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
. 1978 Oct;75(10):5011–5014. doi: 10.1073/pnas.75.10.5011

Purinogenic immunodeficiency diseases: selective toxicity of deoxyribonucleosides for T cells.

B S Mitchell, E Mejias, P E Daddona, W N Kelley
PMCID: PMC336252  PMID: 311004

Abstract

Deoxyadenosine at low concentrations and in the presence of an inhibitor of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) is markedly toxic to lymphoblast cell lines of T cell origin but does not impair growth of B cell lines. Deoxyguanosine is also more toxic for T lymphoblasts. In the presence of deoxyadenosine or deoxyguanosine, elevation of the corresponding deoxyribonucleoside triphosphate (dATP or dGTP) occurs in T cell, but not in B cell, lines. The addition of deoxycytidine or dipyridamole results in lower dATP and dGTP levels and prevents deoxyribonucleoside toxicity. These findings provide a molecular basis for the immunodeficiency observed in individuals with several inborn errors of purine metabolism.

Full text

PDF
5012

Selected References

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

  1. Ballet J. J., Insel R., Merler E., Rosen F. S. Inhibition of maturation of human precursor lymphocytes by coformycin, an inhibitor of the enzyme adenosine deaminase. J Exp Med. 1976 May 1;143(5):1271–1276. doi: 10.1084/jem.143.5.1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bjursell G., Reichard P. Effects of thymidine on deoxyribonucleoside triphosphate pools and deoxyribonucleic acid synthesis in Chinese hamster ovary cells. J Biol Chem. 1973 Jun 10;248(11):3904–3909. [PubMed] [Google Scholar]
  3. Buckley R. H., Gilbertsen R. B., Schiff R. I., Ferreira E., Sanal S. O., Waldmann T. A. Heterogeneity of lymphocyte subpopulations in severe combined immunodeficiency. Evidence against a stem cell defect. J Clin Invest. 1976 Jul;58(1):130–136. doi: 10.1172/JCI108441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  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., 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]
  7. 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]
  8. 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]
  9. 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]
  10. Huang C. C., Hou Y., Woods L. K., Moore G. E., Minowada J. Cytogenetic study of human lymphoid T-cell lines derived from lymphocytic leukemia. J Natl Cancer Inst. 1974 Sep;53(3):655–660. doi: 10.1093/jnci/53.3.655. [DOI] [PubMed] [Google Scholar]
  11. KLENOW H. Further studies on the effect of deoxyadenosine on the accumulation of deoxyadenosine triphosphate and inhibition of deoxyribonucleic acid synthesis in Ehrlich ascites tumor cells in vitro. Biochim Biophys Acta. 1962 Dec 31;61:885–896. doi: 10.1016/0926-6550(62)90005-1. [DOI] [PubMed] [Google Scholar]
  12. Kaplan J., Mastrangelo R., Peterson W. D., Jr Childhood lymphoblastic lymphoma, a cancer of thymus-derived lymphocytes. Cancer Res. 1974 Mar;34(3):521–525. [PubMed] [Google Scholar]
  13. Lowe J. K., Gowans B., Brox L. Deoxyadenosine metabolism and toxicity in cultured L5178Y cells. Cancer Res. 1977 Sep;37(9):3013–3017. [PubMed] [Google Scholar]
  14. Meuwissen H. J., Pollara B., Pickering R. J. Combined immunodeficiency disease associated with adenosine deaminase deficiency. Report on a workshop held in Albany, New York, October 1, 1973. J Pediatr. 1975 Feb;86(2):169–181. doi: 10.1016/s0022-3476(75)80463-x. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Plagemann P. G., Erbe J. The deoxyribonucleoside transport systems of cultured Novikoff rat hepatoma cells. J Cell Physiol. 1974 Jun;83(3):337–343. doi: 10.1002/jcp.1040830303. [DOI] [PubMed] [Google Scholar]
  17. Pyke K. W., Dosch H., Ipp M. M., Gelfand E. W. Demonstration of an intrathymic defect in a case of severe combined immunodeficiency disease. N Engl J Med. 1975 Aug 28;293(9):424–428. doi: 10.1056/NEJM197508282930904. [DOI] [PubMed] [Google Scholar]
  18. Seeger R. C., Robins R. A., Stevens R. H., Klein R. B., Waldman D. J., Zeltzer P. M., Kessler S. W. Severe combined immunodeficiency with B lymphocytes: in vitro correction of defective immunoglobulin production by addition of normal T lymphocytes. Clin Exp Immunol. 1976 Oct;26(1):1–10. [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Solter A. W., Handschumacher R. E. A rapid quantitative determination of deoxyribonucleoside triphosphates based on the enzymatic synthesis of DNA. Biochim Biophys Acta. 1969 Feb 18;174(2):585–590. doi: 10.1016/0005-2787(69)90288-3. [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. Sullivan J. L., Osborne W. R., Wedgewood R. J. Adenosine deaminase activity in lymphocytes. Br J Haematol. 1977 Sep;37(1):157–158. [PubMed] [Google Scholar]
  23. 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]

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