Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1979 Apr;76(4):1998–2002. doi: 10.1073/pnas.76.4.1998

Selective toxicity of purine deoxynucleosides for human lymphocyte growth and function

Erwin W Gelfand 1, Jacob J Lee 1, Hans-Michael Dosch 1
PMCID: PMC383521  PMID: 313053

Abstract

A role for the enzymes adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) and purine-nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyl-transferase, EC 2.4.2.1) in the functional maturation of lymphoid cells has been revealed by the association of inherited deficiencies of these enzymes and profound immune deficiency. Previous studies have suggested that the selective toxicity for lymphocytes may be mediated by the accumulation of toxic deoxynucleoside metabolites, likely through the action of specific kinases enriched in lymphoid cells. In order to study possible mechanisms whereby lymphocyte function may be impaired in these disorders, we have studied the effect of nucleosides and their deoxy analogues on both T and B lymphocyte growth and function. In the presence of deoxyguanosine, there was marked inhibition of T lymphoblast growth, phytohem-agglutinin-induced cell proliferation, and T suppressor cell activity. T helper cell activity and the differentiation of B cells to an antibody-secreting stage were unaffected. Deoxyadenosine was much less inhibitory, but in the presence of an inhibitor of adenosine deaminase, its effects on lymphocyte growth and function were markedly potentiated. The addition of deoxycytidine prevented deoxyadenosine toxicity in all assays, whereas it only interfered with deoxyguanosine effects on T lymphoblast growth. These studies provide some initial understanding for the selective loss of specific lymphocyte functions in individuals with inborn errors of purine metabolism.

Keywords: immune deficiency, cell growth, antibody response

Full text

PDF

Selected References

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

  1. Benke P. J., Dittmar D. Purine dysfunction in cells from patients with adenosine deaminase deficiency. Pediatr Res. 1976 Jul;10(7):642–646. doi: 10.1203/00006450-197607000-00002. [DOI] [PubMed] [Google Scholar]
  2. Boyum A. Separation of blood leucocytes, granulocytes and lymphocytes. Tissue Antigens. 1974;4(4):269–274. [PubMed] [Google Scholar]
  3. Carson D. A., Kaye J., Seegmiller J. E. Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: possible role of nucleoside kinase(s). Proc Natl Acad Sci U S A. 1977 Dec;74(12):5677–5681. doi: 10.1073/pnas.74.12.5677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chechik B. E., Pyke K. W., Gelfand E. W. Human thymus/leukemia-associated antigen in normal and leukemic cells. Int J Cancer. 1976 Nov 15;18(5):551–556. doi: 10.1002/ijc.2910180502. [DOI] [PubMed] [Google Scholar]
  5. Cohen A., Doyle D., Martin D. W., Jr, Ammann A. J. Abnormal purine metabolism and purine overproduction in a patient deficient in purine nucleoside phosphorylase. N Engl J Med. 1976 Dec 23;295(26):1449–1454. doi: 10.1056/NEJM197612232952603. [DOI] [PubMed] [Google Scholar]
  6. Cohen A., Gudas L. J., Ammann A. J., Staal G. E., Martin D. W., Jr Deoxyguanosine triphosphate as a possible toxic metabolite in the immunodeficiency associated with purine nucleoside phosphorylase deficiency. J Clin Invest. 1978 May;61(5):1405–1409. doi: 10.1172/JCI109058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen A., Hirschhorn R., Horowitz S. D., Rubinstein A., Polmar S. H., Hong R., Martin D. W., Jr Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. Proc Natl Acad Sci U S A. 1978 Jan;75(1):472–476. doi: 10.1073/pnas.75.1.472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Coleman M. S., Donofrio J., Hutton J. J., Hahn L., Daoud A., Lampkin B., Dyminski J. Identification and quantitation of adenine deoxynucleotides in erythrocytes of a patient with adenosine deaminase deficiency and severe combined immunodeficiency. J Biol Chem. 1978 Mar 10;253(5):1619–1626. [PubMed] [Google Scholar]
  9. Dosch H-M, Gelfand E. W. Generation of human plaque-forming cells in culture: tissue distribution, antigenic and cellular requirements. J Immunol. 1977 Jan;118(1):302–308. [PubMed] [Google Scholar]
  10. Dosch H. M., Lee J. W., Gelfand E. W., Falk J. A. Severe combined immunodeficiency disease: a model of T-cell dysfunction. Clin Exp Immunol. 1978 Nov;34(2):260–267. [PMC free article] [PubMed] [Google Scholar]
  11. Gelfand E. W., Dosch H. M., Biggar W. D., Fox I. H. Partial purine nucleoside phosphorylase deficiency. Studies of lymphocyte function. J Clin Invest. 1978 Apr;61(4):1071–1080. doi: 10.1172/JCI109006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Giblett E. R., Ammann A. J., Wara D. W., Sandman R., Diamond L. K. Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet. 1975 May 3;1(7914):1010–1013. doi: 10.1016/s0140-6736(75)91950-9. [DOI] [PubMed] [Google Scholar]
  13. Giblett E. R., Anderson J. E., Cohen F., Pollara B., Meuwissen H. J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972 Nov 18;2(7786):1067–1069. doi: 10.1016/s0140-6736(72)92345-8. [DOI] [PubMed] [Google Scholar]
  14. Green H., Chan T. Pyrimidine starvation induced by adenosine in fibroblasts and lymphoid cells: role of adenosine deaminase. Science. 1973 Nov 23;182(4114):836–837. doi: 10.1126/science.182.4114.836. [DOI] [PubMed] [Google Scholar]
  15. Hamet M., Griscelli C., Cartier P., Ballay J., de Bruyn C., Hösli P. A second case of inosine phosphorylase deficiency with severe T-cell abnormalities. Adv Exp Med Biol. 1977;76A:477–480. doi: 10.1007/978-1-4613-4223-6_60. [DOI] [PubMed] [Google Scholar]
  16. Krenitsky T. A., Tuttle J. V., Koszalka G. W., Chen I. S., Beacham L. M., 3rd, Rideout J. L., Elion G. B. Deoxycytidine kinase from calf thymus. Substrate and inhibitor specificity. J Biol Chem. 1976 Jul 10;251(13):4055–4061. [PubMed] [Google Scholar]
  17. Moore E. C., Hurlbert R. B. Regulation of mammalian deoxyribonucleotide biosynthesis by nucleotides as activators and inhibitors. J Biol Chem. 1966 Oct 25;241(20):4802–4809. [PubMed] [Google Scholar]
  18. Shore A., Dosch H., Gelfand E. W. Induction and separation of antigen-dependent T helper and T suppressor cells in man. Nature. 1978 Aug 10;274(5671):586–587. doi: 10.1038/274586a0. [DOI] [PubMed] [Google Scholar]
  19. Siegal F. P., Siegal M. Enhancement by irradiated T cells of human plasma cell production: dissection of helper and suppressor functions in vitro. J Immunol. 1977 Feb;118(2):642–647. [PubMed] [Google Scholar]
  20. Simmonds H. A., Panayi G. S., Corrigall V. A role for purine metabolism in the immune response: Adenosine-deaminase activity and deoxyadenosine catabolism. Lancet. 1978 Jan 14;1(8055):60–63. doi: 10.1016/s0140-6736(78)90002-8. [DOI] [PubMed] [Google Scholar]
  21. Stoop J. W., Zegers B. J., Hendrickx G. F., van Heukelom L. H., Staal G. E., de Bree P. K., Wadman S. K., Ballieux R. E. Purine nucleoside phosphorylase deficiency associated with selective cellular immunodeficiency. N Engl J Med. 1977 Mar 24;296(12):651–655. doi: 10.1056/NEJM197703242961203. [DOI] [PubMed] [Google Scholar]
  22. Tattersall M. H., Ganeshaguru K., Hoffbrand A. V. The effect of external deoxyribonucleosides on deoxyribonucleoside triphosphate concentrations in human lymphocytes. Biochem Pharmacol. 1975 Aug 15;24(16):1495–1498. doi: 10.1016/0006-2952(75)90025-8. [DOI] [PubMed] [Google Scholar]
  23. Wolberg G., Zimmerman T. P., Hiemstra K., Winston M., Chu L. C. Adenosine inhibition of lymphocyte-mediated cytolysis: possible role of cyclic adenosine monophosphate. Science. 1975 Mar 14;187(4180):957–959. doi: 10.1126/science.167434. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES