressor/cytotoxic lymphocyte subsets that distinguish acquired immune deficiency syndrome from other immune subset disorders. Am J Med 76:95–100, 1984Google Scholar
  14. 14.
    Tourtellotte WW, Tavalato B, Parker JA, Comiso P: Cerebrospinal fluid electroimmunodiffusion. An easy, rapid, sensitive, reliable and valid method for the simultaneous determination of immunoglobulin G and albumin. Arch Neurol 25:345–350, 1971Google Scholar
  15. 15.
    Moody DJ, Fahey JL, Ellison GW, Myers LM: One year administration of monthly pulse cyclophosphamide. II. Effects on immunologic parameters in multiple sclerosis in patients (submitted for publication).Google Scholar
  16. 16.
    Chien MM, Ashman RF: The nitrogen mustards melphan and cyclophosphamide inhibit Ig production in vitro by different mechanisms. Fed Proc 43:1427, 1984Google Scholar
  17. 17.
    Spina C: Azathioprine as an immune modulating drug: Clinical implications. Clin Immunol Allergy 4:415–446, 1984Google Scholar
  18. 18.
    Kotzin BL, Benike CJ, Engleman EG: Induction of immunoglobulin-secreting cells in the allogeneic mixed leukocyte reaction: Regulation by helper and suppressor lymphocyte subsets in man. J Immunol 127:931–935, 1981Google Scholar
  19. 19.
    Thorley-Lawson D: The suppression of Epstein-Barr virus infection in vitro occurs after infection but before transformation of the cell. J Immunol 124:745–751, 1980Google Scholar
  20. 20.
    Andersson U, Britton S, DeLey M, Bird G: Evidence for the ontogenetic precedence of suppressor T cell functions in the human neonate. Eur J Immunol 13:6–13, 1983Google Scholar
  21. 21.
    Hasler F, Bluestein HG, Zvaifler NJ, Epstein LB: Analysis of the defects responsible for the impaired proliferation by rheumatoid arthritis lymphocytes. I. Diminished gamma interferon production in response to autologous stimulation. J Exp Med 157:173–188, 1983Google Scholar
  22. 22.
    Martínez-Maza O, Andersson U, Andersson J, Britton S, DeLey M: Spontaneous production of interferon-gamma in adult and newborn humans. J Immunol 132:251–255, 1984Google Scholar
  23. 23.
    Andersson U, Martínez-Maza O, Andersson J, Britton S, Gadler S, DeLey M, Modrow S: Secretion of γ-interferon at the cellular level. Induction by Epstein-Barr virus. Scand J Immunol 20:425–432, 1984Google Scholar
  24. 24.
    Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS: Abnormalities of B-cell activation and immunoregulation in patients with the acquired immune deficiency syndrome. N Engl J Med 309:453–458, 1983Google Scholar
  25. 25.
    Whittle HC, Brown J, Marsh K, Greenwood BM, Seidelin P, Tighe H, Wedderburn L: T-cell control of Epstein-Barr virus-infected B cells is lost during P. falciparum malaria. Nature 312:449–450, 1985Google Scholar
  26. 26.
    Epstein MA: Clues to the role of malaria. Nature 312:398, 1985Google Scholar

Copyright information

© Plenum Publishing Corporation 1987

Authors and Affiliations

  • Otoniel Martínez-Maza
    • 1
  • Dewey J. Moody
    • 1
  • Ali R. Rezal
    • 1
  • George W. Ellison
    • 2
  • Lawrence W. Myers
    • 2
  • Wallace W. Tourtellotte
    • 2
  • John L. Fahey
    • 1
  1. 1.Department of Microbiology and Immunology and Jonsson Comprehensive Cancer CenterUCLA School of MedicineLos Angeles
  2. 2.Department of Neurology and Reed Neurological Research CenterUCLA School of MedicineLos Angeles

Personalised recommendations