Olı́via Bacellar

Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais

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Edgar M. Carvalho

Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais

Lucas P. Carvalho

Universidade Federal da Bahia

Paulo Roberto Lima Machado

Universidade Federal da Bahia

Luiz Henrique Guimarães

Universidade Federal da Bahia

Roque Pacheco de Almeida

Universidade Federal de Sergipe

Ednaldo Lago

Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais

Albert Schriefer

Universidade Federal da Bahia

Amélia Ribeiro de Jesus

Universidade Federal de Sergipe

Pedro Paulo Carneiro

Universidade Federal da Bahia

Thiago M. Cardoso

Fundação Oswaldo Cruz

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Universidade Federal da Bahia

116

Complexo Hospitalar Universitário Professor Edgard Santos

Fundação Oswaldo Cruz

Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais

Hospital Ana Nery

National Council for Scientific and Technological Development

Universidade Federal de Minas Gerais

Universidade de São Paulo

Cornell University

Brazilian Society of Tropical Medicine

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Immunologic response and memory T cells in subjects cured of tegumentary leishmaniasis

BMC Infectious Diseases (2013)

Augusto M. Carvalho Andréa Magalhães Lucas P. Carvalho Olı́via Bacellar Phillip Scott

The main clinical forms of tegumentary leishmaniasis are cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML). L.braziliensis infection is characterized by an exaggerated production of IFN-gamma and TNF-alpha, cytokines involved in parasite destruction, but also in the pathology. Maintenance of an antigen-specific immune response may be important for resistance to re-infection and will contribute for vaccine development. In the present work we investigated the immune response in CL and ML cured individuals. Participants in the present study included 20 CL and 20 ML patients, who were evaluated prior to, as well as 2 to 15 years after therapy. IFN-gamma, IL-2 and TNF-alpha production were determined by ELISA in supernatants of mononuclear cells stimulated with soluble L.braziliensis antigen (SLA). The frequency of memory CD4+ T cell populations was determined by FACS. Here we show that the majority of CL and ML patients did not produce in vitro IFN-gamma in response to SLA after cure. In the cured individuals who responded to SLA, effector memory (CD45RA-CCR7-) CD4+ T cells were the ones producing IFN-gamma. Because a large percent of CL and ML cured patients lost SLA-induced IFN-gamma production in peripheral blood, we performed Leishmania skin test (LST). A positive LST was found in 87.5% and 100% of CL and ML cured individuals, respectively, who did not produce IFN-gamma or IL-2 in vitro. This study shows that in spite of losing in vitro antigen-specific response to Leishmania, cured CL and ML subjects retain the ability to respond to SLA in vivo. These findings indicate that LST, rather than IFN-gamma production, may be a better assessment of lasting immunity to leishmaniasis in human studies, and thus a better tool for assessing immunization after vaccine. Furthermore, in cured individuals which maintains Leishmania-specific IFN-gamma production, effector memory CD4+ T cells were the main source of this cytokine.

Leishmania braziliensis

10.1186/1471-2334-13-529

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Citations (22)

Characterization of the immune response to Leishmania infantum recombinant antigens

Microbes and Infection (2003)

Lucas P. Carvalho Manuel Soto Selma M. B. Jerônimo Blaise Dondji Olı́via Bacellar

Canine leishmaniasis

10.1016/s1286-4579(02)00051-5

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Citations (45)

Infecção canina por Leishmania Braziliensis na área endemica de corte de Pedra-Bahia

Jamile Lago Juliana Silva Lairton Souza Borja Deborah Bittencourt Mothé Fraga Albert Schriefer

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Protective and Pathological Functions of CD8⁺T Cells in Leishmania braziliensis Infection

Infection and Immunity (2014)

Thiago M. Cardoso Álvaro Machado Diego L. Costa Lucas P. Carvalho Adriano Queiroz

Cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a strong Th1 response that leads to skin lesion development. In areas where L. braziliensis transmission is endemic, up to 15% of healthy subjects have tested positive for delayed-type hypersensitivity to soluble leishmania antigen (SLA) and are considered to have subclinical (SC) infection. SC subjects produce less gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) than do CL patients, but they are able to control the infection. The aim of this study was to characterized the role of CD8(+) T cells in SC infection and in CL. Peripheral blood mononuclear cells (PBMC) were stimulated with SLA to determine the frequencies of CD4(+) IFN-γ(+) and CD8(+) IFN-γ(+) T cells. Monocytes from PBMC were infected with L. braziliensis and cocultured with CD8(+) T cells, and the frequencies of infected monocytes and levels of cytotoxicity markers, target cell apoptosis, and granzyme B were determined. The frequency of CD8(+) IFN-γ(+) cells after SLA stimulation was higher for SC individuals than for CL patients. The frequency of infected monocytes in SC cells was lower than that in CL cells. CL CD8(+) T cells induced more apoptosis of infected monocytes than did SC CD8(+) T cells. Granzyme B production in CD8(+) T cells was higher in CL than in SC cells. While the use of a granzyme B inhibitor decreased the number of apoptotic cells in the CL group, the use of z-VAD-FMK had no effect on the frequency of these cells. These results suggest that CL CD8(+) T cells are more cytotoxic and may be involved in pathology.

Leishmania braziliensis

10.1128/iai.02404-14

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Phenotypic and functional characteristics of HLA-DR+ neutrophils in Brazilians with cutaneous leishmaniasis

Journal of Leukocyte Biology (2016)

Richard E. Davis Smriti Sharma Jacilara Conceição Pedro Paulo Carneiro Fernanda O. Novais

Abstract The protozoan Leishmania braziliensis causes cutaneous leishmaniasis (CL) in endemic regions. In murine models, neutrophils (PMNs) are recruited to the site of infection soon after parasite inoculation. However, the roles of neutrophils during chronic infection and in human disease remain undefined. We hypothesized that neutrophils help maintain a systemic inflammatory state in subjects with CL. Lesion biopsies from all patients with CL tested contained neutrophils expressing HLA-DR, a molecule thought to be restricted to professional antigen-presenting cells. Although CL is a localized disease, a subset of patients with CL also had circulating neutrophils expressing HLA-DR and the costimulatory molecules CD80, CD86, and CD40. PMNs isolated from a low-density leukocyte blood fraction (LD-PMNs) contained a higher percentage of HLA-DR+ PMNs than did normal-density PMNs. In vitro coculture experiments suggested LD-PMNs do not suppress T cell responses, differentiating them from MDSCs. Flow-sorted HLA-DR+ PMNs morphologically resembled conventional PMNs, and they exhibited functional properties of PMNs. Compared with conventional PMNs, HLA-DR+ PMNs showed increased activation, degranulation, DHR123 oxidation, and phagocytic capacity. A few HLA-DR+ PMNs were observed in healthy subjects, and that proportion could be increased by incubation in either inflammatory cytokines or in plasma from a patient with CL. This was accompanied by an increase in PMN hladrb1 mRNA, suggesting a possible connection between neutrophil “priming” and up-regulation of HLA-DR. These data suggest that PMNs that are primed for activation and that also express surface markers of antigen-presenting cells emerge in the circulation and infected tissue lesions of patients with CL.

CD86

CD80

HLA-DR

Respiratory burst

10.1189/jlb.4a0915-442rr

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Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis.

The Journal of Immunology (1994)

Edgar M. Carvalho Olı́via Bacellar C Brownell T Regis Robert L. Coffman

Visceral leishmaniasis is associated with a marked depression of T cell responses, which has been characterized by the absence of IL-2 and IFN-gamma production by lymphocytes on in vitro stimulation with Leishmania Ag. The aim of this study was to evaluate both the mechanism of these immunologic abnormalities and the restoration of in vitro T cell responses to Leishmania Ags. A total of 15 untreated visceral leishmaniasis patients were evaluated. Although IFN-gamma and IL-4 levels in the supernatants of lymphocyte cultures were very low or absent, mRNA for these cytokines and for IL-10 were observed in PBMCs. Addition of IFN-gamma plus IL-2 enhanced lymphocyte proliferation by 158%. Restoration of T cell proliferative responses and IFN-gamma production was also observed by the addition of a neutralizing mAb alpha-IL-10. Neutralizing mAb alpha-IL-4 did not restore T cell responses but alpha-IL-10 and alpha-IL-4 mAbs had a synergistic effect on lymphocyte proliferation. The IFN-gamma levels in supernatants of lymphocyte cultures stimulated with Leishmania chagasi Ag or L. chagasi Ag plus alpha-IL-4, alpha-IL-10, or alpha-IL-4 plus alpha-IL-10 mAbs were 26 +/- 30 pg/ml, 41 +/- 18 pg/ml, 146 +/- 73 pg/ml, and 174 +/- 106 pg/ml, respectively. These data indicate that Th2 cell activation occurs in visceral leishmaniasis and that in vitro production of IFN-gamma and lymphocyte proliferation can be restored by blocking the inhibitory effect of the Th2 cytokines on mononuclear cells.

10.4049/jimmunol.152.12.5949

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Citations (224)

Evaluation of the ability of Montenegro skin test to induce specific immune response

Fábio Freire José Indiara Maria da Silva Maria Ilma Araújo Roque Pacheco de Almeida Olı́via Bacellar

The Montenegro skin test, used to diagnose cutaneous leishmaniasis, is now being considered to detect immunogenicity after vaccination. In this study, we evaluated the ability of this test to induce immune response and IFN-g production in subjects not previously exposed to Leishmania. The Montenegro skin test was performed using antigens of L. amazonensis produced by our laboratory (group I) or by FIOCRU-RJ (group II). At day 30, 33% of the subjects from group I and 42% from group II were positive, compared to 67% from group I and 50% from group II at day 90. IFN-y was detected in 56 % of subjects from group I and 17% from group II at day 30 (169±309 and 11±36pg/ml) and in 67% from group I and 58% from group II by day 360 (69±107 and 18±20pg/ml). These data demonstrate that the Montenegro skin test induces not only a delayed hypersensitivity reaction, but also IFN-y production. Key-words: Montenegro skin test. Delayed hypersensitivity skin test. Leishmaniasis diagnosis. 1. Escola Baiana de Medicina e Saude Publica; 2. Servico de Imunologia, Hospital Universitario Professor Edgard Santos da Universidade Federal da Bahia, Salvador, Bahia, Brasil. Endereco para correspondencia: Dr. Edgar Marcelino de Carvalho. Servico de Imunologia/Hospital Universitario Professor Edgard Santo/UFBA. R. Joao da Botas s/n, 5 andar, 40140-160 Salvador, BA, Brasil. Tel: 55 73 237-7353; Fax: 55 71 245-7110. Recebido para publicacao em 2/4/2001. A intradermorreacao idealizada por Montenegro27 representa o principal exame complementar para o diagnostico da leishmaniose tegumentar americana (LTA) em areas endemicas, sendo, portanto, de relevante importância para paises como o Brasil, que, juntamente, com o Afeganistao, Peru, Arabia Saudita e Siria detem 90% dos casos de leishmaniose tegumentar em todo o mundo41. Essa reacao de hipersensibilidade tardia possui sensibilidade variando entre 86 e 100% e especificidade de aproximadamente 100%10 11, o que a consagrou como uma das provas mais usadas na confirmacao da doenca ativa, no diagnostico retrospectivo e em inqueritos epidemiologicos de LTA9 13 30 31 33 36. Uma reacao de Montenegro positiva em individuos de areas endemicas sem historia de leishmaniose tegumentar americana e sem qualquer lesao suspeita, aponta para a possibilidade de formas abortivas ou infeccoes subclinicas11 12 20. A despeito da alta sensibilidade e especificidade do teste de Montenegro, existem relatos de reacao cruzada, principalmente em individuos com doenca de Chagas e individuos curados de leishmaniose visceral35. Resultados falsos negativos tambem tem sido descritos quando a infeccao e precoce8, ou em casos em que a doenca cutânea seja causada por Leishmania amazonensis. Apesar do teste de Montenegro ser plenamente aceito, diferencas na preparacao comercial podem afetar a antigenicidade e a eficacia na deteccao de diversas formas de leishmaniose em diferentes areas geograficas1 2. A negatividade do teste intradermico de Montenegro tem sido utilizado como criterio de inclusao de individuos em estudos que visam caracterizar a resposta imune e a eficacia da imunizacao apos a utilizacao de vacinas contra leishmaniose4 5 22 23 24 28. A demonstracao de que o teste de Montenegro pode sensibilizar o hospedeiro

Montenegro

Skin test

Delayed hypersensitivity

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T Cell Response of Asymptomatic Leishmania chagasi Infected Subjects to Recombinant Leishmania Antigens

Memórias do Instituto Oswaldo Cruz (1999)

Sérgio Ricardo Matos Rodrigues da Costa Argemiro D’Oliveira Júnior Olı́via Bacellar Edgar M. Carvalho

In areas of Leishmania chagasi transmission the ability to control leishmania infection is associated with IFN-g production. In visceral leishmaniasis down-regulation of T cell responses is mediated by interleukin-10 (IL-10). In this study we evaluated the lymphoproliferative response, IFN-g and IL-10 production on lymphocyte cultures stimulated with recombinant leishmania antigens in subjects with asymptomatic L. chagasi infection. There was a statistically significant difference in the lymphoproliferative response of the subjects with asymptomatic infection as compared to patients with visceral leishmaniasis and healthy subjects with respect to crude antigens (p<0.01), gp-63 (p<0.05) and hsp-70 (p<0.01), as well as between asymptomatic L. chagasi infected subjects and patients with visceral leishmaniasis with respect to the response to all antigens tested. The IFN-g production observed in the group with asymptomatic infection with all the three recombinant antigens tested was higher (p<0.01) than that observed in patients with visceral leishmaniasis and in healthy subjects. Furthermore, in individuals with asymptomatic infection, IL-10 levels in cultures stimulated with recombinant antigens were very low. This study shows that lymphocytes from individuals with asymptomatic L. chagasi infection are able to recognize recombinant leishmania antigens with production of a cytokine that is associated with leishmania killing.

Leishmania chagasi

Lymphoproliferative response

10.1590/s0074-02761999000300015

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Citations (26)

Gamma interferon production by lymphocytes from children infected with L. chagasi.

PubMed (1991)

Olı́via Bacellar Manoel Barral‐Netto Roberto Badaró Carvalho Em

The present study was performed to evaluate the ability of lymphocytes from 18 children living in an endemic area of visceral leishmaniasis (VL) to produce gamma-interferon. These children had no previous history of VL and were considered to be infected with Leishmania chagasi based on leishmanial seroconversion. The gamma IFN levels were determined by radioimmunoassay on supernatants of lymphocyte cultures (3 x 10(6)/ml) stimulated with PHA (final dilution 1:10) and Leishmania chagasi antigen (10 micrograms/ml). The gamma-IFN production by lymphocytes from seroconverting children stimulated with PHA (178 +/- 151 U/ml) and Leishmania chagasi (47 +/- 77 U/ml) was significantly higher than that observed in visceral leishmaniasis. For clinical follow-up, these 18 seroconverting children were divided into three groups: asymptomatic infection (N = 4); self-healing subclinical illness (N = 9), and subclinical infection progressing to VL (N = 5). Gamma IFN levels in children with either asymptomatic or subclinical infection (65 +/- 85 U/ml) were significantly higher (P less than 0.003) than those observed in children progressing to VL (9 +/- 6 U/ml). The data demonstrate that there is an association between gamma IFN levels and the clinical course of Leishmania infection.

Subclinical infection

Leishmania chagasi

Seroconversion

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Citations (19)

Cytokine Profile and Immunomodulation in Asymptomatic Human T-Lymphotropic Virus Type 1–Infected Blood Donors

JAIDS Journal of Acquired Immune Deficiency Syndromes (2001)

Edgar M. Carvalho Olı́via Bacellar Aurélia F. Porto Silvane Braga Bernardo Galvão–Castro

The modulation of the immune response has been used as therapy for clinical disorders associated with human T-lymphotropic virus type 1 (HTLV-1) infection. In this study, the cytokine profile was evaluated in 26 asymptomatic HTLV-1 blood donors. Additionally, both the cell responsible for producing interferon-gamma (IFN-gamma) and the role of exogenous interleukin (IL)-10 in downregulating IFN-gamma production were studied. Cytokine levels were determined in supernatants of unstimulated lymphocyte cultures by enzyme-linked immunosorbent assay. The levels of IFN-gamma, tumor necrosis factor-alpha, IL-5, and IL-10 were higher in supernatants of the lymphocyte cultures taken from HTLV-1-infected donors than in those taken from healthy subjects. Although depletion of CD8+ T cells and natural killer cells did not affect IFN-gamma production, depletion of CD4+ T cells significantly decreased IFN-gamma production. Furthermore, at a concentration of 2 ng/ml, IL-10 had only a minimum effect on IFN-gamma production, although at high concentrations (100 ng/ml), IL-10 decreased IFN-gamma production by 50% in HTLV-1-infected individuals. These data indicate that both T helper 1 and T helper 2 cytokines are elevated in HTLV-1 infection and that IL-10 in high concentrations modulates IFN-gamma production in these patients.

Human T-lymphotropic virus

10.1097/00126334-200105010-00001

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Citations (97)