Oral tolerance induction in organ and tissue transplantation. Literature review / Inducción de tolerancia por vía oral en trasplante de órganos y tejidos. Revisión de la Literatura

Abstract Introduction: Oral tolerance is defined as the suppression of the immune response to antigens that have been previously administered orally. The purpose of inducing oral tolerance is to avoid using immunosuppressive drugs since, considering that they are not antigen-specific, they make the host more susceptible to acquire infections and develop neoplasms. Objective: To carry out a literature review on the most relevant theoretical references regarding oral tolerance induction in organ and tissue transplantation to prove that oral tolerance is a viable alternative therapy in transplant patients. Materials and methods: A literature review was conducted in the PubMed, MEDLINE, LILACS and Embase databases using the following search strategy: publication time: no limits; publication language: English and Spanish; type of studies: case-control studies, literature and systematic reviews; search terms: "T-Lymphocytes, Regulatory", "Autoimmunity", Immunosuppression", "Immune system" and "Immune Tolerance", and their equivalents in Spanish. Results: After the initial search was completed, 719 records were retrieved; however, only 99 addressed oral tolerance induction. Once duplicate records and articles without full-text access were removed, 75 studies were included for analysis. Conclusions: Oral administration of antigens is an effective way to induce immune tolerance in transplant patients (murine models) as it eliminates the adverse effects associated with immunosuppressive therapy, which currently is the standard therapy to treat these patients worldwide.

Resumen Introducción. La tolerancia oral es la supresión de la respuesta inmune a antígenos administrados con anterioridad por vía oral; su inducción tiene el propósito de evitar el uso de fármacos inmunosupresores, los cuales, dado que son poco específicos a antígenos, vuelven al huésped más susceptible de contraer infecciones y desarrollar neoplasias. Objetivos. Realizar una revisión de la literatura sobre los referentes teóricos más relevantes de la inducción de a tolerancia oral en lo que respecta al trasplante de órganos y tejidos para demostrar que el uso de esta alternativa terapéutica es viable en pacientes trasplantados. Materiales y métodos. Se realizó una revisión de la literatura en PubMed, MEDLINE, LILACS y Embase mediante la siguiente estrategia de búsqueda: periodo de publicación: sin límites; idiomas: Inglés y Español; tipo de artículos: estudios caso-control, revisiones sistemáticas y de la literatura; términos de búsqueda: "T-Lymphocytes, Regulatory", "Autoimmunity", Immunosuppression", "Immune system" and "Immune Tolerance", y sus equivalentes en español. Resultados. La búsqueda inicial arrojó 719 registros, sin embargo solo 99 abordaban la inducción de la tolerancia oral. Una vez los registros duplicados y los artículos sin acceso a texto completo fueron removidos, se incluyeron 72 estudios en la revisión. Conclusiones. La administración oral de antígenos es una opción efectiva para inducir tolerancia inmunológica en pacientes trasplantados (modelos murinos), pues elimina los efectos adversos que conlleva la terapia inmunosupresora actualmente utilizada.

Regulatory T cells isolated from endometriotic peritoneal fluid express a different number of Toll-like receptors / Células T reguladoras isoladas do fluido peritoneal de mulheres com endometriose expressam um número diferente de receptores do tipo Toll

ABSTRACT Objective To analyze and compare the expression of Toll-like receptors by regulatory T cells present in the peritoneal fluid of patients with and without endometriosis. Methods Regulatory T cells were isolated from peritoneal fluid of women with and without endometriosis, collected during surgery, and mRNA was extracted for analysis of Toll-like receptors expression by reverse-transcriptase polymerase chain reaction. Results Patients with endometriosis presented regulatory T cells expressing a larger number and variety of Toll-like receptors when compared to regulatory T cells from patients in the Control Group. Toll-like receptor-1 and Toll-like receptor-2 in regulatory T cells were expressed in both groups. All other expressed Toll-like receptors types were only found in regulatory T cells from the Endometriosis Group. Conclusion Patients with endometriosis had peritoneal regulatory T cells expressing various Toll-like receptors types.

RESUMO Objetivo Analisar e comparar a expressão de receptores do tipo Toll por células T reguladoras presentes no líquido peritoneal de pacientes com endometriose. Métodos Células T reguladoras foram isoladas do líquido peritoneal de mulheres com e sem endometriose, coletadas durante a cirurgia, e o RNAm foi extraído para análise da expressão de receptores do tipo Toll por reação em cadeia da polimerase com transcriptase reversa. Resultados Pacientes com endometriose apresentaram células T reguladoras expressando maior número e variedade de Toll por células quando comparadas com T reguladoras de pacientes do Grupo Controle. Receptores do tipo Toll-1 e receptores do tipo Toll-2 foram expressos em ambos os grupos. Todos os outros tipos de receptores Toll foram encontrados expressos apenas em células T reguladoras do grupo com endometriose. Conclusão Pacientes com endometriose apresentaram células T reguladoras peritoneais expressando vários tipos de receptores tipo Toll.

Mecanismos da imunoterapia alérgeno-específica / Mechanisms of allergen-specific immunotherapy

A imunoterapia alérgeno-específica tem sido usada há mais de 100 anos como um tratamento de dessensibilização para doenças alérgicas, representando um método potencialmente curativo e específico. O presente estudo tem como objetivo revisar os mecanismos da imunoterapia alérgeno-específica, através de revisão bibliográfica com base em artigos publicados entre 1998 e 2016, disponíveis no banco de dados PubMed. Os mecanismos de ação da imunoterapia incluem modulação de linfócitos T e B, produção de IgG4 alérgeno-específica e redução de IgE alérgenoespecífica, migração de eosinófilos, basófilos e mastócitos nos tecidos, bem como a liberação de seus mediadores. As células T reguladoras (Treg) suprimem as células dendríticas responsáveis pela geração de células T efetoras, inibindo TH1, TH2 e TH17. As células Treg foram identificadas como peças-chave no processo de indução de tolerância periférica aos alérgenos.

Allergen-specific immunotherapy has been used for more than 100 years as a desensitizing therapy for allergic diseases, representing a potentially curative and specific method. The aim of the present study was to review the mechanisms of allergenspecific immunotherapy based on papers published between 1998 and 2016 and available in the PubMed database. The mechanisms of action of immunotherapy include modulation of T-and B-cell responses, induction of allergen-specific IgG4 and suppression of allergen-specific IgE production, migration of eosinophils, basophils, and mast cells to tissues, as well as release of their mediators. Regulatory T cells (Treg) suppress dendritic cells that support the generation of effector T cells, inhibiting TH1, TH2, and TH17 cells. Treg cells have been identified as key regulators of the induction process of peripheral allergen tolerance.

Peripheral blood regulatory T cell counts as a predictive biomarker for the outcome of kidney transplant: A systematic review. / Recuentos de células T reguladoras en sangre periférica como biomarcador predictivo del resultado del trasplante renal: revisión sistemática.

BACKGROUND AND OBJECTIVE: Circulating regulatory T cells could become a suitable biomarker for kidney recipients. The objective of this study was to evaluate the effect of mammalian target of rapamycin (mTOR) inhibitors on regulatory T cell numbers, and the clinical interest of this effect. MATERIAL AND METHODS: Systematic review of published and unpublished studies. Worldwide databases or repositories. Randomised controlled trials and cohort studies comparing regulatory T cell counts and rejection episodes between patients with and without mTOR inhibitors were searched. Correlation of regulatory T cells-glomerular filtration rate might be supplied. Co-dependency regulatory T cells-mTOR inhibitors efficacy was evaluated. RESULTS: Five trials and 9 studies were included. Clinical differences made it difficult to obtain quantitative estimates of the effect of immunosuppression on regulatory T cell numbers. Nevertheless, we found that there are higher regulatory T cell numbers under treatment with sirolimus or everolimus. Rejection episodes were similar under calcineurin inhibitors and mTOR inhibitors despite different regulatory T cell numbers. Pooled correlation regulatory T cells-glomerular filtration rate was, prospectively 0.114 (95% confidence interval [95% CI] 0.062-0.406), and retrospectively 0.13 (95% CI 0.0-0.361). There is direct evidence although of low level (biomarker-stratified randomisation) on the co-dependency regulatory T cells-mTOR inhibitors efficacy. CONCLUSIONS: Regulatory T cells counts may be associated with better outcomes under treatment with mTOR inhibitors (anti-rejection efficacy), considering that there is a relationship between these cells and kidney graft function. REGISTRATION: PROSPERO (CRD42016046285).

Relación entre linfocitos T reguladores (T regs) y anticuerpos anti-receptores de TSH (TRab) y el riesgo de cáncer de tiroides en enfermedad de Graves / Relationship between T regulatory lymphocytes (Tregs) and TSH receptor antibodies (TRab) on risk of thyroid cancer in Graves disease

Durante los últimos años se ha estudiado la relación entre enfermedad de Graves (EG), TSH, TRAb y cáncer de tiroides, existiendo estudios que demuestran mayor prevalencia y agresividad del cáncer de tiroides en pacientes con EG, mientras otros refutan estos hallazgos sugiriendo que serían producto del sesgo de selección. Aquellos estudios que plantean una relación causal entre EG y el desarrollo de cáncer de tiroides, la atribuyen a la presencia de autoanticuerpos TSI, que estimularían el foco de malignidad. Se cree que las citoquinas producidas localmente en pacientes con EG trabajarían en conjunto con los TRAb para determinar la agresividad del cáncer papilar de tiroides en estos pacientes. Dentro de las células reclutadas por el tumor para evadir la respuesta inmune se encuentran los linfocitos Treg, que estarían elevados en paciente con EG, llevando a la disminución de la respuesta inmune y creando un ambiente permisivo para la proliferación celular. Por tratarse de una línea de investigación reciente, no existe consenso sobre el tema y sus implicancias en el tratamiento de los pacientes con EG. La finalidad de este artículo es realizar una revisión de la literatura que exponga y contraste la información disponible a la fecha.

In recent years the relationship between Graves’ disease (GD), TSH, TRAb and thyroid carcinoma has been studied. Research studies show a higher prevalence and aggressiveness of thyroid carcinoma in patients with GD, however other researchers refute these findings suggesting it’s due to selection bias. Increasing evidence suggests a causal relationship between GD and the development of thyroid carcinoma, mainly because of the existence of TSI autoantibodies that could stimulate the focus of malignancy. It is believed that cytokines produced locally in patients with GD work alongside with TRAb regulating the aggressiveness of papillary thyroid carcinoma in these patients. Within the cells recruited by the tumor to elude the immune system we find Treg lymphocytes, which have been found to be increased in patients with GD, leading to a diminished immune response, creating a permissive environment for cell proliferation. Since this is a relatively new line of research, there is no consensus on the subject and its relevance for the treatment of patients with GD. The aim of this article is to show recent literature available on the subject.

CCR5-dependent homing of T Regulatory Cells to the tumor microenvironment contributes of skin squamous cell carcinoma develpment

Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Treg) have a critical role in the modulation of an antitumor immune response, and consequently the SCC development. Because the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5- and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4+CD25+CCR5+, CD4+CD25-CCR5+ or CD8+CCR5+ conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4+CD25+CCR5+ cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8+ T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment.

Avances en las inmunoterapias para alergias alimentarias / New insights in immunotherapies for food allergies / Novas perspectivas em imunoterapias para alergias alimentares

Las enfermedades alérgicas son las inmunopatologías que con mayor prevalencia se presentan en el mundo. Pueden o no estar mediadas por anticuerpos IgE, sin embargo estas últimas son las que más intensamente se han estudiado por el riesgo que presentan para la vida del paciente. Si bien el único tratamiento que logra revertir estos mecanismos es la no exposición al alergeno, esto no siempre es posible. Por esta razón, y a partir del mayor conocimiento alcanzado del sistema inmune de mucosas junto al desarrollo de modelos animales de alergia, existe un marcado interés en la especialidad para el desarrollo de inmunoterapias que controlen y reviertan el estado de alergia. A partir de los ensayos pre-clínicos en animales y la aplicación de protocolos terapéuticos en ensayos clínicos, se han desarrollado terapias mucosales que logran inducir mecanismos de tolerancia específicos del alergeno, los cuales son capaces de revertir la sensibilización alérgica. Dado que el principal escollo siguen siendo las reacciones adversas inducidas durante el tratamiento, se requiere profundizar los estudios para desarrollar protocolos terapéuticos más seguros. En este punto la medicina traslacional encuentra un campo próspero para fortalecer las interacciones entre la ciencia básica, la aplicada y la clínica.

Allergic diseases are the most prevalent immunopathologies worldwide. Although different mechanisms -IgE-independent or IgE-dependent- can be involved in the immunopathogenesis, the latter are the most studied reactions since they can be life-threatening. Nowadays, allergen avoidance is the unique effective treatment for allergic patients. However, this is rather difficult to implement. For this reason, and based on the new insights into the mucosal immune system and the development of animal models of allergy, there is an increasing interest in developing novel therapies to control or reverse allergic disorders. Pre-clinical studies and clinical trials have been successful to prove that immunotherapies may accomplish mucosal mechanisms of allergen-specific tolerance, which are able to revoke the allergic sensitization. Since the main obstacle in these therapies still has adverse reactions induced during treatment, further studies are required to explore safe and effective therapeutic protocols. At this point, translational medicine is a flourishing field in the areas of basic science, applied science, and clinical research.

As doenças alérgicas são as imunopatologias mais prevalentes em todo o mundo. Embora possam estar mediadas ou não por anticorpos IgE, estas últimas são as reacções mais intensamente estudadas, devido ao risco que apresentam para a vida do paciente. Ainda que o único tratamento eficaz para reverter este mecanismos seja a não exposição dos pacientes ao alergeno, isto nem sempre é possível. Por este motivo, e com base nas novas perspectivas sobre o sistema imune de mucosas, junto com o desenvolvimento de modelos e para o animais de alergia, existe um interesse crescente na especialidade para o desenvolvimento de imunoterapias que controlem e revertam o estado de alergia. A partir de estudos pré-clínicos em animais e a aplicação de protocolos terapêuticos em ensaios clínico, foram desenvolvidas terapias mucosas que conseguem induzir mecanismos de tolerância específicos do alergeno, que são capazes de reverter a sensibilização alérgica. Devido a que o principal obstáculo nestas terapias continuam sendo as reações adversas induzidas durante o tratamento, é necessário realizar mais estudos para desenvolver protocolos terapêuticos mais seguros. Neste ponto, medicina translacional é um campo próspero para fortalecer as interações entre a ciência básica, a aplicada e a clínica.

Análise fenotípica de células dendríticas e de linfócitos T efetores, polifuncionais e reguladores no líquen plano / Phenotypic analysis of dendritic cells and effector, polyfunctional and regulators lymphocytes on lichen planus

Líquen plano (LP) é uma doença mucocutânea de natureza inflamatória crônica de etiologia ainda desconhecida. A estimulação da imunidade inata via os receptores Toll-like (TLRs) podem influenciar as células dendríticas e direcionar a resposta de células T CD4+ e CD8+ efetoras, assim como também favorecer o estado inflamatório do LP. OBJETIVOS: Avaliar o perfil fenotípico de células dendríticas mielóides (mDCs) e plasmocitóides (pDCs) e de linfócitos T CD4+ e CD8+ após estímulo com agonistas de TLRs no sangue periférico de pacientes com LP. Além disto, avaliar a frequência, perfil de maturação e os subtipos de células T CD4+ e TCD8+ reguladores. MÉTODOS: Foram selecionados 18 pacientes com LP (15 mulheres, 3 homens), com 41,57 ± 4,73 anos de idade e um grupo controle com 22 indivíduos sadios (18 mulheres, 4 homens), com 43,92 ± 7,83 anos de idade. As células mononucleares (CMNs) de sangue periférico foram avaliadas por citometria de fluxo quanto à: 1) Produção de TNF-? em mDCs e de IFN-? em pDCs em CMNs ativadas por agonistas de TLR 4, 7, 7/8 e 9; 2) Análise de células T CD4+ e CD8+ monofuncionais e polifuncionais após estímulo com agonistas de TLR 4, 7/8, 9 e enterotoxina B de Staphylococcus aureus (SEB); 3) Avaliação de células Th17 e Th22/Tc22 em CMNs após estímulo com SEB; 4) Frequência, perfil de maturação e subtipos de células T CD4+ e CD8+ reguladoras. RESULTADOS: 1) Nos pacientes com LP foi demonstrado um aumento na frequência de mDCs TNF-alfa+ após estímulo com agonistas de TLR4/LPS e TLR7-8/CL097, mas com imiquimode/TLR7 houve diminuição da expressão de CD83. Já nas pDCs do grupo LP, o imiquimode foi capaz de diminuir a expressão de CD80 e o CpG/TLR9 diminuiu a expressão de CD83 no LP. 2) As células T CD4+ secretoras de IL-10 mostraram aumento da frequência nos níveis basais, que diminuiu após estímulo com LPS e SEB. Em contraste, a produção de IFN-y aumentou em resposta ao LPS enquanto diminuiu para CpG. As células...

Lichen planus (LP) is a mucocutaneous disease of chronic inflammatory course of unknown etiology. Stimulation of the innate immune system via Toll-like receptors (TLRs) may influence the dendritic cells and targeting the CD4+ and effector CD8+ T cell responses, as well as promoting inflammatory status of the LP. OBJECTIVES: To evaluate the phenotypic profile of myeloid dendritic cells (mDCs), plasmacytoid (pDCs) and CD4+ and CD8+ T lymphocytes after stimulation with TLR agonists in peripheral blood of patients with LP. Moreover, to evaluate the frequency, maturation profile and subtypes of CD4+ and CD8+ T regulators cells. METHODS: We selected 18 patients with LP (15 women, 3 men) with 41.57 ± 4.73 years old and a control group of 22 healthy subjects (18 women, 4 men), with 43.92 ± 7, 83 years old. Mononuclear cells from peripheral blood (PBMCs) were assessed by flow cytometry for: 1) mDC TNF-alfa production and pDCs IFN-alfa production in PBMCs activated by agonists of TLR 4, 7, 7/8 and 9; 2) Analysis of monofunctional and polyfunctional CD4+ and CD8+ T cells after stimulation with TLR 4 agonists, 7/8, 9 and Staphylococcus aureus enterotoxin B (SEB); 3) Evaluation of Th17 and Th22/ Tc22 cells in PBMCs after stimulation with SEB; 4) Frequency, maturation profile and subtypes of regulatory CD4+ and CD8+ T cells. RESULTS: 1) Patients with LP showed an increased frequency of TNF-alfa+ mDCs after stimulation with agonists of TLR4/LPS and TLR7-8 /CL097, whereas with imiquimod /TLR7 induced a decreased CD83 expression. Already in the pDCs of LP group the imiquimod was able to decrease the CD80 expression and CpG/TLR9 decreased CD83 expression. 2) CD4+ T cells secreting IL-10 demonstrated an increased frequency at the baseline levels, which decreased after stimulation with LPS and SEB. In contrast, the production of IFN-y increased in response to LPS while decreased to CpG. Polyfunctional CD4+ T cells secreting simultaneously 5...

Expressão imuno-histoquímica de IL-17, TGF-ß1 e FOXO3 em granulomas periapicais, cistos radiculares e cistos radiculares periapicais / IL-17 immunohistochemistry Expression of FOXP3 TGF-ß1 in periapical granulomas, cysts and root periapical cysts root

Lesões periapicais crônicas são condições inflamatórias dos tecidos perirradiculares consideradas sequelas diretas de processos infecciosos resultantes da necrose pulpar e consequente progressão para a região periapical. A participação da resposta imunológica e da reabsorção óssea na formação destas lesões tem sido bastante investigada, de modo que diversos tipos celulares e citocinas foram apontados como colaboradores deste processo. Nesta perspectiva, o presente estudo objetivou avaliar a expressão imuno-histoquímica da IL- 17, TGF-β1 e FoxP3 em granulomas periapicais (GPs), cistos radiculares (CRs) e cistos radiculares residuais (CRRs), buscando um melhor entendimento sobre a etiopatogênese destas periapicopatias. Para tanto, foram selecionados 20 casos de GPs, 20 de CRs e 10 de CRRs para serem submetidos à análise morfológica e imuno-histoquímica para os biomarcadores supracitados, sendo esta última realizada quantitativamente através de escores e percentuais médios de imunomarcação para a análise da IL-17 e do TGF-β1, enquanto que para o FoxP3 foram contados apenas os linfócitos positivos. Os resultados demonstraram diferenças estatisticamente significativas entre as imunoexpressões do TGF-β1 e do FoxP3 em relação as lesões periapicais pesquisadas (p = 0,002; p < 0,001, respectivamente), mas não entre a IL-17 e estas (p = 0,355).

Além disso, a análise dos linfócitos FoxP3-positivos revelou diferenças estatísticas significativas no que se refere à intensidade do infiltrado inflamatório (p = 0,003) e também quanto à espessura do revestimento epitelial (p = 0,009). Por fim, observou-se nos casos de GPs, forte correlação positiva entre a quantidade de linfócitos FoxP3-positivos e a imunoexpressão do TGF-β1 (r = 0,755; p < 0,001), assim como moderada correlação positiva entre as imunoexpressões da IL-17 e do TGF-β1 (r = 0,503; p = 0,024). Destarte, pode-se concluir que interações entre células Th17 e Treg parecem ser estabelecidas no local da agressão, sugerindo a participação de citocinas tanto próinflamatórias como imunorregulatórias na patogenia das lesões periapicais. (AU)

Periapical lesions are chronic inflammatory conditions of periradicular tissues considered direct consequences of infectious diseases resulting from pulp necrosis and subsequent progression to periapical region. The participation of the immune response and bone resorption in the formation of these lesions has been investigated, so that different cell types and cytokines have been identified as contributors to this process. In this perspective, this study aimed to evaluate the immunohistochemical expression of IL-17, TGF-β1 and FoxP3 in periapical granulomas (PGs), radicular cysts (RCs) and residual radicular cysts (RRCs), seeking a better understanding of the etiopathogenesis these periapicopatias. To this end, we selected 20 cases of GPs, 20 CRs and 10 RRCs to undergo morphological analysis and immunohistochemistry for biomarkers above, the latter being performed quantitatively using scores and average percentages of immunostaining for the analysis of IL-17 and TGF- β1, while for the FoxP3 were counted only the positive lymphocytes. The results showed statistically significant differences between TGF-β1 and FoxP3 imunoexpressions, in relation to the periapical lesions studied (p = 0.002, p <0.001, respectively) but not between IL-17 and these (p = 0.355).

Furthermore, the analysis of lymphocytes FoxP3-positive revealed significant statistical differences in that refers to the intensity of inflammatory infiltrate (p = 0.003) and also regarding thickness of the epithelial lining (p = 0.009). Finally, it was observed in the case of PGs, strong positive correlation between the amount of FoxP3- positive lymphocytes and the immunohistochemical expression of TGF-β1 (r = 0.755, p<0.001), as well as moderate positive correlation between IL-17 and TGF-β1 imunoexpressions (r = 0.503, p = 0.024). Thus, we can conclude that interactions between Th17 and Treg cells seem to be established at the site of injury, suggesting the involvement of both pro-inflammatory and immunoregulatory cytokines in the pathogenesis of periapical lesions. (AU)

Abnormal phenotypic distribution of regulatory and effector T cells in octogenarian and nonagenarian women / Distribuição fenotípica anormal das células T reguladoras e efetoras em mulheres octogenárias e nonagenárias

SummaryIntroduction:aging is associated with several immunologic changes. Regulatory (Treg) and effector T cells are involved in the pathogenesis of infectious, neoplastic, and autoimmune diseases. Little is known about the effects of aging on the frequency and function of these T cell subpopulations.Methods:peripheral blood mononuclear cells (PBMC) were obtained from 26 young (under 44 years old) and 18 elderly (above 80 years old) healthy women. T cell subpopulations were analyzed by flow cytometry.Results:elderly individuals had lower frequency of several activated effector T cell phenotypes as compared with young individuals: CD3+CD4+CD25+ (3.82±1.93 versus 9.53±4.49; p<0.0001); CD3+CD4+CD25+CD127+(2.39±1.19 versus 7.26±3.84; p<0.0001); CD3+CD4+CD25+ (0.41±0.22 versus 1.86±0.85, p<0.0001); and CD3+CD4+CD25highCD127+(0.06±0.038 versus 0.94±0.64, p<0.0001). Treg (CD3+CD4+CD25+CD127øFoxp3+) presented lower frequency in elderly individuals as compared to young adults (0.34±0.18 versus 0.76±0.48; p=0.0004) and its frequency was inversely correlated with age in the whole group (r=-0.439; p=0.013). The elderly group showed higher frequency of two undefined CD25øFoxp3+ phenotypes: CD3+CD4+CD25øFoxp3+(15.05±7.34 versus 1.65±1.71; p<0.0001) and CD3+CD4+CD25øCD127øFoxp3+(13.0±5.52 versus 3.51±2.87; p<0.0001).Conclusions:the altered proportion of different T cell subsets herein documented in healthy elderly women may be relevant to the understanding of the immunologic behavior and disease susceptibility patterns observed in geriatric patients.

ResumoIntrodução:o envelhecimento está associado a diversas alterações imunológicas. Células T reguladoras e efetoras estão envolvidas na patogênese de enfermidades infecciosas, neoplásicas e autoimunes. Pouco se sabe acerca dos efeitos da idade sobre a frequência e a função dessas populações celulares.Métodos:células mononucleares do sangue periférico foram obtidas de participantes saudáveis (26 com idade inferior a 44 anos e 18 acima de 80 anos). As subpopulações celulares foram analisadas por citometria de fluxo.Resultados:o grupo constituído por idosas apresentou menor frequência de vários fenótipos de células T efetoras ativadas em comparação com jovens: CD3+CD4+CD25+ (3,82±1,93 versus 9,53±4,49, p<0,0001); CD3+CD4+ CD25+CD127+ (2,39±1,19 versus7,26±3,84, p<0,0001); CD3+CD4+CD25high(0,41±0,22 versus 1,86±0,85, p<0,0001); CD3+CD4+CD25highCD127+(0,06±0,038 versus 0,94±0,64, p<0,0001). As células T reguladoras CD3+CD4+CD25highCD127øFoxP3+ apresentaram menor frequência em indivíduos idosos em comparação com adultos jovens (0,34±0,18 versus0,76±0,48, p=0,0004) e sua frequência foi inversamente correlacionada com a idade em todo o grupo (r=-0,439; p=0,013). O grupo de idosas apresentou maior frequência de dois fenótipos indefinidos (CD25øFoxP3+), células CD3+CD4+CD25øFoxP3+ (15,05±7,34 versus 1,65±1,71, p<0,0001) e células CD3+CD4+CD25øCD127øFoxP3+(13,0±5,52 versus 3,51±2,87, p<0,0001).Conclusão:as proporções alteradas de diferentes subpopulações de células T em idosas saudáveis contribuem para a compreensão dos padrões de comportamento e suscetibilidade a doenças imunológicas evidenciadas em pacientes geriátricos.

Regulatory T cells, maternal-foetal immune tolerance and recurrent miscarriage: new therapeutic challenging opportunities.

Because maternal alloreactive lymphocytes are not depleted during pregnancy, local and/or systemic mechanisms have to play a key role in altering the maternal immune response. Peripheral T regulatory cells (pTregs) at the maternal-foetal interface are necessary in situ to prevent early abortion, but only those pTregs that have been previously exposed to paternal alloantigens. It has been showed that pregnancy selectively stimulates the accumulation of maternal Foxp3(+)CD4(+)CD25(+) (Foxp3Tregs) cells with foetal specificity. Interestingly, after delivery, foetal-specific pTregs persist at elevated levels, maintain tolerance to pre-existing foetal antigen, and rapidly re-accumulate during subsequent pregnancy. pTreg up-regulation could be hypothesized as a possible future therapeutic strategy in humans.

Analysis of immune response markers in Jorge Lobo's disease lesions suggests the occurrence of mixed T Helper responses with the dominance of regulatory T cell activity

Jorge Lobo's disease (JLD) is a chronic infection that affects the skin and subcutaneous tissues. Its etiologic agent is the fungus Lacazia loboi. Lesions are classified as localized, multifocal, or disseminated, depending on their location. Early diagnosis and the surgical removal of lesions are the best therapeutic options currently available for JLD. The few studies that evaluate the immunological response of JLD patients show a predominance of Th2 response, as well as a high frequency of TGF-ß and IL-10 positive cells in the lesions; however, the overall immunological status of the lesions in terms of their T cell phenotype has yet to be determined. Therefore, the objective of this study was to evaluate the pattern of Th1, Th2, Th17 and regulatory T cell (Treg) markers mRNA in JLD patients by means of real-time PCR. Biopsies of JLD lesions (N = 102) were classified according to their clinical and histopathological features and then analyzed using real-time PCR in order to determine the expression levels of TGF-ß1, FoxP3, CTLA4, IKZF2, IL-10, T-bet, IFN-γ, GATA3, IL-4, IL-5, IL-13, IL-33, RORC, IL-17A, IL-17F, and IL-22 and to compare these levels to those of healthy control skin (N = 12). The results showed an increased expression of FoxP3, CTLA4, TGF-ß1, IL-10, T-bet, IL-17F, and IL-17A in lesions, while GATA3 and IL-4 levels were found to be lower in diseased skin than in the control group. When the clinical forms were compared, TGF-ß1 was found to be highly expressed in patients with a single localized lesion while IL-5 and IL-17A levels were higher in patients with multiple/disseminated lesions. These results demonstrate the occurrence of mixed T helper responses and suggest the dominance of regulatory T cell activity, which could inhibit Th-dependent protective responses to intracellular fungi such as L. loboi. Therefore, Tregs may play a key role in JLD pathogenesis.

Desequilíbrio imunológico periférico mediado por células Th17/Treg em pacientes com rinite alérgica / Peripheral Th17/Treg cell-mediated immunity imbalance in allergic rhinitis patients

Introdução: A rinite alérgica (RA) é uma doença não infecciosa da mucosa nasal mediada por IgE após o contato com alérgenos. Objetivo: Investigar as células Th17 periféricas e CD4 + CD25 + Foxp3 + células T reguladoras (Treg) e a expressão sérica de citocinas em pacientes com RA. Métodos: De março a maio de 2012, foi coletado o sangue periférico de 14 pacientes com RA (grupo RA) e seis indivíduos saudáveis (grupo controle). A detecção das células Th17 e células Treg foi realizada através da citometria de fluxo e os níveis séricos de IL -17 e TGF- β1. Foram medidos por ELISA. Resultados: A percentagem de células Th17 no grupo RA foi bem maior do que no grupo controle (p < 0,01). A proporção de células Treg no grupo RA também foi drasticamente menor quando comparada ao grupo controle (p < 0,01). No grupo RA, o nível sérico de IL-17 foi significativamente maior do que no grupo controle (p < 0,01). Conclusão: O desequilíbrio de células Th17/Treg periféricas desempenha um papel importante na patogênese da RA. .

Introduction: Allergic rhinitis (AR) is an IgE-mediated non-infectious disease of the nasal mucosa following contact with allergens. Objective: To investigate the peripheral Th17 cells and CD4 + CD25 + Foxp3 + regulatory T (Treg) cells and the expression of cytokines in the serum of AR patients. Methods: The peripheral blood of 14 patients with AR (AR group) and six healthy subjects (control group) was collected from March to May of 2012. Flow cytometry was performed to detect the Th17 cells and Treg cells, and enzyme-linked immunosorbent assay (ELISA) to measure the serum levels of IL-17 and TGF-β1. Results: The proportion of Th17 cells in the AR group was markedly higher than that in the control group (p < 0.01). The proportion of Treg cells in the AR group was also dramatically reduced when compared with the control group (p < 0.01). In the AR group, serum IL-17 levels were markedly higher than those in the control group (p < 0.01). In the AR group, serum TGF-β1 levels were significantly lower than those in the control group (p < 0.01). Conclusion: The imbalance of peripheral Th17/Treg cells plays an important role in the pathogenesis of AR. .

Linfócitos T CD4+CD25+ e a regulação do sistema imunológico: perspectivas para o entendimento fisiopatológico da sepse / CD4+CD25+ T lymphocytes and regulation of the immune system: perspectives for a pathophysiological understanding of sepsis

A resposta inflamatória sistêmica representa o evento patogênico central da sepse, subjazendo às manifestações clínicas e aos achados laboratoriais presentes nos enfermos. Inúmeras pesquisas têm demonstrado que os linfócitos T CD4+CD25+ - também conhecidos como células T reguladoras (Treg) - participam dos processos de desenvolvimento da sepse, em virtude de sua capacidade de suprimir a resposta imune. Com base nessas ideias, propôs-se, no presente artigo, a discussão do papel dos linfócitos Treg na sepse, com base na revisão da literatura com estratégia de busca definida (LILACS, PubMed e SciELO), tendo em vista duas abordagens principais: a participação dessas células nos processos de inflamação e imunidade, e as perspectivas de investigação fisiopatológica computacional da condição mórbida.

The systemic inflammatory response represents the core pathogenic event of sepsis, underlying clinical manifestations and laboratory findings in patients. Numerous studies have shown that CD4+CD25+ T lymphocytes, also known as regulatory T lymphocytes (Treg), participate in the development of sepsis due to their ability to suppress the immune response. The present article discusses the role of Treg lymphocytes in sepsis based on a specific search strategy (Latin American and Caribbean Health Sciences / Literatura Latino-americana e do Caribe em Ciências da Saúde - LILACS, PubMed, and Scientific Electronic Library Online - SciELO) focusing on two main topics: the participation of Treg cells in inflammation and immunity as well as perspectives in the computational physiological investigation of sepsis.

Inmunopatogenia de las enfermedades autoinmunes / Immunophat ogenesis of aut oimmune diseases

Las enfermedades autoinmunes son patologías de gran complejidad clínica, difícil diagnóstico y complejo tratamiento cuya etiología permanece aún desconocida pese a los múltiples avances realizados en los últimos años. En la génesis de estas enfermedades participan múltiples factores que conflyen entre sí para dar origen a cada una de las patologías autoinmunes conocidas, sean estas órgano-específicas o sistémicas. Entre estos elementos se incluyen la pérdida de los mecanismos de tolerancia, factores de susceptibilidad genética (polimorfismos HLA, genes no HLA y mecanismos epigenéticos), factores ambientales (agentes vivos de enfermedad, agentes inorgánicos, hormonas y otros) y factores inmunológicos (linfocitos reguladores, citoquinas y moléculas coestimulatorias, entre otros). La identificación de estos factores permitirá mejorar el conocimiento de los variados mecanismos que median estas complejas enfermedades, facilitando no sólo el entendimiento de su etiología sino también perfeccionar las herramientas terapéuticas para enfrentarlas.

Autoimmune diseases are pathologies of great clinical complexity, difficult diagnosis and treatment complex which etiology still remains unknowns despite the many advances made in recent years. In the genesis of these diseases involves multiple factors that converge together to give rise to each of the autoimmune diseases knows, whether organ specific or systemic. These elements include loss of tolerance mechanisms, genetic susceptibility factors (HLA polymorphisms, genes non-HLA and epigenetic mechanisms), environmental factors (living agents of disease, inorganic agents, hormones, etc.) and immunologic factors (regulators lymphocyte, cytokines, costimulatory molecules and others). Identifying these factors will improve the knowledge of the various mechanisms that mediate these complex diseases facilitating not only the understanding of the etiology but also improve the therapeutic tools to address them.

Efeitos cardiovasculares da transferência adotiva de linfócitos T reguladores em camundongos submetidos à infusão crônica de angiotensina II e de aldosterona / Cardiovascular effects of adoptive transfer of regulatory T lymphocytes in mice submitted to chronic infusion of angiotensin II and aldosterone

A angiotensina (Ang) II e aldosterona induzem hipertensão arterial por mecanismos em parte mediados pela imunidade adaptativa, envolvendo linfócitos T auxiliares respondedores (Tresp). Os linfócitos T reguladores (Treg) são capazes de suprimir os efeitos pró-inflamatórios do sistema imune. O presente estudo avaliou se a transferência adotiva de Treg é capaz de prevenir a hipertensão e a lesão vascular induzidas pela AngII ou pela aldosterona, em dois protocolos distintos. No protocolo com Ang II, camundongos machos C57BL/6 sofreram a injeção endovenosa de Treg ou Tresp, sendo depois infundidos com Ang II (1ug/kg/min), ou salina (grupo controle) por 14 dias. No protocolo com aldosterona, um outro conjunto de animais sofreu injeções de Treg ou Tresp, sendo depois infundido com aldosterona (600ug/kg/d) ou salina (grupo controle), pelo mesmo intervalo de tempo. O grupo tratado com aldosterona recebeu salina 1% na água. Tanto o grupo Ang II como aldosterona apresentaram elevação da pressão arterial sistólica (43% e 31% respectivamente), da atividade da NADPH oxidase na aorta (1,5 e 1,9 vezes, respectivamente) e no coração (1,8 e 2,4 vezes, respectivamente) e uma redução da resposta vasodilatadora à acetilcolina (de 70% e 56%, respectivamente), quando comparados com os respectivos controles (P<0,05). Adicionalmente, a administração de Ang II proporcionou um aumento rigidez vascular (P<0,001), na expressão de VCAM-1 nas artérias mesentéricas (P<0,05), na infiltração aórtica de macrófagos e linfócitos T (P<0,001) e nos níveis plasmáticos das citocinas inflamatórias interferon (INF)-y, interleucina (IL)-6, Tumor necrosis factor (TNF)-a e IL-10 (P<0,05). Ang II causou uma queda de 43% no número de células Foxp3+ no córtex renal, enquanto que a transferência adotiva de Treg aumentou as células Foxp3+ em duas vezes em comparação com o controle. A administração de Treg preveniu o remodelamento vascular induzido pela aldosterona, observado na relação média/lúmen...

Angiotensin (Ang) II and aldosterone (aldo) induce hypertension through mechanisms in part mediated by adaptive immunity and T responder lymphocytes. T regulatory (Treg) lymphocytes suppress pro-inflammatory mediators of the immune system. We questioned whether Treg adoptive transfer will blunt Ang II or aldo-induced hypertension and vascular injury, by evaluating two distinct protocols. In the Ang II protocol, male C57BL/6 mice were injected i.v. with Treg or T responder cells, and then infused with Ang II (1ug/kg/min) or saline, for 14 days. In the aldosterone protocol, another set of animals was injected with Treg or T responder cells, and then infused with aldosterone (600ug/kg/d) or saline, for the same period. The aldosterone group received saline 1% in drinking water. Both Ang II and aldosterone treated mice presented an increase in systolic blood pressure (43% and 31% respectively), of NADPH oxidase activity in aorta (1.5 and 1.9 fold, respectively) and heart (1.8 and 2.4 fold respectively) and an impaired vasodilatory response do acetylcholine (by 70% and 56% respectively), when compared to their controls (P<0.05). In addition, Ang II administration resulted in increased vascular stiffness (P<0.001), mesenteric artery vascular cell adhesion molecule (VCAM-1) expression (P<0.05), aortic macrophage and T cell infiltration (P<0.001), and the plasma levels of the inflammatory cytokines INF-y, IL-6, TNF-a, and IL-10 (P<0,05). And II caused a 43% decrease in the number of Foxp3+ cells in the renal cortex, while Treg adoptive transfer increased Foxp3+ cells 2-fold compared to control. Treg administration prevented aldosterone-induced vascular remodelling, as observed by media to lumen ratio and media cross sectional area analysis of mesenteric arteries (P<0,05). All the above were prevented by Treg but not by T responder cell adoptive transfer. These results demonstrate that Treg suppress Ang II of aldo-mediated vascular injury and BP elevation...

Presencia de linfocitos T reguladores en periodontitis crónica / Presence of T regulatory cells in chronic periodontitis

La enfermedad periodontal requiere de un hospedero susceptible para su desarrollo y progresión. Dentro de las características del hospedero se encuentra la respuesta T reguladora, que otorga tolerancia frente a antígenos propios, participa durante las enfermedades infecciosas limitando el daño tisular, sin disminuir la respuesta antibacteriana. El presente estudio tiene por objetivo determinar la presencia, reclutamiento y función de Tregs en pacientes con periodontitis crónica. En 10 biopsias de tejido periodontal sano y con periodontits crónica se realizó inmunohistoquímica para marcadores (CD4, CD25, Foxp3), quimioquinas (CCL17, CCL22) y citoquinas (TGF-B, IL-10) de Tregs. Además de Western-Blot para detectar las citoquinas. Los resultados obtenidos sugieren una posible asociación entre células Tregs y la infección periodontal, ya que se confirma su reclutamiento y presencia. Sin embargo, son necesarios más estudios del posible desbalance con su contraparte pro-inflamatoria Th17, que expliquen en parte la compleja etiopatogenia de la enfermedad periodontal.

Periodontal disease requires a susceptible host to initiation, development and progression. T regulatory response is one of these inmunoregulatory characteristics of the susceptible host, which provide tolerance, tissular protection during infection without impairing the control of periodontopathogens. The aim of this study is to determinate the presence, homing and function of T regulatory cells (Tregs) in patients with chronic periodontitis. Ten biopsies were taken from pockets, the presence of Tregs markers (CD4, CD25, Foxp3), chemokines (CCL17, CCL22) and cytokines (TGF-p, IL-10) were determinate by immunohistochemistry. Cytokines also were detected with Western-Blot. Our results suggest a possible association between Tregs and periodontal infection, confirming homing and presence of Tregs. However, further studies are required to determine the possible imbalance with pro-inflammatory part Th17, that might explain the complex etiopathogenesis of periodontal disease.

Inmunoterapia del cáncer: Importancia de controlar la inmunosupresión / Cancer immunotherapy: Importance of overcoming immune suppression

Es cada vez mayor la evidencia experimental y clínica de que el sistema inmunitario interviene activamente en la patogénesis y el control de la progresión tumoral. Una respuesta antitumoral efectiva depende de la correcta interacción de varios componentes del sistema inmunitario, como las células presentadoras de antígeno y diferentes sub-poblaciones de linfocitos T. Sin embargo, los tumores malignos desarrollan numerosos mecanismos para evadir el reconocimiento y su eliminación por parte del sistema inmunitario. En esta revisión discutiremos algunos de esos mecanismos y posibles estrategias terapéuticas para contrarrestarlos.

Increasing evidence indicates that the immune system is involved in the control of tumor progression. Effective antitumor immune response depends on the interaction between several components of the immune system, including antigen-presenting cells and different T cell subsets. However, tumor cells develop a number of mechanisms to escape recognition and elimination by the immune system. In this review we discuss these mechanisms and address possible therapeutic approaches to overcome the immune suppression generated by tumors.

Imunologia da retinocoroidite toxoplásmica / Immunology of the toxoplasmic retinochoroiditis

A infecção pelo Toxoplasma gondii é uma importante causa de doença ocular, tanto em indivíduos imunocomprometidos como em imunocompetentes. A patogênese da destruição retinocoroidiana associada a essa infecção ainda não está totalmente esclarecida. Nesta revisão, discute-se o papel do sistema imune no controle da infecção pelo Toxoplasma, especialmente, no olho.

Toxoplasma gondii infection is an important cause of ocular disease in both immunocompromised and immunocompetent subjects. The pathogenesis of retinochoroidal lesion associated with this infection is not fully understood. In this review, the role of the immune system in the control of Toxoplasma infection, especially in the eye, is discussed.

Células dendríticas y linfocitos T reguladores naturales en pacientes con enfermedad crónica de Chagas / Dendritic cells and natural regulatory T lymphocytes in chronic chagasic patients

Dada la cronicidad y persistencia del parásito Trypanosoma cruzi en la enfermedad de Chagas, el control homeostático de la respuesta inmunitaria para prevenir el daño tisular y limitar la duración del proceso inflamatorio involucra células con potencial regulador como las células dendríticas y los linfocitos T reguladores. Es por tal motivo que el objetivo de este estudio fue evaluar la proporción de células dendríticas totales, subpoblaciones de células dendríticas mieloides y plasmacitoides y los linfocitos T reguladores naturales en pacientes con enfermedad de Chagas y controles sanos. Las células mononucleares de sangre periférica de 18 pacientes con enfermedad crónica de Chagas y 16 controles sanos se sometieron a marcación para células dendríticas mieloides Lin- HLA-DR+ CD11c+, CD plasmacitoides Lin- HLA-DR+ CD123+ y linfocitos T reguladores naturales CD3+ CD4+ CD25+ Foxp3+ CD127 bajo. Las proporciones celulares se calcularon mediante el porcentaje obtenido por citometría de flujo. Se encontró que la proporción de células dendríticas plasmacitoides es menor que la de las mieloides, tanto en pacientes con enfermedad crónica de Chagas como en controles sanos, sin diferencias significativas entre ambos grupos. En contraste, se encontró una proporción significativamente mayor de linfocitos T reguladores naturales en los pacientes con enfermedad de Chagas al comparar con los controles sanos. En conclusión, la mayor proporción de linfocitos T reguladores naturales en pacientes con enfermedad crónica de Chagas sugiere que estas células pueden estar contribuyendo en la patogénesis de la enfermedad.

Given the chronicity and persistence of the parasite Trypanosoma cruzi in the Chagas disease victims, the homeostatic control of immune response to prevent tissue damage and limit the duration of the inflammatory process involves cells with regulatory potential as dendritic cells (DC) and regulatory T cells. For this reason, the objective of this study is to evaluate the proportion of total DC, myeloid and plasmacytoid DC subpopulations and natural regulatory T cells in chronic chagasic patients and healthy control subjects. Peripheral blood mononuclear cells (PBMC) from 18 chronic chagasic patients and 16 healthy control subjects were staining to myeloid DC Lin- HLA-DR+ CD11c+, plasmacytoid DC Lin-, HLA-DR+, CD123+ and natural regulatory T lymphocytes CD3+ CD4+ CD25+ Foxp3+ CD127low. Cellular proportions were calculated using the percentage obtained by flow cytometry. It was found that plasmacytoid CD proportion was lower than myeloid CD in both, chronic chagasic patients and healthy control subjects, without significant differences between the two groups. On the contrary, it was found that the proportion of natural regulatory T cells was significantly higher in chronic chagasic patients than in healthy control subjects upon comparing the two. These results suggest that the higher proportion of natural regulatory T cells in chronic chagasic patients might contribute to the disease pathogenesis.