Selective Modulation of Antibody Response and Natural Killer Cell Activity by Purine Nucleoside Analogues

Analogues that are poor substrates for adenosine deaminase or purine nucleoside phosphorylase may mimic immunodeficiencies associated with the enzyme deficiencies, and their activities may be directed toward selected lymphocyte subpopulations. Four analogues were studied for their effects on primary antibody response to either a T-dependent (sheep erythrocytes) or T-independent (trinitrophenyl-conjugated Escherichia coli lipopolysaccharide) antigen as well as effects on T-cytotoxic and natural killer cell activities in mice. The nucleosides were: an adenosine analogue, tubercidin; two deoxyadenosine analogues, 2-chloro, 2'-deoxyadenosine and 2-fluoroadenine arabinoside-5'-phosphate; and a deoxyguanosine analogue, 9-beta-D-arabinosylguanine. Drugs were given i.p. once daily for 3 consecutive days. Immune responses were determined in spleen cell suspensions 1 day after the last dose. Tubercidin inhibited both T-cytotoxic and natural killer cell activities at doses that did not reduce primary antibody response, whereas the reverse was true for 2-chloro, 2'-deoxyadenosine and 2-fluoroadenine arabinoside-5'-phosphate. At higher doses, T-cytotoxic lymphocytes appeared to be more sensitive than natural killer cells to the deoxyadenosine analogues. 9-beta-D-Arabinosylguanine did not selectively inhibit the immune responses at doses that clearly reduced the yield of spleen lymphocytes. Assuming the analogues mimic endogenous nucleosides, the results suggest that natural killer cells are more sensitive to adenosine than are those cells responsible for primary antibody response, whereas the reverse is true for deoxyadenosine.