Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The association of adenosine deaminase (ADA) deficiency with immunodeficiency disease has emphasized the importance of this purine metabolic enzyme for human lymphocyte growth and function. This report describes the natural occurrence of ADA deficiency in a human histiocytic lymphoma cell line, DHL-9. The minimal ADA activity in DHL-9 extracts, 0.028 nmol/min/mg protein, was less than 50% of the activity in two B-lymphoblastoid cell lines from ADA-deficient patients and was resistant to the potent ADA inhibitor deoxycoformycin. A sensitive radioimmunoassay failed to detect immunoreactive ADA in DHL-9 cells. Moreover, in DHL-9 cells, deoxycoformycin did not augment either the growth-inhibitory effects of adenosine and deoxyadenosine or the accumulation of deoxyadenosine triphosphate from deoxyadenosine. When compared to six other human hematopoietic cell lines, DHL-9 had 5.6-fold-higher levels of adenosylhomocysteinase. Chromosome 20, which bears the structural gene for ADA and adenosylhomocysteinase, was diploid and had a normal Giemsa banding pattern. The parental DHL-9 cell line was used for the selection and cloning of secondary mutants deficient in deoxycytidine kinase and adenosine kinase.
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PMID:Characterization of an adenosine deaminase-deficient human histiocytic lymphoma cell line (DHL-9) and selection of mutants deficient in adenosir kinase and deoxycytidine kinase. 630 63

Defects in the enzymes involved in the pathway of S-adenosylmethionine (AdoMet) metabolism, or inhibition of those enzymes, results in profound immunodeficiency. We have examined MDL 28,842, a novel irreversible inhibitor of S-adenosyl-L-homocysteine hydrolase (AdoHcyase), an enzyme involved in AdoMet metabolism, to determine its effect on the immune system and to investigate its potential as an immunosuppressive agent. The stimulation of human mononuclear cell proliferation in vitro with Con A, a T cell mitogen, and PWM, a T-dependent B cell mitogen, were inhibited by MDL 28,842. The 50% inhibitory concentration for both were 0.33 microM. In murine spleen cells, MDL 28,842 was a potent, nontoxic, inhibitor of Con A-stimulated T cell proliferation (IC50 = 0.19 microM) but did not affect LPS-induced B cell proliferation. This selective suppression was also observed when enriched murine T and B cells were stimulated with mitogens, although S-adenosyl-L-homocysteine (AdoHcy), the substrate of AdoHcyase, was similarly elevated in both populations. In addition to proliferation in response to a number of stimuli, IL-2 production and the expression of IL-2R by mitogen-stimulated T cells were inhibited by MDL 28,842. These results suggest a direct effect of MDL 28,842 on T cells. In vivo, the antibody response to a T cell-dependent Ag, OVA, was inhibited by MDL 28,842. The response of splenic T cells from these animals to OVA in vitro were similarly depressed compared with controls. The results demonstrate that MDL 28,842 is a potent nontoxic immunosuppressive agent, which has selectivity for T cells and therefore may be useful in the treatment of T cell-mediated disorders, such as autoimmune disease and tissue transplantation.
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PMID:Selective inhibition of T cell activation by an inhibitor of S-adenosyl-L-homocysteine hydrolase. 846 68