SummaryThe activities of CDP reductase and thymidine kinase in 10 6 to 5 X 10 6 phytohemagglutinin (PHA)-stimulated lymphocytes isolated from 2 to 5 ml of peripheral blood of individual subjects were measured. The activities of CDP reductase (pmolfh/10 7 cells) and thymidine kinase (nmolfh/10 7 cells) were high in infants, 698 ± 307 and 64.2 ± 20.2, constant in subjects of 1-40 years old, 401 ± 181 and 38.1 ± 15.3, and low in persons of more than 80 years old, 121 ± 113 and 22.3 ± 17.8, respectively.The ratio of thymidine kinase to CDP reductase activity increased with age, indicating that dependency on the salvage pathway of DNA synthesis in lymphocytes increased with age. The activities of CDP reductase and thymidine kinase were reduced in patients with the hyperimmunoglobulin E syndrome, congenital cytomegalovirus infection, anhidrotic ectodermal dysplasia with hyperimmunoglobulin A, Bloom's syndrome, immunodeficiency with hyperimmunoglobulinemia, and Down's syndrome. The clinical symptoms of these diseases seem to be due to impaired DNA synthesis of PHA-stimulated lymphocytes, but the degrees of reduction of enzyme activities were generally greater than that of thymidine incorporation in these patients.
AbbreviationsPHA, phytohemagglutinin HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid Ribonucleotide reductase and thymidine kinase are thought to be rate-limiting enzymes in the de novo and salvage pathways, respectively, of DNA biosynthesis. Since the activities of these enzymes have been shown to be increased in rapidly proliferating tissues, such as tumors (8,24,28), developing organs (8, 12, 16), and regenerating liver (15, 28), it has been thought that these activities closely reflect the rate of DNA synthesis (25,28).Deficiencies of adenosine deaminase and purine nucleoside phosphorylase are observed in severe combined immunodeficiency. Immunodeficiency is thought to be due to inhibition of ribonucleotide reductase by the accumulation of deoxyadenosine triphosphate in adenosine deaminase deficiency (6) and deoxyguanosine triphosphate in purine nucleoside phosphorylase deficiency (5), because both deoxynucleotides are strong inhibitors of mammalian ribonucleotide reductase (9). From these considerations, ribonucleotide reductase activity in lymphocytes may closely reflect the manifestation of immunity.On stimulation by PHA, lymphocytes are.transformed into cells showing enhanced DNA synthesis arid consequently increased thymidine incorporation into DNA. Thymidine kinase catalyzes the first and rate-limiting step from thymidine to DNA in this pathway. Since measurement of [3H]thymidine incorporation is reported not to be a precise assay of cell proliferation (2), measurements of ribonucleotide reductase and thymidine kinase activities should indicate better whether immunodeficiency and various other diseases are attributable to impaired DNA synthesis. These enzymes are difficult to assay in normal tissues because their activities are so low (25), but their activities are considerably increased i...