The ontogeny of immune responsiveness, as assayed by antibody formation in vitro, of mouse spleen lymphocytes to thymus-independent antigens is reviewed. Responsiveness to trinitrophenyl (TNP)-lipopolysaccharide and TNP-Brucella abortus appear soon after birth and one to two weeks before TNP-Ficoll or capsular polysaccharide of Streptococcus pneumoniae (SSS-III) elicits significant antibody formation. This hierarchy of responsiveness to antigens is also apparent in the CBA/N mutant mouse strain, which has a bone marrow-derived (B-) cell maturation arrest and fails to respond to either TNP-ficoll or SSS-III. These findings are interpreted to suggest sequential maturation of different populations or lines of B-lymphocytes, each of which can respond to a defined class of thymus-independent antigens. The implication for vaccine use in humans is that a late-appearing subclass of B-cells may be required for adequate immune responses to polyaccharide antigens.
A B S T R A C T Procainamide (PA) induces the production of a number of autoantibodies in a high proportion of treated individuals and in some a syndrome closely resembling systemic lupus erythematosus. The mechanism underlying this action of PA is unclear. To examine the possibility that PA might induce autoantibody formation by altering normal immunoregulatory mechanisms, the action of this drug on an in vitro model of antibody formation in man was examined. PA was found to augment the generation of immunoglobulin-secreting cells (ISC) from human peripheral blood mononuclear cells (PBM) in response to pokeweed mitogen but had no effect on pokeweed mitogen-induced tritiated thymidine incorporation. When purified populations of B and T cells were used, PA enhanced the generation of ISC in B-cell cultures supported by untreated T cells but not by T cells treated with mitomycin C. These results indicate that PA augmented B-cell responses by inhibiting suppressor T-cell activity and not by augmenting helper T-cell or B-cell function. N-Acetyl-procainamide had no effect on the generation of ISC in this system.The effect of PA on concanavalin A (Con A)-induced suppressor cell activity was also examined to determine whether PA altered the generation or expression of suppressor T-cell function. PBM were cultured with 30 Aig/ ml of Con A for 48 h to generate suppressor cells. When these were co-cultured with fresh PBM, the number of ISC generated was decreased by 58.1±3.4% (mean ±SEM, n = 6). Cells that had been similarly incubated without Con A were not inhibitory. The addition of PA to the Con A-stimulated cultures inhibited the generation of suppressor cells as indicated by the fact that the response of fresh cells co-cultured with the Con A-stimulated cells was diminished by only 27.2±4.3%. In this system too, N-acetyl-procaimamide had no effect. By contrast, adding PA only to the co-culture of Con A-
Hapten-specific tolerance was induced in vitro by trinitrophenyl-human gamma globulin (TNP32HGG) to a comparable degree in B cells from adult autoimmune (NZB X NZW)F1 (B/W) mice and normal BDF1, CBA/J, and DBA/1J mice. When a lower epitope density tolerogen (TNP7HGG) was used, B/W mice were significantly less sensitive than normal mice to the induction of B cell tolerance. This finding of defective B cell tolerance in adult B/W mice is consistent with previous reports that document other B cell abnormalities that may relate to the expression of autoimmune disease.
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