RESUMO
La epidemia por el virus Ébola, en África occidental (2014), ha suscitado una serie de interrogantes éticos en torno a las medidas de salud pública para su contención, el uso de medicamentos experimentales y el desarrollo de vacunas contra esta enfermedad. El presente trabajo explora algunas de estas preguntas desde la perspectiva de la ética en investigación biomédica. La epidemia por el virus Ébola es un modelo de estudio adecuado para abordar esfuerzos multilaterales en investigación, así como para analizar aspectos antropológicos en salud pública y determinantes sociales, económicos y políticos en salud a nivel global.
The Ebola virus epidemic in West Africa (2014) has raised some ethical questions surrounding public health measures for its containment, the use of experimental drugs and the development of vaccines against this disease. This paper explores some of these issues from the perspective of ethics in biomedical research. Ebola virus epidemic is a suitable study model to address multilateral efforts in research as well as to analyze anthropological aspects of public health and social, economic and political determinants of global health.
A epidemia pelo vírus Ebola, na África Ocidental (2014), tem levantado uma série de questões éticas em torno às medidas de saúde pública para a sua contenção, o uso de medicamentos experimentais e o desenvolvimento de vacinas contra esta doença. Este artigo explora algumas destas questões a partir da perspectiva da ética na pesquisa biomédica. A epidemia pelo vírus Ebola é um modelo de estudo adequado para abordar esforços multilaterais em pesquisa, como também para analisar aspectos antropológicos em saúde pública e determinantes sociais, econômicos e políticos em saúde a nível global.
RESUMO
We examined the effect of Salmonella typhi (wild-type Ty2 and mutant strain TYT1231)-infected U937 cells on natural killer cell (NKC) cytotoxicity of peripheral blood mononuclear cells (PBMCs) and highly purified NKC (HPNKCs; CD16(+)/CD56(+) > 95%; the rest corresponding to CD3(+) T cells). We also analyzed the possible role of various protein kinases involved in natural cytotoxicity on these processes. PBMC cytotoxicity against S typhi-infected U937 cells was significantly higher (paired Student t test; P < 0.05) than its lytic effect against noninfected cells (control) at the various effector-to-target cell ratios used (30:1 [24.4 +/- 9.7, 25.1 +/- 11.8, and 17.5 +/- 8.6]; 50:1 [26.6 +/- 9.7, 26.7 +/- 12.8, and 21.2 +/- 7.5] and 70:1 [32.4 +/- 14.4, 30.1 +/- 12.4, and 23.1 +/- 7.2], respectively). PBMC NKC activity seemed to be dependent on such ratios and was similar against both Salmonella strains studied. Approximately half of the individual samples tested (n = 12; 8 male and 4 female subjects of comparable age) showed at least a 20% specific lysis increase against their own control; essentially no changes or smaller increases in NKC activity were observed in all other samples. Similar results were obtained using HPNKCs as effector cells (5:1 ratio [38.9 +/- 12.3, 43.3 +/- 11.2, and 27.5 +/- 4.9] and 10:1 ratio [51.3 +/- 9.1, 46.1 +/- 9.8, and 37.7 +/- 15.5, respectively]). In general, specimens significantly lysed after incubation with PBMCs responded in a similar manner to a challenge with HPNKCs. PBMC and HPNKC cytotoxicity against S typhi wild-type-infected U937 cells was significantly decreased in a dose-dependent manner by the addition of genistein (50-200 micromol) or GFX (0.5-2.0 micromol) to the cytotoxicity assay mixture. NKC activity was almost completely inhibited at the highest genistein and GFX concentrations. In similar experiments, wortmannin (100-500 nmol) failed to inhibit PBMC cytotoxicity and significantly decreased HPNKC activity only at the highest concentration tested. These results show that in the process of NKC recognition and lysis of S typhi-infected U937 cells, there is not a requisite for full bacterial intracellular survival capacity and that S typhi-infected U937 cells are a significantly better target than noninfected U937 cells. NKC signaling pathways activated during the S typhi-infected U937 cell recognition and lysis process are mainly protein tyrosine kinase and protein kinase-C, and they can be blocked by the same protein kinase inhibitors known to inhibit natural cytotoxicity.
Assuntos
Proteínas de Transporte/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Salmonella typhi/efeitos dos fármacos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Salmonella typhi/imunologia , Células U937RESUMO
Peripheral blood mononuclear cell (PBMC) cytotoxicity against S. typhi (wild type or mutant strain TYT1231)-infected U937 cells was significantly higher than its lytic effect against noninfected cells (control) at the various effector-to-target cell ratio used (30:1, 50:1 and 70:1). Natural killer cell activity [expressed as % specific lysis (mean +/- SEM); 30:1 (25.4 +/- 3.6, 25.1 +/- 4.2 and 16.3 +/- 3.3); 50:1 (27.8 +/- 3.7, 26.7 +/- 4.5 and 20.9 +/- 2.9) and 70:1 ratio (33.2 +/- 5.9, 29.4 +/- 4.2 and 22.8 +/- 2.8), respectively] appeared to be dependent on such ratios and independent of the S strain studied. Most (80%) of individual samples tested showed at least a 20% specific lysis increase over their own control; essentially no changes or smaller increases in NKC activity were observed in all other samples. Similar results were obtained when using highly purified NKC (HPNKC) preparations as effector cells [NKC activity (mean +/- SEM); 5:1 (46.2 +/- 4.7, 43.2 +/- 5.0 and 25.2 +/- 2.3) and 10:1 effector-to-target cell ratio (49.3 +/- 4.9, 44.7 +/- 5.2 and 27.2 +/- 2.6, respectively)]. All individual samples tested showed at least a 20% specific lysis increase over their own control. These results show that S. typhi-infected U937 cells are a significantly better target for NKCs than control cells and indicate that intracellular bacteria survival capacity is not a critical factor for infected cells becoming a NKC target.