Natürlich vorkommende regulatorische T-Zellen spielen eine entscheidende Rolle für die intestinale Immunhomöostase und Limitierung von (Auto)-Immunität. Sie exprimieren den Transkriptionsfaktor Foxp3 und an der Oberfläche die α-Kette des IL-2 Rezeptors (CD25). Im Tiermodell verhindern regulatorische T-Zellen Autoimmunopathien, Transplantatabstoßungen und entzündliche Darmerkrankungen. Da Foxp3+ regulatorische T-Zellen nur äußerst geringe Mengen an Interleukin-2 synthetisieren, sind sie auf eine adäquate Versorgung angewiesen. Konventionelle T-Zellen werden als bedeutende IL-2 Quelle für Treg-Zellen vermutet, doch über die Mechanismen und räumlich-zeitliche Dynamik der Treg-Effektor-Zellinteraktion ist bisher nur wenig bekannt. In dieser Arbeit wurden Foxp3+ regulatorische T-Zellen in Mausgeweben analysiert und Zellinteraktionen mit Effektorzellen im Darm charakterisiert. Es wurde ein theoretisches Modell zur Evaluierung von Zell-Zellkontakten erarbeitet und experimentell überprüft. Es konnte gezeigt werden, dass in der Akutphase einer T-Zell-induzierten Kolitis und im Kolon von gesunden Wildtyp-Mäusen Foxp3+ regulatorische T-Zellen an Ki-67+ proliferierenden T-Zellen akkumulieren. Diese Zellinteraktionen sind abhängig von Interleukin-2, da IL-2 defiziente Mäuse keine signifikanten Treg-Effektor-Zellakkumulationen aufweisen. Die Analyse der Genexpression konnte zeigen, dass Ki-67+ Zellen Interleukin-2 produzieren. Lokal sezerniertes Interleukin-2 könnte als Sensor für Entzündungsprozesse chemotaktisch auf Foxp3+ regulatorische T-Zellen wirken und die Akkumulation an proliferierenden, IL-2 produzierenden Effektorzellen bedingen. Dieser Mechanismus könnte einerseits zur lokalen Versorgung mit IL-2 dienen und gleichzeitig regulierend auf Effektorzellen in unmittelbarer Umgebung wirken. Dieser Prozess würde zur Erhaltung von regulatorischen T-Zellen in der Peripherie und zur Sicherung der intestinalen Immunbalance beitragen.

Une immunité concomitante à long terme est mise en place lors d’infections persistantes avec des parasites protozoaires intracellulaires responsables, par exemple, de la leishmaniose et du paludisme. Dans un modèle murin de leishmaniose, il a ainsi été démontré que les cellules T régulatrices CD4+CD25+ sont impliquées dans la persistance des leishmanies aux sites d’infection cutanés et protègent l’hôte contre une ré-infection.Le protozoaire Toxoplasma gondii est également à l’origine d’une infection chronique liée à l’installation du parasite dans le cerveau et les muscles de l’hôte dans des formes kystiques. Il était donc pertinent de s’intéresser à l’implication des cellules T régulatrices dans l’installation et la persistance du toxoplasme.Pour atteindre cet objectif, nous avons utilisé l’anticorps monoclonal anti-CD25 dans des expériences de déplétion pendant la phase aiguë de la toxoplasmose après infection de souris non consanguines avec une souche de toxoplasmes de type II. Aucune différence significative que ce soit en terme de mortalité ou de charge parasitaire cérébrale n’a été observée entre les souris infectées et déplétées et les souris infectées non déplétées. En complément de ces expériences, nous avons pu montrer que les cellules régulatrices CD4+CD25+Foxp3+ (Treg) sont une cible potentielle de l’anticorps anti-CD25 ainsi que les cellules T effectrices CD4+CD25+Foxp3- (Teff); cellules qui expriment le marqueur CD25 en phase aiguë de l’infection. / Long term concomitant immunity is developed in case of persistant infections with intracellular protozoan parasites like for example in leishmaniosis and malaria. In a murine model of leishmaniosis, it has been demonstrated that CD4+CD25+ regulatory T (Treg) cells are involved in the persistance of leishmania parasites at cutaneous sites of infection and protect the host against re-infection.The protozoan parasite Toxoplasma gondii is also responsible for a chronic infection associated with the settlement of parasite in the brain and the muscles of the host in the form of cysts. It was therefore pertinent to know about the implication of Treg cells in the development and the persistance of toxoplasma. To attain this objective, we have used a monoclonal antibody anti-CD25 in depletion experiments during the acute phase of toxoplasmosis after infection of outbred mice with a type II toxoplasma strain. No significant difference was found in terms of mortality or in brain cyst load between depleted mice and non-depleted mice. In addition to these experiments, we have shown that not only the CD4+CD25+Foxp3+ regulatory T (Treg) cells but also the CD4+CD25+Foxp3- T effector (Teff) cells are a potential target of anti-CD25 antibody-depletion. These cells are induced to express CD25 during acute phase of the infection.

The development and function of T helper (Th) cells and regulatory T cells (Tregs) are plastic processes that are regulated by cytokines. In our project we first analyzed the effect of different cytokines on the development of induced (i) Tregs. It has been demonstrated that iTregs arise from CD4+ CD25- T cells upon stimulation with alloantigen in the presence of transforming growth factor β (TGF-β). The development of these Tregs and their proliferation were inhibited by interleukin (IL)-4 and IL-12. The aquired results also demonstrated distinct responses of naturally occuring (n) Tregs and iTregs to the regulatory action of IL-4 and an opposite role of IL-4 in maintenance of nTregs and iTregs phenotype. An important role in the induction of T cell subsets may play also mesenchymal stem cells (MSCs) which can, under specific conditions, produce TGF-β and IL-6. Depending on the current production of TGF-β or IL-6, MSCs can qualitatively regulate the ration between Tregs and Th17 cells. Anti-inflammatory Tregs and pro-inflammatory Th17 cells are induced upon stimulation in the presence of TGF-β and TGF-β and IL-6, respectively. In addition to our previous work we studied the role of IL-12 in the development of Tregs and Th17 cells. It was shown that Treg and also Th17 cell differentiation was...

Regulatory T cells expressing the transcription factor Foxp3 have a critical role in the maintenance of tolerance to both self and innocuous exogenous antigens. Humans and mice die from overwhelming autoimmunity in the absence of Foxp3+ Treg whilst administration of regulatory T cells has shown promise therapeutically in ameliorating autoimmunity in several animal models. Regulatory T cells arise naturally in the thymus (nTreg) but may also be induced from naïve Foxp3- cells in the presence of TGF-β (iTreg), both in vitro and in vivo. This thesis focuses on in vitro generated mouse iTreg, testing the hypothesis that they are able to effect bystander suppression; iTreg activated by a given antigen are able to suppress other responding cells with different antigen reactivities. Chapter 3 details an in vitro assay system using iTreg and responder cells recognising different antigens (TCR transgenic cells). Evidence for bystander suppression is presented and that did not require the presence of iTreg-relevant antigen but did require iTreg-relevant MHC Class II. The kinetics of iTreg suppression are discussed, with evidence presented that iTreg exert their effects early in co-culture. Chapter 4 identifies the production of three pro-inflammatory cytokines by iTreg - IFN-γ, GM-CSF, and TNF. These were not involved in the in vitro suppressive mechanism, but early abrogation of TGF-β signalling did inhibit suppression. Chapter 5 describes the in vivo function of iTreg under various experimental protocols. iTreg did not limit initial proliferation of naïve T cells in response to antigen but did limit the development of effector cells producing pro-inflammatory cytokines. Exposure to a pro-inflammatory environment in vivo led to iTreg producing IFN-γ and TNF, but not GM-CSF. This could be replicated in vitro by exposure to IL-6, IL-12 or IL-27. Finally, evidence for bystander suppression by iTreg in vivo is presented, with a reduction in effector cells producing pro-inflammatory cytokines shown in an allergic airways diease model.

La Leucémie Lymphoïde Chronique (LLC) se caractérise par une hétérogénéité d’évolution avec des formes indolente et progressive. Cette dernière reste incurable avec les options thérapeutiques classiques. Mon objectif de thèse a consisté à définir phénotypiquement et fonctionnellement le potentiel régulateur des lymphocytes B de LLC induisant un contexte favorable à leur survie. Après purification des cellules B leucémiques de 30 patients LLC, nos résultats montrent que les sous-populations B sécrètent des cytokines immuno-régulatrices dont l’IL-10 et le TGFβ1. De façon intéressante, ces sous-populations lymphocytaires expriment également le facteur de transcription FOXP3, caractéristique des cellules T régulatrices. La signature phénotypique de ces sous-populations est spécifique au néoplasme avec des marqueurs de lymphocytes B mémoires activés. Nos approches fonctionnelles in vitro démontrent que ces sous-populations B modulent la prolifération et orientent la différenciation et les sécrétions des cellules T, contribuant à l’absence d’immuno-surveillance chez les patients. Enfin, une analyse statistique combinant les expressions de l’IL-10, du TGFβ1 et de FOXP3 dans ces sous-populations B permet de définir un indice polyfonctionnel qui corrèle avec deux facteurs clés du risque de progression de la LLC. L’ensemble de mes travaux de thèse a permis de caractériser de nouvelles sous-populations B impliquées dans la progression de la maladie et donne un rationnel à la survie des cellules leucémiques dans l’environnement ganglionnaire. / Chronic Lymphocytic Leukemia (CLL) is a clonal B cell malignancy of the elderly. This neoplasm is characterized by a heterogeneous clinical course from indolent chronic disease to progressive lymphadenopathy that remains incurable. The aim of my PhD was to undertake a comprehensive phenotypic and functional analysis of the B cell subpopulations responsible for their survival advantage. CLL B cell purification from 30 patients indicate the presence in various extents of leukemic B cell subpopulations producing immune-regulatory cytokines, notably IL-10 and TGFβ1. Remarkably, these CLL subpopulations express the FOXP3 transcription factor, a marker of regulatory T cells. These subpopulations present a phenotypic signature, distinguishable from regulatory B cells populations, with specific markers of activated memory B cells. Functional studies prove their regulatory capacities on T cell differentiation, proliferation and secretion, contributing to the T cell dysfunction observed in CLL. Finally, statistical analysis combining IL-10, TGFβ1 and FOXP3 expressions for these subpopulations allows generating a poly-functional index correlated with two major risk factors of CLL progression. Our data characterize novel CLL B cell subpopulations that are involved in disease progression and give a rational to CLL B cell survival in secondary lymphoid organs.

Regulatorische T-Lymphozyten differenzieren sich im fetalen Thymus unter dem Einfluss des Transkriptionsfaktors FoxP3. Sie sind für die Aufrechterhaltung des Gleichgewichts des Immunsystems wichtig. Es wurde untersucht ob eine Chorioamnionitis, induziert durch intraamniotische Endotoxingabe, die fetale Thymusentwicklung beeinflusst. Den Mutterschafen wurde fünf Tage, zwei Tage, einen Tag oder fünf Stunden vor der Sectio cesarea 10mg Endotoxin intraamniotisch verabreicht. Die Sectio cesarea wurde bei einem Gestationsalter von 123 Tagen durchgeführt. Der entnommene Thymus wurde gewogen, Nabelschnurblutlymphozyten und Plamakortisolwerte wurden bestimmt. Glukokortikoidrezeptoren, aktivierte Caspase-3-, Ki67-, PCNA-, NFkB- und FoxP3-positive Zellen wurden immunohistochemisch nachgewiesen. Das Thymusgewicht war im Verhältnis zum Körpergewicht der Lämmer nach intraamniotischer Endotoxingabe zu allen gemessenen Zeitpunkten verringert. Die zirkulierenden Lymphozyten im Nabelschnurblut nahmen einen Tag nach Endotoxingabe um 40% ab. Die Endotoxingabe führte zu einem vorübergehenden Anstieg der Plasmakortisolwerte, zu einer Verdoppelung NFkB positiver Zellen und zu einer Abnahme Foxp3 positiver Zellen in der Thymusrinde einen Tag nach Endotoxingabe. Die intraamniotische Verabreichung eines Endotoxins führte im Schafmodell zu Veränderungen im fetalen Thymus. / Regulatory T-lymphocytes differentiate in the fetal thymus under the control of the transcription factor FoxP3. T-lymphocytes mediate homeostasis of the immune system. The objective was whether chorioamnionitis, caused by endotoxin,would modulate fetal thymus development. An intaamniotic injection of 10mg endotoxin was given to the sheep five days, two days, one day or five hours before delivery at 123 gestation days. Thymus weight, cord blood lymphocytes and plasma cortisol were measured. Glucocorticoid receptor-, activated caspase-3-, Ki67-, proliferating cell nuclear antigen-, nuclear factor kB-, and FoxP3-positive cells were immunohistochemically evaluated. Thymus-to-body weight ratios were reduced in all endotoxin groups. There was a decrease of circulation lymphoctes after intraamniotic endotoxin exposure by 40% after one day. Plasma cortisol concentration increased transiently, nuclear factor kB positive cells in thymic cortex doubled and FoxP3 positive cells were reduced one day after endotoxin exposure. Intraamniotic exposure to endotoxin induced thymic changes in fetal sheep.

Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS). In the current thesis, we have preformed an immunological investigation of patients with MS and developed an immunosuppressive cell therapy that could be beneficial for these patients. MS has been considered to be driven by T helper type1 (Th1) lymphocytes but new data indicate the involvement of Th17 responses. T cells from patients with MS that were evaluated for immunological status secreted both interferon-γ and interleukin-17 upon stimulation. However, T cells from patients with MS in remission, in contrast to relapse, had poor proliferative capacity suggesting that they are controlled and kept in anergy. T regulatory cells (Tregs) are important to maintain self-tolerance and the role of CD4+CD25+FoxP3+ Tregs in autoimmunity has been extensively investigated. We analyzed Tregs from patients with MS in relapse and remission by multicolor flow cytometry for the expression of CD3, CD4, IL2R (CD25), FoxP3 and the IL7R (CD127). Patients in relapse exhibited higher levels of FoxP3-positive Tregs lacking CD25 compared to healthy controls, indicating that Tregs might attempt to restrain immune activity during relapse. In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, therapy with suppressive cells such as Tregs or mesenchymal stromal cells (MSCs) has proven beneficial. However, systemic administration of such cells may immunologically compromise the recipient and promote infections due to general immunosuppression. We hypothesized that suppressive cells can be equipped with a CNS-targeting receptor and be delivered intra-nasally to avoid systemic exposure. CD4+ T cells were modified with a lentiviral vector system to express a myelin oligodendrocyte (MOG)-targeting receptor in trans with the FoxP3 gene that drives Treg differentiation. Genetically engineered Tregs demonstrated suppressive capacity in vitro and localized to the brain and suppressed ongoing encephalomyelitis in vivo. Cured mice were rechallenged with an EAE-inducing inoculum but remained healthy. MSCs are a heterogeneous population of stromal cells residing in most connective tissues and have the capacity to suppress effector cells of the immune system. MSCs were engineered to express MOG-targeting receptors using lentiviral vectors. Genetically engineered MSCs retained their suppressive capacity in vitro and successfully targeted the brain upon intranasal delivery. Engineered MSCs cured mice from disease symptoms and these mice were resistant to further EAE challenge. Encephalitic T cells isolated from cured mice displayed an anergic profile while peripheral T cells were still responsive to stimuli. In conclusion, MS patients have peripheral CNS-reactive T cells of both Th1 and Th17 type that, while in remission, are kept in anergy. Also, MS patients in relapse exhibit increased levels of CD25 negative Tregs indicating an attempt to restrain immune activity. Finally, immunosuppressive cells can be genetically engineered to target CNS and efficiently suppress encephalomyelitis in an active EAE model upon intranasal delivery.

<p>Naturally occurring CD4+CD25+Foxp3+ regulatory T cells (TReg) are a cell lineage that develops in the thymus and exits to the periphery, where they represent 5-10% of the peripheral CD4+ T cell population. Phenotypically, they are characterized by the expression of the cell surface markers CD25, as known as the IL-2 receptor alpha chain, glucocorticoid-induced tumor necrosis factor receptor (GITR), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), as well as forkhead box P3 (Foxp3), a transcription factor considered to be the most specific TReg marker. Functionally, TReg cells are defined by their ability to suppress the activation of multiple cell types including CD4+ and CD8+ T cells, B cells, natural killer (NK) cells, and dendritic cells (DCs). Suppression can be achieved by the production of immunosuppressive cytokines or direct cell-to-cell contact, with these mechanisms directly affecting suppressed cells or indirectly affecting them by modulating antigen presenting cells (APCs). The suppressive abilities of TReg cells are crucial in maintaining dominant tolerance--the active, trans-acting suppression of the immune system for the prevention of autoimmune diseases. In addition to preventing autoimmune diseases, studies have also demonstrated critical roles for TReg cells in down-modulating anti-tumor immunity, suppressing allergic diseases, such as asthma, and achieving transplant tolerance. Recent studies have also demonstrated roles for TReg cells during pathogen infection, which will be the focus of this thesis.</p><p>Studies examining TReg cells during infection have largely focused on chronic infection models. These studies have shown that TReg cells can affect responses to pathogens in various ways that can be beneficial or detrimental for either the host or the invading pathogen. In some infections, TReg cells downregulation effector responses, which can lead to pathogen persistence and, in some cases, concomitant immunity. TReg cell-mediated suppression can also reduce immunopathology at sites of infection, which can occur as a result of a vigorous anti-pathogen immune response. </p><p>In contrast to chronic infection, how TReg cells behave and function following acute infections remains largely unknown as, to date, very few studies have been conducted. Current work with acute infection models has indicated that TReg cells affect immune responses in some acute infection models, but not in all. Furthermore, the results of these studies have implicated that current approaches to examine TReg cells during acute infection by depleting the total TReg cell repertoire, as opposed to targeting pathogen-specific TReg cells, may not be ideal. Finally, it is unclear what happens to activated TReg cells following the resolution of infection. </p><p>Due to the lack of knowledge about the role of pathogen-specific TReg cells during acute infection, we sought to employ a different approach to address some of the outstanding questions in the field. Here, we utilized CD4+ non-TReg and TReg cells from T cell receptor (TCR) transgenic mice that recognize a pathogen-specific epitope found in three different models of acute viral infection: recombinant vaccinia virus, recombinant adenovirus, and influenza. Using this model system, we were able to track pathogen-specific TReg cells following acute viral infection to determine their kinetics during the course of infection, as well as their influence on CD4+ non-TReg cells during different times after infection. We also employed major histocompatibility complex (MHC) Class II tetramer technology to track the fate of endogenous pathogen-specific TReg cells following infection with influenza. </p><p>Using these models systems, we show that pathogen-specific TReg cells can be activated and expand upon acute viral infections in vivo. The activated TReg cells then contract to form a "memory" pool after resolution of the infection. These "memory" TReg cells expand rapidly upon a secondary challenge, secrete large amounts of IL-10, and suppress excessive immunopathology, which is elicited by the expansion of non-TReg cells, via an IL-10-dependent mechanism. The work presented in this thesis reveals a previously unknown "memory" TReg cell population that develops after acute viral infections and may help design effective strategies to circumvent excessive immunopathology.</p> / Dissertation

Submitted by Pós Imunologia (ppgimicsufba@gmail.com) on 2017-02-07T18:45:00Z No. of bitstreams: 1 TESE_CINTIA MARQUES.pdf: 774112 bytes, checksum: 4eb77463eb7b53260c945d76b45ec8f9 (MD5) / Approved for entry into archive by Delba Rosa (delba@ufba.br) on 2017-02-08T16:17:19Z (GMT) No. of bitstreams: 1 TESE_CINTIA MARQUES.pdf: 774112 bytes, checksum: 4eb77463eb7b53260c945d76b45ec8f9 (MD5) / Made available in DSpace on 2017-02-08T16:17:19Z (GMT). No. of bitstreams: 1 TESE_CINTIA MARQUES.pdf: 774112 bytes, checksum: 4eb77463eb7b53260c945d76b45ec8f9 (MD5) / CAPES / Asma e atopia são condições determinadas por fatores genéticos e ambientais, que podem atuar tanto independentemente quanto em interação. Diversos estudos de associação ampla do genoma têm sido desenvolvidos para tentar compreender quais componentes genéticos influenciam na asma. No entanto, genes localizados no cromossomo X são frequentemente pouco representados. Um dos genes localizados nesse cromossomo, o FOXP3, codifica uma fator de transcrição que está diretamente relacionado à ativação e diferenciação de células T regulatórias. Tais células constituem um importante mecanismo relacionado ao controle de doenças alérgicas. Diversos polimorfismos já foram descritos nas regiões codificante e regulatória do FOXP3, o que sugere que os mesmos possam ter um impacto funcional sobre a proteína correspondente. Desta forma, fatores genéticos que afetam o gene FOXP3 podem determinar diferenças na susceptibilidade a doenças alérgicas, tais como a asma. Neste contexto, o presente trabalho teve como objetivo avaliar o impacto de polimorfismos em genes localizados no cromossomo X, a exemplo FOXP3, no desenvolvimento da asma e atopia. Para analisar a associação de polimorfismos presentes no cromossomo X e asma, foi realizado um X-WAS (Estudo da Associação Ampla do Cromossomo X). Já para verificar a associação de polimorfismos no gene FOXP3 com asma e atopia foi realizado um estudo de gene-candidato. Como resultados mais importantes destaca-se a associação do polimorfismo rs12007907 no gene IL1RAPL com sintomas de asma (P = 3.33x10-6; OR=0.49, 95% IC= 0.37 - 0.67) e níveis de produção de IL-13 (p = 0.045) no X-WAS; a associação dos polimorfismos no gene FOXP3 rs2232368 (OR = 1,95; 95% IC= 1.04 – 3,66) com sintomas de asma, rs2232368 (OR = 2,31; 95% IC= 1,16 – 4,59), rs3761549 (OR = 1,44; 95% IC= 1,028 – 2,018) e rs2280883 (OR = 0,836; 95% IC= 0,704 – 0,992) com atopia, além da interação entre o rs2280883 no FOXP3 e infecção com EBV no desenvolvimento de atopia definida por SPT (OR = 0,64; 95% IC: 0,47 – 0,87) e IgE específico para aeroalérgenos (OR = 0,62; 95% IC: 0,46 – 0,83). Estes achados sugerem que polimorfismos em genes do cromossomo X, dentre eles FOXP3 e IL1RAPL, possuem impacto no desenvolvimento de asma e alergia em nossa população. No entanto, novos estudos devem ser conduzidos na tentativa de elucidar melhor o impacto funcional destes polimorfismos aqui descritos no desenvolvimento de asma e alergia, além da replicação em outras populações. / Asthma and atopy are conditions determined by genetic and environmental factors, which can act independently and in interaction. Several Genome Wide Association Studies has been conducted to try to understand which genetic components influence asthma. However, genes located on the X chromosome are often underrepresented. One of the genes located in this chromosome, the FOXP3, encodes a transcription factor that is directly related to the activation and differentiation of regulatory T cells. Such cells are an important mechanism related to the control of allergic diseases. Several polymorphisms have been described in coding and regulatory regions of the FOXP3, which suggests that they may have a functional impact on the corresponding protein. Thus, genetic factors affecting the FOXP3 gene can determine differences in susceptibility to allergic diseases such as asthma. In this context, this study aimed to assess the impact of polymorphisms in genes located on the X chromosome, such the FOXP3, in the asthma and atopy risk. To analyze the association between polymorphisms on chromosome X and asthma, it was carried out an X-WAS (Study of Wide Association of Chromosome X). To verify the association of polymorphisms in the FOXP3 gene with asthma and atopy, a gene-candidate study was conducted. The meaningful results were the association of rs12007907 polymorphism in IL1RAPL gene with asthma symptoms (p = 3.33x10-6; OR = 0.49, 95% CI = 0.37 - 0.67) and IL-13 production levels (p = 0.045) in X-WAS; furthermore we observed association of rs2232368 in the FOXP3 gene with asthma symptoms (OR = 1.95; 95% CI = 4.1 - 3.66) and a association with atopy for the rs2232368 (OR = 2.313; 95% CI = 1.16 to 4.59), the rs3761549 (OR = 1.44; 95% CI = 1.03 to 2.02) and rs2280883 (OR = 0.836, 95% CI = 0.70 to 0.99). In addition, we reported an interaction between the rs2280883 located on FOXP3 and infection with EBV in the atopy development defined by SPT (OR = 0.64; 95% CI: 0.47 - 0.87) and specifc IgE to allergens (OR = 0.62; 95% CI: 0.46 - 0.83). These findings suggest that polymorphisms in genes of the X chromosome, including FOXP3 and IL1RAPL, have potential impact on the development of asthma and allergy in our population. However, further studies should be conducted to elucidate the functional impact of these polymorphisms described in this study in the asthma and atopy, as well as replication in other populations.

Submitted by Hiolanda Rêgo (hiolandar@gmail.com) on 2013-09-17T18:42:20Z No. of bitstreams: 1 Tese_ICS_Murilo Pedreira Neves Junior.pdf: 3966713 bytes, checksum: 7ad2357837ebe9ba4e68dd6c08edab38 (MD5) / Made available in DSpace on 2013-09-17T18:42:20Z (GMT). No. of bitstreams: 1 Tese_ICS_Murilo Pedreira Neves Junior.pdf: 3966713 bytes, checksum: 7ad2357837ebe9ba4e68dd6c08edab38 (MD5) / Serviço de Imunologia UFBA / Introdução: Tumores da tiróide são endócrinopatias comuns na população entre 20 e 60 anos. O FOXP3 é um membro da família de reguladores da transcrição que está envolvida na regulação do desenvolvimento e função do sistema imune. Esta expresso em células normais linfoides e em células neoplásicas de vários tecidos como pulmão, mama, cólon, melanoma e leucemias, este estudo tem o objetivo de identificar a presença do FOXP3 no carcinoma papilíferos da Tireoide Metodologia Foi realizado um estudo de série de casos coletados no período de 2000 a 2008, quando foram realizadas 1438 tiroidectomias totais no Serviço de Cirurgia do Hospital São Rafael, Salvador, Bahia. Destes casos, foram selecionados aqueles com diagnóstico de carcinoma papilíferos da Tireoide, perfazendo um total de 466 casos, dos quais foram coletadas informações demográficas de prontuários eletrônicos do hospital. Foi realizada revisão das lâminas para classificação dos subtipos histológicos do carcinoma papilíferos da Tireoide e identificação de tireoidite de Hashimoto. Os dados foram dispostos em banco de dados para análise estatística. Posteriormente, foram randomicamente selecionadas 30 casos de CPT para fins de exame imunoistoquímico com o anticorpo contra FOXP3. Resultados: Dos 29 casos submetidos ao exame de imunoistoquímica observou-se que 23 (79.3%) casos eram do sexo feminino e seis (20.7%) eram do sexo masculino. A média de idade foi de 42 anos. 18 pacientes (62.1%) foram diagnosticados apenas com CPT e 11 (37.9%) tinham TH concomitante. A marcação positiva para FOXP3 na imunoistoquímica esteve presente em 21 (72.4%) de todos os casos analisados Conclusão: O FOXP3 apresentou alta positividade no carcinoma papilíferos da Tireoide. Não houve diferença com relação coexistência de tireoidite de Hashimoto ou não. / Salvador