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. 1978 Dec;34(3):393–401.

Effect of methotrexate on the response of rat lymphocytes to phytohaemagglutinin

A Mansour, Julia A Henderson, D S Nelson
PMCID: PMC1537544  PMID: 743808

Abstract

The proliferative responses of rat peripheral blood lymphocytes (PBL) and spleen cells to phytohaemagglutinin (PHA) were studied following either single or multiple (daily for 4 days) doses of methotrexate (MTX). Lymphopenia developed 72 hr after a single dose of MTX. Multiple doses of MTX caused a dose-limited lymphopenia. In vitro, MTX depressed the response of PBL but enhanced the response of spleen cells to PHA. The administration of single or multiple doses of MTX led to increased responses of the remaining PBL and spleen cells. Folinic acid protected against the toxicity of multiple doses of MTX and the previously enhanced spleen cells were less responsive. In some conditions MTX treatment led to the enhancement of PBL responses by the serum of treated rats; in other conditions serum became inhibitory. MTX inhibited the primary antibody response to sheep erythrocytes. These studies demonstrate that MTX treatment initially enhances the proliferative response of lymphocytes to PHA and then causes depression at the onset of lymphopenia; that serum after MTX treatment has a variable effect on lympho-proliferative responses; and also that MTX is selectively more depressive of antibody formation than of responsiveness to PHA.

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Selected References

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

  1. BERENBAUM M. C. A screen for agents inhibiting the immune response and the growth of tumours. Nature. 1962 Oct 27;196:384–385. doi: 10.1038/196384a0. [DOI] [PubMed] [Google Scholar]
  2. BERENBAUM M. C. PROLONGATION OF HOMOGRAFT SURVIVAL BY METHOTREXATE WITH PROTECTION AGAINST TOXICITY BY FOLINIC ACID. Lancet. 1964 Dec 26;2(7374):1363–1365. doi: 10.1016/s0140-6736(64)91157-2. [DOI] [PubMed] [Google Scholar]
  3. Bach M. A., Bach J. F. Activities of immunosuppressive agents in vitro. II. Different timing of azathioprine and methotrexate in inhibition and stimulation of mixed lymphocyte reaction. Clin Exp Immunol. 1972 May;11(1):89–98. [PMC free article] [PubMed] [Google Scholar]
  4. Borel J. F. Comparative study of in vitro and in vivo drug effects on cell-mediated cytotoxicity. Immunology. 1976 Oct;31(4):631–641. [PMC free article] [PubMed] [Google Scholar]
  5. Chabner B. A., Myers C. E., Coleman C. N., Johns D. G. The clinical pharmacology of antineoplastic agents (first of two parts). N Engl J Med. 1975 May 22;292(21):1107–1113. doi: 10.1056/NEJM197505222922107. [DOI] [PubMed] [Google Scholar]
  6. DiLorenzo J. A., Griswold D. E., Bareham C. R., Calabresi P. Selective alteration of immunocompetence with methotrexate and 5-fluorouracil. Cancer Res. 1974 Jan;34(1):124–128. [PubMed] [Google Scholar]
  7. Djerassi I., Farber S., Abir E., Neikirk W. Continuous infusion of methotrexate in children with acute leukemia. Cancer. 1967 Feb;20(2):233–242. doi: 10.1002/1097-0142(1967)20:2<233::aid-cncr2820200209>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  8. FRIEDMAN R. M., BUCKLER C. E., BARON S. The effect of aminomethylpteroylglutamic acid on the development of skin hypersensitivity and on antibody formation in guinea pigs. J Exp Med. 1961 Aug 1;114:173–183. doi: 10.1084/jem.114.2.173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ford W. L. Lymphocyte migration and immune responses. Prog Allergy. 1975;19:1–59. doi: 10.1159/000313381. [DOI] [PubMed] [Google Scholar]
  10. Frei E., 3rd Symposium on immunosuppressive drugs. Effect of cancer chemotherapeutic agents on normal tissues in man. Fed Proc. 1967 May-Jun;26(3):918–924. [PubMed] [Google Scholar]
  11. Goldman I. D. Effects of methotrexate on cellular metabolism: some critical elements in the drug-cell interaction. Cancer Treat Rep. 1977 Jul;61(4):549–558. [PubMed] [Google Scholar]
  12. HERTZ R., LEWIS J., Jr, LIPSETT M. B. Five year's experience with the chemotherapy of metastatic choriocarcinoma and related trophoblastic tumors in women. Am J Obstet Gynecol. 1961 Sep;82:631–640. doi: 10.1016/0002-9378(61)90283-6. [DOI] [PubMed] [Google Scholar]
  13. Hoffmann C. C., Ho Y. K., Blakley R. L., Thompson J. S. Comparative effects of selected antifolates on transforming human lymphocytes and on established human lymphoblastic cell lines. Biochem Pharmacol. 1976 Sep 1;25(17):1947–1954. doi: 10.1016/0006-2952(76)90048-4. [DOI] [PubMed] [Google Scholar]
  14. Hryniuk W. M., Bishop A., Foerster J. Clinical correlates of in vitro effect of methotrexate on acute leukemia blasts. Cancer Res. 1974 Oct;34(10):2823–2829. [PubMed] [Google Scholar]
  15. Jaffe N., Frei E., 3rd, Traggis D., Bishop Y. Adjuvant methotrexate and citrovorum-factor treatment of osteogenic sarcoma. N Engl J Med. 1974 Nov 7;291(19):994–997. doi: 10.1056/NEJM197411072911902. [DOI] [PubMed] [Google Scholar]
  16. Kessel D., Hall T. C., Roberts D. Modes of uptake of methotrexate by normal and leukemic human leukocytes in vitro and their relation to drug response. Cancer Res. 1968 Mar;28(3):564–570. [PubMed] [Google Scholar]
  17. Kessel D., Hall T. C. Studies on drug transport by normal human leukocytes. Biochem Pharmacol. 1967 Dec;16(12):2395–2403. doi: 10.1016/0006-2952(67)90224-9. [DOI] [PubMed] [Google Scholar]
  18. Levitt M., Mosher M. B., DeConti R. C., Farber L. R., Skeel R. T., Marsh J. C., Mitchell M. S., Papac R. J., Thomas E. D., Bertino J. R. Improved therapeutic index of methotrexate with "leucovorin rescue". Cancer Res. 1973 Jul;33(7):1729–1734. [PubMed] [Google Scholar]
  19. MALMGREN R. A., BENNISON B. E., McKINLEY T. W., Jr Reduced antibody titers in mice treated with carcinogenic and cancer chemotherapeutic agents. Proc Soc Exp Biol Med. 1952 Mar;79(3):484–488. doi: 10.3181/00379727-79-19419. [DOI] [PubMed] [Google Scholar]
  20. Mansour A., Nelson D. S. Effect of cyclophosphamide treatment on the response of rat peripheral blood lymphocytes to phytohemagglutinin. Cell Immunol. 1977 May;30(2):272–281. doi: 10.1016/0008-8749(77)90071-5. [DOI] [PubMed] [Google Scholar]
  21. Mansour A., Nelson D. S. Effect of hydrocortisone on the response of rat lymphocytes to phytohaemagglutinin. Aust J Exp Biol Med Sci. 1978 Jun;56(3):301–311. doi: 10.1038/icb.1978.32. [DOI] [PubMed] [Google Scholar]
  22. Nelson D. S., Gatti R. A. Humoral factors influencing lymphocyte transformation. Prog Allergy. 1976;21:261–341. [PubMed] [Google Scholar]
  23. Nelson D. S., Mildenhall P. Studies on cytophilic antibodies. 1. The production by mice of macrophage cytophilic antibodies to sheep erythrocytes: relationship to the production of other antibodies and the development of delayed-type hypersensitivity. Aust J Exp Biol Med Sci. 1967 Apr;45(2):113–130. [PubMed] [Google Scholar]
  24. Nelson D. S., Shneider C. N. Effect of normal mouse serum on mouse lymphocyte transformation in vitro. Eur J Immunol. 1974 Feb;4(2):79–86. doi: 10.1002/eji.1830040205. [DOI] [PubMed] [Google Scholar]
  25. Pegoraro L., Benzio G. Effect of methotrexate on DNA synthesis and thymidine kinase activity of human lymphocytes stimulated with phytohaemagglutinin. Experientia. 1971 Jan 15;27(1):33–34. doi: 10.1007/BF02137725. [DOI] [PubMed] [Google Scholar]
  26. SANTOS G. W., OWENS A. H., Jr A COMPARISON OF THE EFFECTS OF SELECTED CYTOTOXIC AGENTS ON THE PRIMARY AGGLUTININ RESPONSE IN RATS INJECTED WITH SHEEP ERYTHROCYTES. Bull Johns Hopkins Hosp. 1964 Jun;114:384–401. [PubMed] [Google Scholar]
  27. Santos G. W., Owens A. H., Jr 19S and 17S antibody production in the cyclophosphamide- or methotrexate-treated rat. Nature. 1966 Feb 5;209(5023):622–624. doi: 10.1038/209622a0. [DOI] [PubMed] [Google Scholar]
  28. TURK J. L. STUDIES ON THE MECHANISM OF ACTION OF METHOTREXATE AND CYCLOPHOSPHAMIDE ON CONTACT SENSITIVITY IN THE GUINEA PIG. Int Arch Allergy Appl Immunol. 1964;24:191–200. doi: 10.1159/000229459. [DOI] [PubMed] [Google Scholar]
  29. Zaharko D. S., Dedrick R. L. Antifolates: in vivo kinetic considerations. Cancer Treat Rep. 1977 Jul;61(4):513–518. [PubMed] [Google Scholar]

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