Two stages in lymphocyte mediator production by differential susceptibility to blockade using niridazole.

Abstract

Sera from guinea pigs given niridazole, an anti-schistosomal compound, have been shown to reversibly block the production of antigen-induced migration inhibitory factor by sensitized guinea pig lymph node cells. Since niridazole itself has no effect in vitro, the blockade of production of migration inhibitory factor is probably due to drug metabolites in the serum. We report here further studies on the mechanism of this drug-induced suppression of cellular hypersensitivity; the data show that niridazole active serum does not block the production of migration inhibitory factor once it has been initiated. Indeed, if niridazole active serum is added as little as 60 sec after the addition of antigen, the lymphocytes will produce migration inhibitory factor. These results suggest the presence of at least two stages in production of migration inhibitory factor after the addition of antigen to lymphocytes. The first, lasting less than 60 sec, is susceptible to lockade by niridazole active serum; the second is not. The elucidation of the mechanism of this blockade should lead to further understanding of the early events after antigen triggering of sensitized lymphocytes. In recent studies, it has been shown that niridazole, an antischistosomal compound, will markedly suppress a number of manifestations of cellular hypersensitivity. These include granuloma formation, delayed footpad swelling, and graft rejection in mice (1, 2), as well as delayed hypersensitivity skin reactions in man (3) and guinea pigs (4). On the other hand, niridazole only suppresses antibody responses minimally (5).In studying the mechanism of the suppression of cellular hypersensitivity, we found that sera obtained from guinea pigs given a single dose of niridazole would block the production of migration inhibitory factor (MIF) by sensitized lymph node cells in vitro (4). This blockade was reversible. Since niridazole itself had no effect in vitro, the blockade of MIF production is probably due to drug metabolites in the serum. For the sake of simplicity, the sera from niridazoletreated animals is referred to as "niridazole active serum" or NAS.The studies reported here were undertaken to further analyze the mechanism of this drug-induced suppression of cellular hypersensitivity; the data indicate that NAS will not block the production of MIF once it has been initiated. Indeed, it was surprising to find that if NAS was added to cells as little as 60 sec after the addition of antigen, the lymphocytes produced MIF. The results reveal the presence of at least two stages in MIF production after the addition of antigen to lymphocytes. The first, lasting less than 60 sec. is susceptible to blockade by NAS; the second is not susceptible. The elucidaAbbreviations: MIF, migration inhibitory factor; NAS, niridazole active serum; NGPS, normal guinea pig serum; OCB-BGG, orthochloro-benzoyl chloride-bovine gamma globulin.

Anti-T Cell Activity of Niridazole in Experimental Autoimmune Encephalomyelitis

“…The antischistosomal drug niridazole clearly suppressed signs of disease and his tological lesions of EAE in mice, especially when treatment preceded immunization. This is in keeping with earlier evidence [3,4,[9][10][11] that niridazole selectively inter feres with expressions of cellular as opposed to humoral immunity, in that EAE is known to be an expression of a cell-mediated at tack on the target autoantigen (BPM) in the central nervous system (CNS) [5][6][7]12]. …”

“…On the other hand, Daniels et al [3,4] showed that ser um containing metabolites of niridazole would block production of M IF by sensi tized lymph node cells of guinea pigs when added to this in vitro system, but could not block release of M IF once the process had been initiated [4], We infer therefore that niridazole does not prevent recognition of immunogen, nor processes involved in 'sen sitization', but interferes with events which occur when an activated sensitized T lym phocyte first encounters antigen, which could be the basic protein of myelin in our model disease system.…”

“…In doses which were therapeutic for schistosomiasis, niridazole suppressed cell-mediated immun ity to various antigens in man [13], guinea pigs [3,4] and mice [9,10], and also mark edly prolonged the survival of allogeneic skin grafts in mice [10]. We report here the inhi bitory effect of niridazole on the develop ment of the model autoimmune disease, ex perimental autoimmune encephalomyelitis (EAE), which results from an immune at tack by activated T lymphocytes on myelin of the central nervous system [5][6][7]12].…”

“…Niridazole, which is used in the treat ment of schistosomiasis, has recently been found to be selectively immunosuppressive for the T cell system [3,4,[9][10][11] and has minimal effects on primary and secondary humoral antibody responses [11]. In doses which were therapeutic for schistosomiasis, niridazole suppressed cell-mediated immun ity to various antigens in man [13], guinea pigs [3,4] and mice [9,10], and also mark edly prolonged the survival of allogeneic skin grafts in mice [10].…”

Effect of Phenytoin on the Immune Response in Rabbits

“…Levamisole can also potentiate or suppress the antibody response [12,18], by influencing the phagocytosis [11]. The production of mi gration inhibition factor by T lymphocytes may be reduced, as reported for the similar drug niridazole [3], Both IgM and IgG responses were influ enced by phenytoin, as shown by the results of gel filtration experiments and of aggluti nation of sheep erythrocytes. These results agree with those reported by Aarli and Tonder [1], They found reduced IgA in ser um and saliva of a number of patients treat ed with phenytoin, while IgM and IgG was reduced in a smaller number.…”