Adenosine‐deaminase‐associated immunodeficiency. I. Differential sensitivities of lymphocyte subpopulations exposed to 2‐deoxycoformycin in vivo

SUMMARY In order to obtain a better understanding of the degree of immune dysfunctions caused by the absence of adenosine deaminase, we gave a single i.p. injection of 2′‐deoxycoformycin (2‐dcf), a potent inhibitor of the enzyme ADA at various doses into adult Syrian hamsters. These animals were examined for their ability to mount primary in vivo antibody responses to helper T cell dependent (Th‐d) and helper T cell independent (Th‐ind) antigens. Hamsters treated with 0·5 mg/kg of 2‐dcf mounted enhanced splenic plaque‐forming cell (PFC) responses to sheep erythrocytes, a Th‐d antigen, and to pneumococcal polysaccharide type III (SIII), a Th‐ind antigen. Treatment of animals with 1·0 mg/kg of 2‐dcf resulted in a significantly depressed ( P < 0·001) PFC response to Th‐d antigen, but a further enhanced response to Th‐ind antigen. One mechanism which may be responsible for such a dichotomous response to these two types of antigens was selective dysfunction of T cell subpopulations. At higher doses (1·5–4·0 mg/kg), PFC responses to both types of antigens were significantly suppressed. Immunoenhancement at low doses of 2‐def was attributed to an increased susceptibility of T suppressor cells to 2‐dcf. This hypothesis was confirmed by priming the 2‐dcf‐treated animals with low‐dose Th‐ind antigens. These animals failed to induce low‐dose tolerance by stimulation of antigen‐specific suppressor T cell subsets. At low doses, B cells and T helper cell functions were found to be intact, as further confirmed by priming the animals with the carrier keyhole limpet haemocyanin (KLH) and challenging with trinitrophenyl‐KLH. This dose‐dependent selective susceptibility of various T cell subpopulations and B cells may explain the heterogeneity of clinical, biochemical and immunological parameters observed in children with ADA deficiency severe combined immunodeficiency.