Priebe T, Kandil O, Nakic M, Pan B F, Nelson J A
Department of Experimental Pediatrics, University of Texas, M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Cancer Res. 1988 Sep 1;48(17):4799-803.
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.
作为腺苷脱氨酶或嘌呤核苷磷酸化酶不良底物的类似物，可能会模拟与这些酶缺乏相关的免疫缺陷，并且它们的活性可能针对特定的淋巴细胞亚群。研究了四种类似物对小鼠针对T细胞依赖性抗原（绵羊红细胞）或T细胞非依赖性抗原（三硝基苯基偶联的大肠杆菌脂多糖）的初次抗体反应的影响，以及对T细胞毒性和自然杀伤细胞活性的影响。这些核苷分别是：一种腺苷类似物，杀结核菌素；两种脱氧腺苷类似物，2-氯-2'-脱氧腺苷和5'-磷酸-2-氟阿拉伯糖腺嘌呤；以及一种脱氧鸟苷类似物，9-β-D-阿拉伯糖基鸟嘌呤。药物通过腹腔注射给药，连续3天每天一次。在最后一剂药物后的第1天，在脾细胞悬液中测定免疫反应。杀结核菌素在不降低初次抗体反应的剂量下，抑制了T细胞毒性和自然杀伤细胞的活性，而2-氯-2'-脱氧腺苷和5'-磷酸-2-氟阿拉伯糖腺嘌呤的情况则相反。在较高剂量下，T细胞毒性淋巴细胞似乎比自然杀伤细胞对脱氧腺苷类似物更敏感。9-β-D-阿拉伯糖基鸟嘌呤在明显降低脾淋巴细胞产量的剂量下，并没有选择性地抑制免疫反应。假设这些类似物模拟内源性核苷，结果表明自然杀伤细胞对腺苷的敏感性高于负责初次抗体反应的细胞，而对脱氧腺苷的敏感性则相反。
