Adenosine-deaminase-associated immunodeficiency. I. Differential sensitivities of lymphocyte subpopulations exposed to 2-deoxycoformycin in vivo.
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 less than 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.
Bagasra
O
O
Department of Medicine, Jefferson Medical College, Philadelphia, PA 19107.
Howeedy
A
A
Pomerantz
R J
RJ
D000243:Adenosine Deaminase / Q000172:deficiency / Q000276:immunology*; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D000937:Antigen-Antibody Reactions; D001402:B-Lymphocytes / Q000276:immunology; D006224:Cricetinae; D004306:Dose-Response Relationship, Immunologic; D006241:Haptens; D006433:Hemocyanins; D006462:Hemolytic Plaque Technique; D007111:Immunity, Cellular; D016131:Lymphocyte Subsets / Q000276:immunology*; D008297:Male; D015649:Pentostatin / Q000494:pharmacology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D006241:Haptens; C054401:trinitrophenyl keyhole limpet hemocyanin; D015649:Pentostatin; D006433:Hemocyanins; D000243:Adenosine Deaminase; C032808:keyhole-limpet hemocyanin