Mechanisms of Adenosine and 2’-Deoxyadenosine Inhibition of Immune Function in Mouse Lymphocytes

Abstract

Adenosine (Ado) has been recognized as having an inhibitory influence on the immune system since 1970, when it was reported that this purine nucleoside inhibits the mitogenic stimulation of human peripheral blood lymphocytes by phytohemagglutinin [1]. Widespread interest in the possible immune modulatory role of Ado was sparked by the 1972 report of Giblett and her colleagues [2] describing the genetic deficiency of the enzyme Ado deaminase (ADA) in two children with severe combined immunodeficiency. This inherited disorder is characterized by a marked reduction of functional T and B lymphocytes. With the discovery of additional immunodeficient patients lacking ADA, an extensive research effort was begun to elucidate the biochemical mechanisms by which ADA deficiency results in the rather selective demise of the immune system. From 1972 until 1978, it was widely assumed that this immunodeficiency disease results from the buildup of high concentrations of Ado and/or adenine ribonucleotides in ADA-deficient patients. Indeed, in 1976 Mills et al. [3] reported that plasma Ado and adenine, and erythrocyte ATP, were elevated in an ADA-deficient child. Accordingly, on the basis of results obtained with a number of in vitro model systems, several hypotheses were introduced to explain the role of Ado in the pathophysiology of ADA-deficient immunodeficiency, the more prominent of which were Ado-induced pyrimidine starvation, Ado-stimulated increases in cAMP, and Ado-mediated accumulation of S-adenosylhomocysteine (AdoHcy) and consequent inhibition of methylation reactions (for reviews see [4–7]). Subsequently, in 1978, it was reported that 2′-deoxyadenosine (dAdo) was elevated in the plasma and urine of ADA-deficient children and that dATP was elevated in their erythrocytes and lymphocytes. With the further important observation that dAdo is more toxic than Ado to proliferating lymphoid cells, the emphasis in biochemical studies concerning the causal relationship between ADA deficiency and severe combined immunodeficiency shifted away from Ado toward dAdo. The historical development of this interesting field has been the subject of several recent reviews [4–7].