Modulation of T cell responses in HTLV-1 carriers and in patients with myelopathy associated with HTLV-1.

OBJECTIVE: Human T lymphotropic virus-type 1 (HTLV-1) activates the immune system leading to a persistent and exacerbated T-cell response with increased production of IFN-gamma and TNF-alpha. Overproduction of pro-inflammatory cytokines is correlated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), although some HTLV-1 carriers also show high levels of these cytokines. In this study, the ability of regulatory cytokines and cytokine antagonists to inhibit spontaneous IFN-gamma production was investigated. METHOD: IFN-gamma levels were measured by ELISA before and after addition of cytokines or anti-cytokines. RESULTS: Addition of IL-10 significantly reduced spontaneous IFN-gamma synthesis in cell cultures from HTLV-1 carriers, while no differences were observed in HAM/TSP patients. There was also a tendency to decreased IFN-gamma levels in cell cultures from HTLV-1 carriers with exogenous addition of TGF-beta. In paired analysis, neutralization of IL-2 significantly decreased IFN-gamma production in HTLV-1 carriers but not in HAM/TSP patients. Neutralization of IL-15 was less effective than neutralization of IL-2 in modulating IFN-gamma production. In HTLV-1 carriers, anti-IL-2 and simultaneous addition of anti-IL-2 and anti-IL-15 decreased IFN-gamma synthesis by 46 and 64%, respectively, whereas in patients with HAM/TSP simultaneous neutralization of both anti-cytokines only decrease IFN-gamma levels by 27%. CONCLUSIONS: Although a large proportion of HTLV-1 carriers produced high levels of pro-inflammatory cytokines similar to those observed in HAM/TSP patients, immune response can be downregulated by cytokines or cytokine antagonists in most HTLV-1 carriers. This modulation can be an important step in the prevention of tissue damage and progression from the HTLV-1 carrier state to HAM/TSP.

Spontaneous neutrophil activation in HTLV-1 infected patients

Human T cell lymphotropic Virus type-1 (HTLV-1) induces lymphocyte activation and proliferation, but little is known about the innate immune response due to HTLV-1 infection. We evaluated the percentage of neutrophils that metabolize Nitroblue tetrazolium (NBT) to formazan in HTLV-1 infected subjects and the association between neutrophil activation and IFN-gamma and TNF-alpha levels. Blood was collected from 35 HTLV-1 carriers, from 8 patients with HAM/TSP (HTLV-1- associated myelopathy); 22 healthy individuals were evaluated for spontaneous and lipopolysaccharide (LPS)-stimulated neutrophil activity (reduction of NBT to formazan). The production of IFN-gamma and TNF-alpha by unstimulated mononuclear cells was determined by ELISA. Spontaneous NBT levels, as well as spontaneous IFN-gamma and TNF-alpha production, were significantly higher (p<0.001) in HTLV-1 infected subjects than in healthy individuals. A trend towards a positive correlation was noted, with increasing percentage of NBT positive neutrophils and levels of IFN-gamma. The high IFN-gamma producing HTLV-1 patient group had significantly greater NBT than healthy controls, 43±24 percent and 17±4.8 percent respectively (p< 0.001), while no significant difference was observed between healthy controls and the low IFN-gamma-producing HTLV-1 patient group (30±20 percent). Spontaneous neutrophil activation is another marker of immune perturbation resulting from HTLV-1 infection. In vivo activation of neutrophils observed in HTLV-1 infected subjects is likely to be the same process that causes spontaneous IFN-gamma production, or it may partially result from direct IFN-gamma stimulation.

Spontaneous neutrophil activation in HTLV-1 infected patients.

Human T cell lymphotropic Virus type-1 (HTLV-1) induces lymphocyte activation and proliferation, but little is known about the innate immune response due to HTLV-1 infection. We evaluated the percentage of neutrophils that metabolize Nitroblue tetrazolium (NBT) to formazan in HTLV-1 infected subjects and the association between neutrophil activation and IFN-gamma and TNF-alpha levels. Blood was collected from 35 HTLV-1 carriers, from 8 patients with HAM/TSP (HTLV-1- associated myelopathy); 22 healthy individuals were evaluated for spontaneous and lipopolysaccharide (LPS)-stimulated neutrophil activity (reduction of NBT to formazan). The production of IFN-gamma and TNF-alpha by unstimulated mononuclear cells was determined by ELISA. Spontaneous NBT levels, as well as spontaneous IFN-gamma and TNF-alpha production, were significantly higher (p<0.001) in HTLV-1 infected subjects than in healthy individuals. A trend towards a positive correlation was noted, with increasing percentage of NBT positive neutrophils and levels of IFN-gamma. The high IFN-gamma producing HTLV-1 patient group had significantly greater NBT than healthy controls, 43+/-24% and 17+/-4.8% respectively (p< 0.001), while no significant difference was observed between healthy controls and the low IFN-gamma-producing HTLV-1 patient group (30+/-20%). Spontaneous neutrophil activation is another marker of immune perturbation resulting from HTLV-1 infection. In vivo activation of neutrophils observed in HTLV-1 infected subjects is likely to be the same process that causes spontaneous IFN-gamma production, or it may partially result from direct IFN-gamma stimulation.

Infecçäo bacteriana em pacientes portadores de Leishmaniase visceral / Bacterial infection in patients with visceral leishmaniasis

Uma análise retrospectiva de 63 casos de Leishmaniose visceral (L.V.) revelou a presença, em 33 deles, de infecçäo bacteriana associada. Infecçöes do trato respiratório foram observadas em 13 (39,3%) pacientes, comprometimento de pele em 4 (12%), do trato urinário em 4 (12%), do ouvido em 3 (9%), e de orofaringe em 2 (6%). Sete (21%) pacientes apresentaram infecçäo concomitante em múltiplos sítios. Documentaçäo bacteriológica através de isolamneto do agente etiológico foi obtida em 10, näo havendo predominância estatisticamente significante de bactérias Gram positivas ou negativas. Houve 9 casos de óbito nestes 63 pacientes, sendo que em 8 deles a infecçäo bacteriana fazia parte do quadro clínico final. A análise das taxas de globulinas séricas revelou que infecçäo esteve presente de modo significativo (p < 0.05) em 15/20 (75%) dos pacientes com níveis de globulina sérica <- 4,0g%. Näo houve diferença significativa (p > 0.05) com relaçäo ao número de neutrófilos entre os grupos com e sem infecçäo bacteriana. Concluiu-se, portanto, que infecçäo bacteriana é um achado freqüente em pacientes com L.V. e se constitui num sinal de mau prognóstico da doença