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Purine Nucleoside Phosphorylase Deficiency: A Molecular Model for Selective Loss of T Cell Function¹

From the Department of Pediatrics, University of Washington, School of Medicine, Seattle, Washington 98195

Abstract

Absence of purine nucleoside phosphorylase (NP) is associated with severe T cell immune deficiency and normal B cell function. Patients with this enzyme defect accumulate inosine, guanosine, and their respective deoxycompounds, all of which are substrates for NP. We have evaluated the effect of these four NP substrates on PHA-stimulated lymphocytes and lymphoblastoid cell lines with B and T cell characteristics. Inosine and deoxyinosine had little inhibitory effect on human lymphocytes, whereas guanosine and deoxyguanosine inhibited DNA and protein synthesis in both PHA-stimulated human lymphocytes and hyman lymphoblastoid cells. In all experiments, deoxyguanosine was more toxic than guanosine.

Human lymphoblastoid cells with T cell characteristics (T-LCL) were found to be particularly sensitive to the presence of deoxyguanosine. At low µM concentrations ³H-thymidine and ³H-leucine incorporation into the T-LCL was markedly decreased. At a concentration of 10 µM, no cell growth occurred and 50% of the cells were killed. Partial reversal of the toxic effect of deoxyguanosine on the T-LCL could be achieved with simultaneous addition of deoxycytidine. Human lymphoblastoid cells with B cell characteristics (B-LCL) were not inhibited at these low deoxyguanosine levels but cell growth and incorporation of ³H-thymidine and ³H-leucine were moderately decreased at higher deoxyguanosine concentrations. In a B-LCL established from a patient with NP deficiency, neither DNA nor protein synthesis was inhibited by guanosine or deoxyguanosine at concentrations that affected other B cell lines.

The extreme sensitivity of the T lymphoblasts and relative resistance of B lymphoblasts to the toxicity of deoxyguanosine or one of its metabolic products may explain the selective loss of T cell function in patients with NP deficiency.

Footnotes

¹ This work was supported in part by Public Health Service Grants GM 01218 and AI 12617, and the National Foundation.

² Dr. H. D. Ochs is an investigator of the Howard Hughes Medical Institute.