Efeito de derivados antraquinônicos análogos da mitoxantrona na modulação da resposta imune: modelo de encefalomielite autoimune experimental e de alergia pulmonar

Abstract

Mitoxantrone is an antineoplasic agent of the anthracenedione family, capable of reduce T cell numbers, suppress humoral immunity and in vivo activate suppressor T cells. Multiple Sclerosis (MS) affects about one million people worldwide, is characterized by an autoimmune chronic inflammatory demyelinating disease of the central nervous system, and, in most cases, severe and disabling. Moreover, the current therapy for MS has often unsatisfactory effects, being still ineffective in relation to its healing and full recovery of patients in advanced stages. Asthma is a chronic inflammatory disease of the airways that affects approximately 300 million people worldwide. Currently, the treatment of asthma is intended to control the disease and the drugs used show systemic side effects that are generally observed with the use of high doses for long time. In this context, this study aimed to evaluate the effect of a series of anthraquinone derivatives, analogs of mitoxantrone, in the modulation of in vitro response of murine macrophages activated with lipopolysaccharide and IFN-g, and check the action in the modulation of the in vivo immune response of experimental autoimmune encephalomyelitis (EAE) and pulmonary allergy (PA). In the in vitro stage was evaluated the cytotoxicity of the compounds and the levels of nitric oxide produced. In the in vivo stage, the O,O’-bis-(3’-iodopropyl)-1,4-dihidroxyanthraquinone (CS56) derivative was investigated in the evolution of EAE induced in C57Bl/6 mice by applying MOG35-55, and in the modulation of PA and PA exacerbation by Rhinovirus, induced in BALB/c mice by inhalation of dust allergens. The results showed that the structural modifications performed on the anthraquinone derivatives produced less cytotoxic analogs with high ability to inhibit the NO concentration. The data obtained in vivo indicate that treatment of EAE with CS56 improves the clinical score of disease and this may be correlated with a reduction in the release of inflammatory cytokines and chemokines involved in the increase of cells in the central nervous system. The results of PA model demonstrate that treatment with CS56 improves respiratory mice by reducing the parameters of pulmonary allergy, such as bronchial hyperresponsiveness, mucus hypersecretion and infiltration of eosinophils. Thus, the data suggest an immunomodulatory role of the derivative in EAE and PA with potential therapeutic applicability for asthma and multiple sclerosis.