Effects of clofazimine alone or combined with dapsone on neutrophil and lymphocyte functions in normal individuals and patients with lepromatous leprosy

Abstract

The effects of clofazimine on neutrophil activities such as random motility, migration to the leukoattractants endotoxin-activated serum and N-formyl-Lmethionyl-L-leucyl-L-phenylalanine phagocytosis of Candida albicans, postphagocytic hexose-monophosphate shunt activity, and myeloperoxidase-mediated iodination and the effects of clofazimine on lymphocyte transformation to mitogens were assessed in vitro and after ingestion of the drug by normal individuals and patients with lepromatous leprosy. For in vitro studies, the concentration range of the drug investigated was 10-6 M to 10-2 M. For in vivo studies, subjects ingested 200 mg of clofazimine daily for a period of 5 days. At concentrations of 5 x 10-6 M to 5 x 10-3 M clofazimine caused a progressive dose-dependent inhibition of neutrophil motility without detectable effects on phagocytosis, postphagocytic hexose-monophosphate shunt activity, or myeloperoxidase-mediated iodination. Over the same concentration range, clofazimine inhibited lymphocyte transformation. The inhibitory effect on neutrophil motility was associated with a spontaneous stimulation of oxidative metabolism and could be prevented by coincubation of dapsone with clofazimine. After ingestion of clofazimine responsiveness of lymphocytes to mitogens was decreased in normal volunteers and leprosy patients; neutrophil motility in normal individuals was likewise inhibited.Clofazimine (5), also known as B663 or Lamprene, is an extensively used anti-leprosy drug. Apart from its anti-mycobacterial activity, clofazimine has also been reported to possess antiinflammatory activity (17). This property enhances the value of clofazimine in leprosy, since it may also be used to control adverse immunological reactions. In this study, we have investigated the effects of clofazimine in vitro and in vivo on the motility, phagocytosis, and postphagocytic metabolic activities of neutrophils and transformation to mitogens of lymphocytes from normal individuals and patients with lepromatous leprosy. The effects of combinations of clofazimine and dapsone on the motility of neutrophils from patients with leprosy have also been investigated.MATERIALS AND METHODS Chemotherapeutic agents. Clofazimine in 100-mg capsules of pure drug was obtained from Ciba-Geigy, Johannesburg. For in vitro studies, the drug was solubilized in dimethyl sulfoxide (DMSO) to give a concentration range of 106 M to 10-3 M (equivalent to 0.3 to 300 j.Lg/ml) in Hanks balanced salt solution (HBSS) for studies of motility, 0.15 M phosphatebuffered saline for phagocytic studies and TC199 for lymphocyte studies. Both HBSS and TC199 were obtained from GIBCO Laboratories, Grand Island, N.Y. Control systems were included for each clofazimine concentration investigated, and these contained the corresponding DMSO concentrations: 0.0015 to 1.5% DMSO for 10-6 M to 10-3 M clofazimine.

Limited Activity of Clofazimine as a Single Drug in a Mouse Model of Tuberculosis Exhibiting Caseous Necrotic Granulomas

“…CFZ also possesses anti-inflammatory effects, such as inhibition of neutrophil motility and activation of phospholipase A 2 in neutrophils, leading to the production of prostaglandin E 2 and other anti-inflammatory mediators (32)(33)(34). In addition to its effect upon neutrophils, CFZ also inhibits the lymphocyte proliferative response to mitogens, which may be related to its binding to the Kv1.3 potassium channel and perturbation of calcium oscillations required for optimal T cell receptor signaling and T cell proliferation (34,35). In order to ensure that the altered immune status of the Kramnik mouse model was not responsible for the lack of activity of CFZ, we evaluated the drug in the GKO mouse model.…”

Enhancement by clofazimine and inhibition by dapsone of production of prostaglandin E2 by human polymorphonuclear leukocytes in vitro

“…Direct and indirect enhancement of cell-mediated immunity by dapsone may lead to the development of reversal immunity reactions (2). Clofazimine inhibits lymphocyte proliferation (8,18) and may be useful in controlling reversal immunity reactions (13,17). We have suggested previously that the anti-inflammatory, immunosuppressive properties of clofazimine and the nonspecific immunostimulatory effects of dapsone are related to the respective proand anti-oxidant activities of these agents (2,18).…”

“…Dapsone, on the other hand, possesses both antimicrobial and nonspecific immunostimulatory properties and this agent is likely to precipitate or exacerbate ENL reactions (10,20). The opposite effects of clofazimine and dapsone on ENL reactions are probably related to inhibition and potentiation, respectively, by these agents of polymorphonuclear leukocyte (PMNL) migration and lymphocyte proliferation (2,18).…”

Prooxidative activities of 10 phenazine derivatives relative to that of clofazimine

“…The reactive oxidant hydrogen peroxide is produced during the respiratory burst of polymorphonuclear leukocytes (PMN) as a result of superoxide dismutation (11). Various antibiotics have been shown to increase the release of reactive oxidants from PMN (10), including the antileprosy drug clofazimine (B663) (20). Clofazimine is a phenazine derivative (2-5) which apart from its antimycobacterial activity also possesses immunosuppressive properties (15,21).…”