Therapeutic approaches for tumor necrosis factor inhibition

Tumor necrosis factor (TNF) consists of an inflammatory cytokine essential for homeostasis and organism defense. Despite its physiological relevance, both increased biosynthesis and release of TNF lead to the exacerbation of inflammatory and oxidative responses, which are related to the pathogenesis of a host of diseases of an inflammatory, autoimmune and/or infectious nature. In this context, effective therapeutic approaches for the modulation of TNF have been the focus of research efforts. Approximately one million individuals worldwide have been treated with biotechnological inhibitors of this cytokine, the so-called anti-TNF biopharmaceuticals. However, given the high risk of infection and the limitations related to cost and administration routes, new therapeutic approaches aimed at biological targets that directly or indirectly modulate the production and/or activation of TNF appear promising alternatives for the discovery of new anti-inflammatory and immunomodulatory orally active drugs and are therefore discussed in this paper.

O fator de necrose tumoral (do inglês, tumor necrosis factor - TNF) consiste em uma citocina inflamatória essencial para a homeostase e defesa do organismo. A despeito de sua relevância fisiológica, o aumento da biossíntese e liberação do TNF conduzem à exacerbação das respostas inflamatória e oxidativa, as quais estão relacionadas à patogênese de várias doenças de natureza inflamatória, auto-imune e/ou infecciosa. A busca por abordagens terapêuticas eficientes na modulação do TNF tem sido alvo de diversos esforços de pesquisa. Aproximadamente um milhão de pessoas ao redor do mundo já foi tratado com inibidores biotecnológicos desta citocina, os chamados biofármacos anti-TNF. Entretanto, em face ao elevado risco de infecções e as limitações relacionadas ao custo e a via de administração, novas abordagens terapêuticas com foco em alvos que modulem, de forma direta ou indireta, a produção e/ou ativação do TNF surgem como alternativas promissoras para a descoberta de novos fármacos antiinflamatórios e imunomoduladores ativos por via oral e serão discutidas neste trabalho.

[Rate of production of inflammatory cytokines TNF and IL- by peripheral blood mononuclear cells stimulated with mycolactone]

Mycobacterium ulcerans is the etiological agent of Buruli ulcer [BU]; the third most common mycobacterial infection in humans after tuberculosis and leprosy. BU is now considered by the WHO to be an emerging infection of major concern. M. ulcerans produces mycolactone toxin, which is required for the organism's virulence. Mycolactone destroys tissue and suppresses host immune responses. In this descriptive analytical study, peripheral blood mononuclear cells from three volunteers with no history of buruli ulcer were used. IL-6 and TNF produced by these cells at different preincubation times with LPS and mycolactone were measured by using ELISA kits. This study showed hyper inhibition of IL-6 and TNF production by mycolactone. TNF levels in the control tubes [containing LPS] in 4hours reached its maximum value and then decreased. While the production of IL-6 in the tube with fresh cells [zero time] had the highest value, after 16hours, it reached its minimum. Since TNF and IL-6 are important immunity inflammatory cytokines, it can be well imagined that decrease of TNF production by this bacterium plays a role in weakening of inflammatory response. So Mycobacterium ulcerans destroys macrophages and at the same time prevents TNF production by important cells in innate immune mechanism

Haematological changes in falciparum malaria and tumor necrosis factor

Tumor necrosis factor and various haematological parameters were studied in 90 patients suffering from falciparum malaria. They were divided into three groups on the basis of haemoglobin level. The difference in haemoglobin level between group-1 [Hb<7 gm/dl] and group-2 [Hb 7-10 gm/dl], as well as group-I and group-3 was statistically significant. The geometric mean TNFalpha concentrations in group-1 [193.9 pg/ml] and group-2 [132.2 pg/mI] were higher as compared to group-3; however, the difference was statistically non-significant. The TNF concentration in group-2 correlated negatively with haemoglobin level [r=-.43, p=.05]. As a whole, 21% patients had leukocytosis, 3% leukopenia, 46% increased ESR and 26% elevated levels of fibrin degradation products. The platelet count was done only in 4 patients with bleeding problems. Twenty-five healthy subjects were included in the study as controls. The difference between TNF and haemoglobin level in group-1 and controls was statistically significant [p<.05, p<.001 each]. The role of tumor necrosis factor in the production of these changes is discussed