Publications (18)74.03 Total impact
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Article: BALB/c mice infected with antimony treatment refractory isolate of Leishmania braziliensis present severe lesions due to IL-4 production.
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ABSTRACT: Leishmania braziliensis is the main causative agent of cutaneous leishmaniasis in Brazil. Protection against infection is related to development of Th1 responses, but the mechanisms that mediate susceptibility are still poorly understood. Murine models have been the most important tools in understanding the immunopathogenesis of L. major infection and have shown that Th2 responses favor parasite survival. In contrast, L. braziliensis-infected mice develop strong Th1 responses and easily resolve the infection, thus making the study of factors affecting susceptibility to this parasite difficult. Here, we describe an experimental model for the evaluation of the mechanisms mediating susceptibility to L. braziliensis infection. BALB/c mice were inoculated with stationary phase promastigotes of L. braziliensis, isolates LTCP393(R) and LTCP15171(S), which are resistant and susceptible to antimony and nitric oxide (NO), respectively. Mice inoculated with LTCP393(R) presented larger lesions that healed more slowly and contained higher parasite loads than lesions caused by LTCP15171(S). Inflammatory infiltrates in the lesions and production of IFN-γ, TNF-α, IL-10 and TGF-β were similar in mice inoculated with either isolate, indicating that these factors did not contribute to the different disease manifestations observed. In contrast, IL-4 production was strongly increased in LTCP393(R)-inoculated animals and also arginase I (Arg I) expression. Moreover, anti-IL-4 monoclonal antibody (mAb) treatment resulted in decreased lesion thickness and parasite burden in animals inoculated with LTCP393(R), but not in those inoculated with LTCP15171(S). We conclude that the ability of L. braziliensis isolates to induce Th2 responses affects the susceptibility to infection with these isolates and contributes to the increased virulence and severity of disease associated with them. Since these data reflect what happens in human infection, this model could be useful to study the pathogenesis of the L. braziliensis infection, as well as to design new strategies of therapeutic intervention.PLoS Neglected Tropical Diseases 01/2011; 5(3):e965. · 4.69 Impact Factor -
Article: Resistance of Leishmania (Viannia) braziliensis to nitric oxide: correlation with antimony therapy and TNF-alpha production.
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ABSTRACT: Nitric oxide (NO) produced in macrophages plays a pivotal role as a leishmanicidal agent. A previous study has demonstrated that 20% of the L. (V.) braziliensis isolated from initial cutaneous lesions of patients from the endemic area of Corte de Pedra, Bahia, Brazil, were NO resistant. Additionally, 5 to 11% of the patients did not respond to three or more antimony treatments" (refractory patients). The aim of this study is to investigate if there is an association between the resistance of L. (V.) braziliensis to NO and nonresponsiveness to antimony therapy and cytokine production. We evaluated the in vitro toxicity of NO against the promastigotes stages of L. (V.) braziliensis isolated from responsive and refractory patients, and the infectivity of the amastigote forms of these isolates against human macrophages. The supernatants from Leishmania infected macrophage were used to measure TNF-alpha and IL-10 levels. Using NaNO2 (pH 5.0) as the NO source, L. (V.) braziliensis isolated from refractory patients were more NO resistant (IC50 = 5.8 +/- 4.8) than L. (V.) braziliensis isolated from responsive patients (IC50 = 2.0 +/- 1.4). Four isolates were selected to infect human macrophages: NO-susceptible and NO-resistant L. (V.) braziliensis isolated from responsive and refractory patients. NO-resistant L. (V.) braziliensis isolated from refractory patients infected more macrophages stimulated with LPS and IFN-gamma at 120 hours than NO-susceptible L. (V.) braziliensis isolated from refractory patients. Also, lower levels of TNF-alpha were detected in supernatants of macrophages infected with NO-resistant L. (V.) braziliensis as compared to macrophages infected with NO-susceptible L. (V.) braziliensis (p < 0.05 at 2, 24 and 120 hours), while no differences were detected in IL-10 levels. These data suggest that NO resistance could be related to the nonresponsiveness to antimony therapy seen in American Tegumentary Leishmaniasis.BMC Infectious Diseases 01/2010; 10:209. · 3.12 Impact Factor -
Article: Cutaneous leishmaniasis during pregnancy: exuberant lesions and potential fetal complications.
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ABSTRACT: Cutaneous leishmaniasis affects millions of people worldwide. After observations of atypical lesions in pregnant women at the health centers of Corte de Pedra, Brazil, 9 years of records were reviewed, and 26 pregnant patients were identified. A retrospective case-control study revealed that lesions in pregnant women were much larger than those in nonpregnant patients in an age- and sex-matched group (mean area, 6.08 cm2 vs. 1.46 cm2; P=.008), and many lesions had an exophytic nature. Despite foregoing treatment until after delivery, response to pentavalent antimony therapy was favorable (rate of cure with 1 course of treatment, 85%). High rates of preterm births (10.5%) and stillbirths (10.5%) were reported. Cutaneous leishmaniasis during pregnancy produces distinct lesions and may have adverse fetal effects.Clinical Infectious Diseases 09/2007; 45(4):478-82. · 9.15 Impact Factor -
Article: Resistance of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis to nitric oxide correlates with disease severity in Tegumentary Leishmaniasis.
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ABSTRACT: Nitric oxide (NO*) plays a pivotal role as a leishmanicidal agent in mouse macrophages. NO* resistant Escherichia coli and Mycobacterium tuberculosis have been associated with a severe outcome of these diseases. In this study we evaluated the in vitro toxicity of nitric oxide for the promastigote stages of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis parasites, and the infectivity of the amastigote stage for human macrophages. Parasites were isolated from patients with cutaneous, mucosal or disseminated leishmaniasis, and NO* resistance was correlated with clinical presentation. Seventeen isolates of L. (L.) amazonensis or L. (V.) braziliensis promastigotes were killed by up to 8 mM of more of NaNO2 (pH 5.0) and therefore were defined as nitric oxide-susceptible. In contrast, eleven isolates that survived exposure to 16 mM NaNO2 were defined as nitric oxide-resistant. Patients infected with nitric oxide-resistant Leishmania had significantly larger lesions than patients infected with nitric oxide-susceptible isolates. Furthermore, nitric oxide-resistant L. (L.) amazonensis and L. (V.) braziliensis multiplied significantly better in human macrophages than nitric oxide-susceptible isolates. These data suggest that nitric oxide-resistance of Leishmania isolates confers a survival benefit for the parasites inside the macrophage, and possibly exacerbates the clinical course of human leishmaniasis.BMC Infectious Diseases 02/2007; 7:7. · 3.12 Impact Factor -
Article: Differential effects of antigens from L. braziliensis isolates from disseminated and cutaneous leishmaniasis on in vitro cytokine production.
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ABSTRACT: Disseminated leishmaniasis is an emerging infectious disease, mostly due to L. braziliensis, which has clinical and histopathological features distinct from cutaneous leishmaniasis. In the current study we evaluated the in vitro production of the cytokines IFN-gamma, TNF-alpha, IL-5 and IL-10 by peripheral blood mononuclear cells (PBMC) from 15 disseminated leishmaniasis and 24 cutaneous leishmaniasis patients upon stimulation with L. braziliensis antigens genotyped as disseminated leishmaniasis or cutaneous leishmaniasis isolates. Regardless of the source of L. braziliensis antigens, PBMC from cutaneous leishmaniasis patients produced significantly higher IFN-gamma than PBMC from disseminated leishmaniasis patients. Levels of TNF-alpha by PBMC from cutaneous leishmaniasis patients were significantly higher than disseminated leishmaniasis patients only when stimulated by genotyped cutaneous leishmaniasis antigens. The levels of IL-5 and IL-10 production by PBMC were very low and similar in PBMCs from both disseminated leishmaniasis and cutaneous leishmaniasis patients. The immune response of each patient evaluated by the two L. braziliensis antigens was assessed in a paired analysis in which we showed that L. braziliensis genotyped as disseminated leishmaniasis isolate was more potent than L. braziliensis genotyped as cutaneous leishmaniasis isolate in triggering IFN-gamma and TNF-alpha production in both diseases and IL-5 only in cutaneous leishmaniasis patients. This study provides evidence that antigens prepared from genotypically distinct strains of L. braziliensis induce different degrees of immune response. It also indicates that both parasite and host play a role in the outcome of L. braziliensis infection.BMC Infectious Diseases 02/2006; 6:75. · 3.12 Impact Factor -
Article: Correlation between cell‐mediated immunity and degree of infection in subjects living in an endemic area of schistosomiasis
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ABSTRACT: Cell-mediated immunity to Schistosoma mansoni antigens, unrelated antigens and mitogens was evaluated in 50 subjects with the same degree of exposure to infection living in an endemic area of schistosomiasis. The degree of infection, assessed by the number of eggs/g of stool, was variable in this population (0-5604), suggesting differences in susceptibility to infection. Absence of lymphoproliferative response was observed in 56% of this group, despite having a response to purified protein derivative of tuberculin (PPD) and tetanus toxoid (TT) antigens and to pokeweed mitogen. The 50 subjects were divided into two groups, according to their degree of infection. The lymphoproliferative responses to schistosomula and adult worm antigens in the group with a low degree of infection (≤400 eggs/g of stool) were higher than the ones documented in patients with a high degree of infection (>400 eggs/g of stool), and these differences were statistically significant (p ≤0.001). An inverse correlation between the lymphocyte proliferation in response to S. mansoni antigens and the degree of infection was also observed (p = 0.02), indicating that subjects with a lower degree of infection have a higher lymphoproliferative response to schistosomula and adult worm antigens. No differences in the lymphocyte reactivity to other antigens (PPD and TT) were detected in these groups. An impairment of interferon-γ in vitro production was observed when the lymphocytes from these subjects were stimulated with S. mansoni adult worm antigen, although they produced gamma interferon in response to phytohemag-glutinin.European Journal of Immunology 12/2005; 23(1):152 - 158. · 5.10 Impact Factor -
Article: Activated inflammatory T cells correlate with lesion size in human cutaneous leishmaniasis.
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ABSTRACT: Leishmaniasis is an important parasitic disease affecting millions worldwide. In attempts to understand the clinical relevance of immunological measurements as determined using flow cytometry, several immunological phenotypes were determined for a group of well defined human leishmaniasis patients and correlated with clinical measurements of the disease (Montenegro skin test (MST) and lesion area). The analysis demonstrated a positive correlation between the MST size and the frequency of ex vivo recent activated CD4(+) T cells. In contrast, higher frequencies of recent activated CD8(+) T cells were correlated with a smaller MST size. Moreover, a positive correlation was observed between the lesion total area and the frequency of activated CD69(+) (ex vivo) and CD40L(+) (cultured with Leishmania soluble antigen (SLA)) T lymphocytes. Finally, larger lesions were also correlated with a higher frequency of SLA specific inflammatory cytokine (IFN-gamma or TNF-alpha) producing lymphocytes. These studies demonstrate that immunological markers are correlated with clinical indicators of human leishmaniasis and serve to better understand the evolution of this important parasitic disease.Immunology Letters 12/2005; 101(2):226-30. · 2.53 Impact Factor -
Article: Successful treatment of refractory cutaneous leishmaniasis with GM-CSF and antimonials.
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ABSTRACT: Therapeutic failure in the treatment of cutaneous leishmaniasis (CL) occurs in 5% of patients infected by Leishmania braziliensis. This study evaluates the use of topically applied granulocyte macrophage colony-stimulating factor (GM-CSF) combined with the standard dose of antimony to treat refractory cases of CL. Five patients who had received three courses or more of antimony were enrolled in an open-label clinical trial. One to 2 mL of the GM-CSF solution (10 mug/mL in 0.9% saline) was reapplied topically, and dressings were changed three times per week for 3 weeks, associated with standard parenteral antimony (20 mg kg(-1) day(-1) for 20 days). All the patients healed their CL ulcers; 3 healed within 50 days (21, 27, and 44 days) and 2 in 118 and 120 days after beginning therapy. There were no side effects. This study shows that combined topically applied GM-CSF and antimony can be effective and well tolerated in the treatment of relapsed CL.The American journal of tropical medicine and hygiene 08/2005; 73(1):79-81. · 2.59 Impact Factor -
Article: Antimony plus recombinant human granulocyte-macrophage colony-stimulating factor applied topically in low doses enhances healing of cutaneous Leishmaniasis ulcers: a randomized, double-blind, placebo-controlled study.
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ABSTRACT: Cutaneous leishmaniasis (CL) requires 2-6 months to heal. In an effort to reduce this healing time, we studied topically applied granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to antimonial therapy. Ten patients received antimony plus topical GM-CSF, and 10 patients received antimony plus placebo (saline). GM-CSF was diluted for topical use and was applied 3 times weekly for 3 weeks (1-2 microg/cm2/lesion). The mean +/- SD healing time was 43 +/- 14 days in the GM-CSF group and was 104+/-79 days in the placebo group (P=.043). Ten (100%) of 10 patients in the GM-CSF group healed within 60 days, compared with 5 (50%) of 10 patients in the placebo group. Two of the patients in the placebo group required retreatment with antimony. In conclusion, topically applied GM-CSF is effective in the management of CL.The Journal of Infectious Diseases 12/2004; 190(10):1793-6. · 6.41 Impact Factor -
Article: Adhesion molecule expression patterns indicate activation and recruitment of CD4+ T cells from the lymph node to the peripheral blood of early cutaneous leishmaniasis patients.
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ABSTRACT: Adhesion molecules play a crucial role in cell migration and recruitment. Expression of adhesion molecules that preferentially address cells to inflammatory sites is a critical event in the formation and maintenance of leishmaniasis lesions. In this work, we analyzed the expression of CD11a, CD11b and CD62L, adhesion molecules involved in cell activation and circulation, in CD4+ and CD8+ T cells from peripheral blood and lymph nodes of patients with early cutaneous leishmaniasis. The percentage of expression of CD62L, CD11a and CD11b in total lymphocytes was lower in lymph nodes as compared to peripheral blood. Moreover, differences in adhesion molecule expression between blood and lymph nodes were more striking in CD4+ than CD8+ T cells. Stimulation of PBMC from leishmaniasis patients with soluble Leishmania antigens (SLA) lead to the expansion of CD4+CD62Lhigh cells, CD4+CD11b+ cells and to an increase in the intensity of expression of CD11a in CD4+, but not CD8+ T cells. Our data suggest that early activation events that occur in the lymph nodes of patients recently infected with Leishmania lead to changes in T cell adhesion molecule expression, favoring migration to the periphery and increasing the likelihood of further recruitment to lesion sites.Immunology Letters 01/2004; 90(2-3):155-9. · 2.53 Impact Factor -
Article: Disseminated leishmaniasis: a new and emerging form of leishmaniasis observed in northeastern Brazil.
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ABSTRACT: During the past decade, there has been an increase in the number of patients with disseminated leishmaniasis (DL), which is characterized by a large number of acneiform and papular skin lesions, with very few or no parasites in the skin tissue. The present report describes 42 cases of DL identified between 1992 and 1998 in an area where Leishmania braziliensis transmission is endemic; 8 of the patients were prospectively diagnosed. In a contrast to localized cutaneous leishmaniasis (LCL), acquisition of DL was associated with age >19 years (P<.05), male sex (P<.05), and agricultural occupation (P<.001). Patients with DL presented with 10-300 lesions that were a mixture of acneiform, papular, nodular, and ulcerated types. Twelve (29%) of 42 patients had mucosal involvement. Patients with DL had lower levels of interferon-gamma (P<.05) and tumor necrosis factor-alpha (P<.05) production, compared with patients with LCL. DL is an emerging clinical distinct form of leishmaniasis associated with agricultural activities and host immunological response.The Journal of Infectious Diseases 12/2002; 186(12):1829-34. · 6.41 Impact Factor -
Article: Failure of early treatment of cutaneous leishmaniasis in preventing the development of an ulcer.
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ABSTRACT: The clinical characteristics and treatment outcome were determined for 26 patients who presented with early-stage cutaneous leishmaniasis. Illness duration ranged from 8 to 20 days, and the commonest clinical presentation was the presence of a papule with small central crust on a lower extremity. Prominent regional adenopathy was found in 22 (85%) of 26 patients. The results of an intradermal skin test for Leishmania were positive for 96% of those patients, and results of serologic testing were positive for 61% of patients tested. Ten (46%) of 22 patients for whom follow-up data were available developed enlargement and ulceration of the lesion despite early antimony therapy and required additional courses of treatment. Histopathological studies of samples from the lesions of 3 patients showed vasculitis. These data show that early therapy for cutaneous leishmaniasis does not prevent the development of an ulcer in one-half of patients. This unfavorable outcome underlines the relevance of local exacerbated inflammatory and immune response in the pathogenesis of the disease.Clinical Infectious Diseases 07/2002; 34(12):E69-73. · 9.15 Impact Factor -
Article: Epidemiologic and immunologic findings for the subclinical form of Leishmania braziliensis infection.
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ABSTRACT: The epidemiologic and immunologic findings for 104 subjects with subclinical Leishmania braziliensis infection were compared with those for 29 patients with cutaneous leishmaniasis (CL) from the same area of endemicity. Subjects had a positive leishmania skin test result and remained asymptomatic during the next 4 years of follow-up were considered to have subclinical infection. Patients with CL were younger, had larger-diameter indurations after skin testing, and were more likely to have positive serologic markers than were those with subclinical infection (P<.05). In subjects with subclinical infection, levels of interferon-gamma and tumor necrosis factor-alpha in lymphocyte supernatants were lower than they were in patients with CL (P<.05); however, mean interleukin-5 levels were slightly higher in patients with subclinical infection than in patients with CL. These data indicate that, unlike patients with CL, individuals who do not develop disease when infected with L. braziliensis may have the ability to modulate their immune response.Clinical Infectious Diseases 06/2002; 34(11):E54-8. · 9.15 Impact Factor -
Article: Immune responses to an inactive vaccine against American cutaneous leishmaniasis together with granulocyte-macrophage colony-stimulating factor.
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ABSTRACT: The immunological response in healthy subjects to a crude leishmania antigen vaccine (Leishvacin) plus rhGM-CSF without prior Montenegro (DTH) skin testing was evaluated. Fifty-six healthy volunteers received vaccine plus either placebo or rhGM-CSF at day 0, followed by either a vaccine booster or placebo at day 21. IFN-gamma and IL-5 levels were significantly enhanced by day 21. The adjuvant group had a higher percentage of individuals with a significant response to vaccination than the corresponding placebo group. Eighty-six percent of all volunteers were DTH-positive by day 42. Leishvacin is capable of sensitizing lymphocytes from individuals not previously exposed to leishmania antigen. Use of rhGM-CSF enhanced the immune response, indicating that it may improve immunological response to the vaccine.Vaccine 02/2002; 20(9-10):1365-8. · 3.77 Impact Factor -
Article: Immunoglobulin E antileishmanial antibody response in cutaneous leishmaniasis.
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ABSTRACT: High levels of antileishmanial immunoglobulin E (IgE) antibodies are associated with disease activity in visceral leishmaniasis. Herein, we report our observations about the relationship between antileishmanial IgE antibodies and clinical aspects of cutaneous leishmaniasis. This study was carried out with 45 patients (29 male and 16 female), with ages ranging from 11 to 48 years. All subjects were from an area to which leishmaniasis is endemic, Corte de Pedra (Bahia, Brazil), and the duration of the illness was </=30 days. The patients were classified as positive or negative for IgE serology in enzyme-linked immunosorbent assay with leishmanial antigens. IgE antibodies were detected in 18 patients (optical density, 0.421 +/- 0.30; 95% confidence interval, 0.27 to 0.57), and only 3 (17%) had more than one ulcer. In this group the diameter of Montenegro's reaction was 18 +/- 12.2 mm. In the group with negative IgE serology, 11 of 27 patients (48%) presented two or more cutaneous ulcers, and the mean of the skin test result was 9 +/- 6.9 mm. There was a positive correlation between IgE antibody levels and Montenegro's reaction size and an inverse correlation between IgE antileishmanial antibodies and the number of skin ulcers. The presence of antileishmanial IgE antibodies in cutaneous leishmaniasis may be a result of immunoregulatory events with clinical implications.Clinical and Diagnostic Laboratory Immunology 01/2002; 9(1):101-4. · 2.51 Impact Factor -
Article: Evaluation of IFN-gamma and TNF-alpha as immunological markers of clinical outcome in cutaneous leishmaniasis.
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ABSTRACT: To evaluate if IFN-gamma and TNF-alpha levels could be used as markers of therapeutic response in cutaneous leishmaniasis, 54 patients with history of one ulcerated cutaneous lesion, with up to 30 days onset, were enrolled in the study. IFN-gamma and TNF-alpha were measured by ELISA in lymphocyte cultures supernatant before and 60 days after initiating therapy. Cure was considered to be a complete healing of lesion 60 days after treatment. IFN-gamma and TNF-alpha levels were similar in both groups of patients before therapy. There was a tendency to increase IFN-gamma levels in patients that were cured in 60 days, however the values did not reach statistical significance. In both groups of patients, TNF-alpha levels were similar before therapy and fell significantly after treatment, irrespective of cure or maintenance of active lesion.Revista da Sociedade Brasileira de Medicina Tropical 35(1):7-10. · 0.68 Impact Factor -
Article: Adhesion molecule expression patterns indicate activation and recruitment of CD4+ T cells from the lymph node to the peripheral blood of early cutaneous leishmaniasis patients
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ABSTRACT: Adhesion molecules play a crucial role in cell migration and recruitment. Expression of adhesion molecules that preferentially address cells to inflammatory sites is a critical event in the formation and maintenance of leishmaniasis lesions. In this work, we analyzed the expression of CD11a, CD11b and CD62L, adhesion molecules involved in cell activation and circulation, in CD4+ and CD8+ T cells from peripheral blood and lymph nodes of patients with early cutaneous leishmaniasis. The percentage of expression of CD62L, CD11a and CD11b in total lymphocytes was lower in lymph nodes as compared to peripheral blood. Moreover, differences in adhesion molecule expression between blood and lymph nodes were more striking in CD4+ than CD8+ T cells. Stimulation of PBMC from leishmaniasis patients with soluble Leishmania antigens (SLA) lead to the expansion of CD4+CD62Lhigh cells, CD4+CD11b+ cells and to an increase in the intensity of expression of CD11a in CD4+, but not CD8+ T cells. Our data suggest that early activation events that occur in the lymph nodes of patients recently infected with Leishmania lead to changes in T cell adhesion molecule expression, favoring migration to the periphery and increasing the likelihood of further recruitment to lesion sites.Immunology Letters. -
Article: Differential effects of antigens from L. braziliensis isolates from disseminated and cutaneous leishmaniasis on in vitro cytokine production
Top co-authors
Top Journals
Institutions
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2006–2010
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Universidade Federal de Sergipe
- Departamento de Fisiologia
São Cristóvão, Estado de Sergipe, Brazil
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2007
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Weill Cornell Medical College
New York City, NY, USA
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2002–2007
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Universidade Federal da Bahia
Salvador, Estado da Bahia, Brazil -
Complexo Hospitar Universitário Prof. Edgard Santos (HUPES)
Salvador, Estado da Bahia, Brazil -
Cornell University
New York City, NY, USA
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