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Sensitivity of Human T and B Lymphoblasts to Immunoregulatory Drugs

  • Irene S. Kazmers
  • A. Paulette Dalke
  • Peter E. Daddona
  • William N. Kelley
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 165)

Abstract

The precise mechanisms by which many clinically useful immunorequlatory aqents produce immunologic dysfunction are not clear, even though many of their cytotoxic and mutagenic effects are well understood. Adenosine deaminase (ADA) deficiency and purine nucleoside Phosphorylase (PNP) deficiency are both inborn errors of purine metabolism characterized by severe immunodeficiency with the biochemical derangements in these diseases including the toxic accumulation of dATP or dGTP, respectively, (see Figure 1).1 Under the appropriate conditions, both the biochemcial changes and the selective lymphotoxicity observed in the ADA and PNP deficiency diseases can be reproduced in an in vitro cell culture system. A low concentration of deoxyadenosine in the presence of an ADA inhibitor leads to the accumulation of dATP and toxicity in cultured T lymphoblasts but not in B lymphoblasts, thus mimicking ADA deficiency disease.2 The addition of deoxyguanosine (50 μM) to culture medium leads to a selective increase in the level of dGTP and toxicity for T cells but not for B cells, analogous to changes observed in PNP deficiency disease.2 In the present study, we have used this lymphoblast tissue culture system to determine whether any of a selected group of immunoregulatory drugs were inhibitory to the growth of cultured T and B cells and, if so, to establish whether the toxicity could be attributed to interference with either ADA or PNP activity or related to an accumulation of dATP or dGTP.

Keywords

Inborn Error Cell Culture System Adenosine Deaminase Severe Combine Immunodeficiency Purine Metabolism 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

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    B.S. Mitchell, E. Mejias, P.E. Daddona and W.N. Kelley, Purinogenic immunodeficiency diseases: Selective toxicity of deoxyribonucleotides for T-cells, Proc. Natl. Acad. Sci. U.S.A. 75: 5011 (1978).PubMedCrossRefGoogle Scholar
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    I.S. Kazmers, P.E. Daddona, A.P. Dalke and W.N. Kelley, Effects of immunoregulatory agents on human T and B lymphoblasts, submitted for publication.Google Scholar

Copyright information

© Springer Science+Business Media New York 1984

Authors and Affiliations

  • Irene S. Kazmers
    • 1
  • A. Paulette Dalke
    • 1
  • Peter E. Daddona
    • 1
  • William N. Kelley
    • 1
  1. 1.Departments of Internal Medicine and Biological ChemistryUniversity of Michigan Medical CenterAnn ArborUSA

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