Immunomodulatory effect of procainamide in man. Inhibition of human suppressor T-cell activity in vitro.

Abstract

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-

Thrombosis Associated with Procainamide-Induced Lupus Anticoagulant

“…Our findings concur with the recent observations of Triplett et al [5] who noted thromboembolic events in approximately onethird of patients with drug-induced lupus anticoagu lants. Although the pathogenesis of thrombosis which occurs in association with the lupus anticoagulant is not clear, a prominent consideration in procain amide-treated patients is immune perturbation with resultant autoantibody formation [8][9][10][11], The lupus anticoagulant exhibits immunologic specificity tow ard anionic phospholipids involved in generation of the prothrombin complex [10,12], Such interaction with platelet phospholipids and other cell membranes may contribute to cell damage, platelet activation, and thrombocytopenia as seen in patient 1, inhibition of prostacyclin production by vascular endothelium, and altered regulation of protein C and plasminogen activation [2,4,[13][14][15][16][17], Development of the lupus anticoagulant in pro cainamide-treated patients may heighten the risk of thromboembolic complications and contribute signi ficantly to patient morbidity. Indeed, development of the related anticardiolipin antibodies in patients un dergoing coronary artery bypass surgery [18] and in survivors of myocardial infarction [19] has recently been associated with graft failure and recurrent car diovascular events, respectively.…”

Effects of long‐term procainamide therapy on immunoglobulin synthesis

“…There is evidence both in vivo (28) and in vitro (14,30,31) to indicate that PA interferes with such mechanisms. In this investigation, experiments have been carried out to further explore the effect of PA on immunoregulation in patients receiving long-term PA therapy, by measuring the separate functions of their T lymphocytes, B lymphocytes, and macrophages in PWM-stimulated cultures.…”

“…Nonspecific suppressor cell activity was evaluated by a 2-stage method as described by Ochi et al (30). Briefly, 5 x 106/ml unseparated PBMC were stimulated with concanavalin A (Pharmacia Fine Chemicals, Uppsala, Sweden) at a final concentration of 30 pg/ml and cultured at 37°C in 5% CO-, in petri dishes, with continuous shaking for 48 hours.…”

“…The T:B cell ratio varied between 0.5 and 4. In a parallel series of experiments, T cells were pretreated with mitomycin C to abrogate the activity of the suppressor population before mixing with the B cells (30,34,36). It was observed that in 3 of the 6 patients, diminished generation of PWM-ISC was associated with decreased function of both B and T cells; in the other 3 patients, this was associated with decreased B cell function alone (Table 2).…”

“…Genetic factors (1,11, 13,[23][24][25] and the pharmacologic properties of the drug (26,27) appear to have important roles in the pathogenesis of the autoimmunity. Recently, evidence has shown that PA may interfere with the regulation of the immune system, either directly (14,(28)(29)(30)(31) or indirectly (2,32).…”