Regulatory T cells (Treg) are a suppressive subset of helper T cells that controls immune responses using a variety of mechanisms. Despite initially being thought of as a homogenous population, Treg cells were recently found to adapt their function to their environment and acquire specialized phenotypes depending on their tissue of residence. The molecular mechanisms underlying this functional and tissular adaptation remain to be fully elucidated.In the course of this work, we studied the role of transcription factor c-Maf in the differentiation and the function of Treg cells. For this, we used a murine model invalidated for c-Maf specifically in Treg cells. Transcription factor c-Maf is preferentially expressed by intestinal Treg cells, particularly among the RORγt+ Treg subset, which controls immune responses directed towards the gut microbiota. We have shown that the differentiation of RORγt+ Treg cells results from the integration of multiple environmental signals, highlighting the plasticity of Treg specialization. Furthermore, we have shown that c-Maf is required for the differentiation of RORγt+ Treg cells as well as the expression of the anti-inflammatory cytokine IL-10 by intestinal Treg cells, thus endowing Treg cells with the ability to control homeostatic Th17 responses in the intestine. Mice deficient for c-Maf in Treg cells exhibit an exacerbated Th17 response and spontaneously develop colitis. However, c-Maf-deficient mice develop fewer polyps in a model of colitis-associated colon cancer. This suggests that c-Maf expression in Treg cells plays a beneficial role on intestinal homeostasis at steady state, but is detrimental in a tumoral context.Our results allow a better understanding of the mechanisms involved in the specialization of intestinal Treg cells. The knowledge of these mechanisms is crucial for the identification of new therapeutic targets in the context of inflammatory bowel disease and colon cancer. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Made available in DSpace on 2018-08-01T23:58:44Z (GMT). No. of bitstreams: 1 tese_10317_Dissertação - Jéssica Freire Fonseca.pdf: 12083394 bytes, checksum: a4d0fe16c3f88fe319963eacc405de4e (MD5) Previous issue date: 2016-06-15 / Os problemas mais comuns nos pavimentos asfálticos são o trincamento por fadiga e a deformação permanente que podem ocorrer mesmo antes do pavimento atingir sua vida útil de projeto. Esses problemas estão relacionados a fenômenos de menores escalas, como as microtrincas, concentração de tensão na interface entre os agregados e o ligante asfáltico e a dissipação de energia devido ao comportamento viscoelástico do material. O principal objetivo deste estudo foi avaliar a potencialidade do uso do Resíduo do Beneficiamento de Rochas Ornamentais (RBRO) e Escória Moída de Aciaria (EMA) como fíler na porção fina das misturas asfálticas, conhecida como Matriz de agregados finos (MAF). Para atingir este objetivo, cinco diferentes misturas de MAF foram feitas substituindo: 2% como fíler de RBRO, 2% como fíler de EMA, 2% como fíler de RBRO+EMA, 2% como fíler de cal hidratada e a mistura de referência. Os efeitos destes materiais na MAF foram investigados realizando-se ensaios de varredura de frequência para avaliação das características da rigidez viscoelástica linear, ensaio de fratura em amostra de geometria semi-circular e ensaio de varredura de tempo para avaliar as características de fratura. Dessa forma, obteve-se um melhor entendimento da influência do tipo de fíler (RBRO e EMA) nas propriedades viscoelásticas da MAF, através de análises das curvas mestras do módulo complexo e ângulo de fase e das características de dano da MAF, através de análises da energia de fratura e curvas características do dano (C x S). Os resultados mostraram que, no geral, a mistura que apresentou o melhor desempenho, para as características de fratura e da rigidez viscoelástica linear, foi com 2% de RBRO+EMA, apresentando a mesma tendência encontrada em outros trabalhos que também utilizaram os mesmos resíduos. Pode-se concluir que a utilização dos dois resíduos aplicados conjuntamente em concretos asfálticos apresenta-se, a princípio, viável tanto do ponto de vista ambiental quanto tecnológico. Palavras-chave: Rochas ornamentais, Matriz de Agregados Finos (MAF), Trincamento por fadiga, Rigidez viscoelástica, Escória de Aciaria.

No description available.

Yes / Mycobacterium africanum (Maf) causes a substantial proportion of human tuberculosis in some countries of West Africa, but little is known on this pathogen. We compared the genomes of 253 Maf clinical isolates from Ghana, including N = 175 Lineage 5 (L5) and N = 78 Lineage 6 (L6). We found that the genomic diversity of L6 was higher than in L5 despite the smaller sample size. Regulatory proteins appeared to evolve neutrally in L5 but under purifying selection in L6. Even though over 90% of the human T cell epitopes were conserved in both lineages, L6 showed a higher ratio of non-synonymous to synonymous single nucleotide variation in these epitopes overall compared to L5. Of the 10% human T cell epitopes that were variable, most carried mutations that were lineage-specific. Our findings indicate that Maf L5 and L6 differ in some of their population genomic characteristics, possibly reflecting different selection pressures linked to distinct ecological niches. / Supported by the Wellcome Trust Intermediate Fellowship awarded to DYM (Grant Number 097134/Z/11/Z) and by the Swiss National Science Foundation (grants 310030_166687, IZRJZ3_164171 and IZLSZ3_170834), the European Research Council (309540-EVODRTB) and SystemsX.ch.

Les macrophages ont une contribution essentielle dans la bonne santé et la maladie. Comment les macrophages sont capables d'auto-renouvellement reste une question sans réponse. Au sein du laboratoire il a était démontré que les macrophages déficients pour MafB et c-Maf (Maf-DKO) ont la capacité de s'autorenouveller indéfiniment in vitro et ceci sans perdre leur identité de macrophages ni devenir cancéreux (Aziz et al. 2009). En utilisant les macrophages Maf-DKO comme outil d'étude de l'auto-renouvellement, nous avons pu identifier un réseau de genes qui permet l'auto-renouvellement des macrophages en absence de MafB. De plus nous montrons que des macrophages génétiquement non modifiés sont capables d'exprimer des genes du réseau d'auto-renouvellement des cellules souches embryoniques. Ce réseau d'auto-renouvellement est inhibé par MafB, qui peut-être sous exprimé in vivo. Les macrophages alvéolaires (MA) expriment constitutivement de faibles niveaux de MafB et c-Maf comme montré par Gautier et al. 2013. Les MA montrent une importante capacité d'auto-renouvellement, ils peuvent être amplifiés ex vivo. La surpression de MafB dans les MA in vitro et in vivo réduit la capacité d'auto-renouvellement de ces derniers. Nous avons finalement identifié GSK3 comme une cible pharmacologique pour l'inhibition de MafB dans les macrophages. Il a était montré que GSK3 tait nécessaire pour l'activation de MafB par phosphorylation directe. Nous avons montré que par inhibition de GSK3, les macrophages étaient capables s'auto-renouveler même s'ils exprimés de façon endogène/exogène MafB et c-Maf. / Macrophages contribute to essential functions in health and disease. Some macrophages are short lived but some macrophages are able to self-renew. However, in which manner macrophages are able to self-renew remains an open question. In our lab, we have demonstrated that macrophages deficient in MafB and c-Maf (Maf-DKO macrophages) can self-renew indefinitely in vitro, without neither loosing their macrophage identity nor becoming cancerous (Aziz et. al 2009).Using Maf-DKOs as a tool to study molecular mechanisms of self-renewal of macrophages, we have now been able to identify a network of genes, which allows macrophage self-renewal in the absence of MafB. We identified 25 genes, which affected only self-renewal. Additionally, we show that genetically unmodified macrophages are able to express self-renewal gene network. This self-renewal network is inhibited by MafB, which can be downregulated in vivo after mitogenic stimuli. Recently, Gautier et al., showed that Alveolar macrophages (AMs) constitutively express very low levels of MafB and c-Maf. We were able to demonstrate that AMs are able to self-renew in vitro and in vivo. Overexpression of MafB in AM in vitro and in vivo reduced the ability of AMs to self-renew. Additionally, we identified GSK3 as a pharmaceutical target for MafB regulation in macrophages. GSK3 has been shown to be required for Maf activation through direct phosphorylation. We showed that by inhibiting GSK3, macrophages were able to self-renew even if they were expressing endogenous or exogenous MafB and c-Maf.

Chez les métazoaires, les cellules spécialisées se caractérisent par la sortie du cycle cellulaire alors que les cellules souches et progénitrices se caractérisent par un intense potentiel d'auto-renouvellement, lequel est perdu durant la différenciation. L'auto-renouvellement est contrôlé par une combinaison de facteurs intrinsèques et extrinsèques qui déclenchent une prolifération cellulaire équilibrée. Dans ce contexte, nous avons montré que le knock-out des facteurs de transcription MafB et c-Maf dans les monocytes, résulte en une expansion prolongée des monocytes et macrophages matures en culture, sans aucun signe de perte du phénotype différencié ou de la fonction. Etant donné que les macrophages sont impliqués dans la majorité des maladies dégénératives, les maladies inflammatoires ainsi que la biologie du cancer, l'amplification de macrophages consisterait en un atout considérable pour les applications thérapeutiques. Dans cette optique, et comme les macrophages sont également connus pour promouvoir le développement tumoral, nous avons étudié le comportement des macrophages Maf-DKO dans le contexte tumoral. Initialement, nous avons montré que les macrophages Maf-DKO sont capables d'empêcher l'installation de la tumeur ainsi que de réduire une masse tumorale établie, et ce indépendamment du model tumoral étudié. Ceci consiste en une nouvelle approche thérapeutique contre le cancer. Nous nous sommes ensuite intéressés à fournir une « preuve de principe » quant à la prolifération des monocytes humains après inhibition de l'expression des gènes MafB et c-Maf humains et à étudier leur potentiel dans des applications thérapeutiques. / In metazoans, specialized cells are typically withdrawn from the cell cycle, whereas stem cells and progenitor cells have extensive self-renewal potential that is usually lost on differentiation. Self-renewal is controlled by a combination of cell-intrinsic and extrinsic signals that trigger balanced cellular proliferation. In this context, we previously reported that the knock-out of two monocytic transcription factors, MafB and c-Maf, enables extended expansion of mature monocytes and macrophages in culture without loss of differentiated phenotype and function. As macrophages are involved in degenerative diseases, inflammatory diseases and cancer biology, amplified macrophages may provide potential therapeutic applications. In this context and since macrophages are also known to enhance tumor development, we aim to investigate Maf-DKO macrophages behavior in a tumor context Initially, we have shown that regardless of tumor model (ID8 ovarian carcinoma or B16 melanoma), Maf-DKO macrophages have the ability to prevent tumor growth and reduce established tumor mass in tumor bearing mice. The potential provides a novel therapeutic approach for cancer cell therapies. Next we aimed to provide a proof of principle for the amplification of human monocytes by the inhibition of MafB/c-Maf genes and to investigate their potential in therapeutic applications. So far, we have shown that the down-regulation of MafB and c-Maf in human monocytes results in a colony formation in semi-solid medium, reflecting that the knock down of MafB and c-Maf results in proliferative advantage.

Les facteurs de transcription de la famille MAF sont impliqués d’une part au cours du développement dans des processus de différenciation terminale et d’autre part dans la carcinogenèse. Un découplage fonctionnel est observé. En effet, les gènes cibles mis en jeu au cours des processus cancéreux et de différenciation terminale semblent différents. L'activité oncogénique des protéines MAF dépend du contexte cellulaire. Ainsi, il a été proposé qu'elles exercent leur activité oncogénique dans des tissus où elles ne sont pas exprimées normalement. De plus, leur pouvoir transformant est régulé par phosphorylation. Mon travail de thèse a porté sur le rôle oncogénique de ces protéines en étudiant ces deux aspects. J'ai identifié le rôle oncogénique de NRL, un membre de la famille MAF, dans le Médulloblastome et j'ai étudié la régulation par phosphorylation des MAF dans le Myélome Multiple. L’activité oncogénique du facteur de transcription NRL, connu pour son rôle dans la différenciation terminale d’un type cellulaire de la rétine, n’avait jamais été établie. Alors que NRL n'est pas exprimé dans le cervelet sain, des études de transcriptome ont montré que NRL est surexprimé dans un sous-groupe agressif de médulloblastome, une tumeur pédiatrique du cervelet. J’ai montré pour la première fois que NRL est un oncogène. Il participe directement à la carcinogénèse de médulloblastomes, en protégeant les cellules de l’apoptose, à travers la régulation d’un membre anti-apoptotique de la famille BCL, BCL-XL. L’inhibition des protéines BCL pourrait constituer une stratégie thérapeutique potentielle dans des Médulloblastomes de mauvais pronostic et résistants aux traitements classiques.Au sein du laboratoire, un projet, auquel j’ai participé, a porté sur la régulation de l’activité oncogénique des facteurs de transcription MAF, dans des Myélomes Multiples, de mauvais pronostic. Ce travail établit que l’activité oncogénique de deux membres de la famille MAF, MAFB et c-MAF, est régulée par phosphorylation induite par la Ser/Thr kinase GSK3. La phosphorylation des facteurs de transcription MAF augmente leur activité oncogénique et paradoxalement induit leur dégradation par le protéasome. Ce travail a permis d’identifier un mécanisme de résistance potentiel de ces tumeurs et de proposer une nouvelle approche thérapeutique, basée sur l’inhibition de la phosphorylation des protéines MAF. / MAF (MusculoAponeurotic Fibrosarcoma) transcription factors are involved in terminal differentiation during normal development, and also in oncogenesis. A functional uncoupling is observed between these two functional activities. Indeed, target genes involved in cancer or terminal differentiation look different. The oncogenic activity of MAF proteins is dependent on the cellular context. Thus, it was suggested that they exert their oncogenic activity in tissues where they are not normally expressed. In addition, their transforming ability is regulated by phosphorylation. My work focused on the oncogenic role of these proteins by studying these two aspects. I identified the oncogenic role of NRL, a member of the MAF family in Medulloblastoma and I studied the regulation by phosphorylation of MAF in Multiple Myeloma.The oncogenic activity of the transcription factor NRL, known for its role in the terminal differentiation of a cell type in the retina, has never been established. While NRL is not expressed in the healthy cerebellum, transcriptome studies showed that NRL is overexpressed in an aggressive subgroup of medulloblastoma, a pediatric tumor of the cerebellum. I showed for the first time that NRL is an oncogene. NRL is directly involved in the carcinogenesis of medulloblastoma, protecting cells from apoptosis through regulation of an anti-apoptotic member of the BCL family, BCL-XL. Inhibition of the protein BCL could be a potential therapeutic strategy for medulloblastoma with a poor prognosis and resistant to conventional therapies.In the laboratory, I also participated in a project which focused on the regulation of the oncogenic activity of transcription factors, MAF, in rarely curable multiple myeloma. This work establishes that the oncogenic activity of two MAF members, MAFB and c-MAF, are regulated by phosphorylation-induced Ser/Thr kinase GSK3. Phosphorylation of transcription factors MAF increases their oncogenic activity and paradoxically induces their degradation by the proteasome. This work has identified a potential mechanism of resistance of these tumors providing a new therapeutic approach, based on the inhibition of MAF protein phosphorylation.

Les CPGs (Central Pattern Generators) sont des circuits neuronaux capables de générer de façon autonome des comportements rythmiques essentiels à la vie tels que la respiration ou la locomotion. Chez la larve de Drosophile, le CPG locomoteur est composé de motoneurones (MNs) et d’une grande diversité d’interneurones (INs). Combien d’entre eux sont nécessaires pour former une CPG fonctionnel et comment ils interagissent reste un mystère. Au cours de mon doctorat, j’ai étudié une population neuronale restreinte caractérisée par son expression du facteur de transcription (FT) de la famille des Maf, Traffic Jam (TJ). En utilisant une technique d’intersection génétique et grâce à une lignée TJ-Flp générée au cours de mon doctorat, j’ai démontré pour la première fois que différentes sous-populations de neurones TJ+ ont des fonctions distinctes dans le comportement locomoteur de la larve de Drosophile. Au travers de cette sous-division fonctionnelle, j’ai finalement identifié 3 neurones TJ+ per+ GABAergic par segment qui régulent la vitesse de locomotion des larves. Une caractérisation moléculaire poussée de ces cellules a permis de confirmer qu’elles appartiennent au groupe connu des « midline cells », et plus particulièrement des mnb progeny, dont la fonction était jusqu’à maintenant inconnue. Par ailleurs, le code combinatoire de FTs trouvé chez ces mnb progeny rappelle celui exprimé par les V2b, une population d’interneurones qui régulerait également la vitesse de locomotion chez les vertébrés. Ces similarités entre mnb progeny et V2b laissent à penser que cette population de neurones pourrait être conservée au cours de l’évolution. En outre, des résultats préliminaires suggèrent que les interneurones TJ+ ont également un rôle chez la mouche adulte. / CPGs (Central Pattern Generators) are neural networks able to autonomously generate essential rhythmic behaviours such as walking or breathing. In Drosophila larvae, the locomotor CPG is made up of motoneurons (MNs) and a huge variety of interneurons (INs). How many are actually necessary to constitute a functional CPG and how they interact is not known. During the course of this PhD, I studied a discrete neuronal population singled out by its expression of the Maf transcription factor (TF) Traffic Jam (TJ). Thanks to an intersectional genetics approach and a TJ-Flp line generated during my PhD, I showed for the first time that TJ+ neurons subpopulations have distinct functions in Drosophila larva locomotion. Functional subdivision of TJ+ population eventually led to the identification of 3 TJ+ per+ GABAergic neurons that regulate the speed of locomotion. Thorough molecular characterization of this population permitted to identify them as mnb progeny neurons, a well studied subgroup of midline cells whose function had never been described before. The TF combinatorial code expressed by these cells is highly reminiscent of the one found in V2b INs, a population in vertebrates thought to regulate the speed of locomotion as well in vertebrates; this opens the possibility of a functional conservation across evolution. Preliminary results furthermore suggest that TJ+ INs would have functional roles in the adult fly.

En el ámbito minero, los estudios geoestadísticos multivariables para la estimación de recursos son complejos, ya que necesitan modelar no solamente la continuidad espacial de cada variable sino que también las dependencias entre ellas. En investigaciones recientes, se ha desarrollado una técnica llamada maximum/minimum autocorrelation factors (MAF) para simplificar dichos estudios, creando nuevas variables (factores) descorrelacionadas a dos distancias diferentes de separación, mediante una combinación lineal de las variables originales. En ciertos casos estos factores pueden considerarse como totalmente independientes, reduciendo así el problema de modelamiento multivariable a una serie de problemas univariables. En este trabajo se presentan y comparan la técnica de cosimulación de leyes vía MAF y la forma tradicional, para determinar sus ventajas y desventajas. Se estudia dos bases de datos, correspondientes a un yacimiento de cobre y otro de fierro. Se usa como referencia la forma tradicional de cosimular múltiples variables, la que consiste en transformar las variables originales en variables Gaussianas, ajustar un modelo lineal de corregionalización (variogramas simples y cruzados), generar realizaciones y condicionarlas a los datos por cokriging. En el caso MAF, se simula cada uno de los factores independientes y luego se recombinan para obtener las variables originales. Se concluye que la cosimulación vía MAF tiene varias ventajas sobre la cosimulación tradicional: se simplifica el problema de modelamiento (sólo se debe ajustar los variogramas simples de los factores MAF, en lugar de un modelo de corregionalización completo) y se reduce el tiempo de simulación. En los casos estudiados, la cosimulación vía MAF reproduce bastante bien las distribuciones univariables, correlaciones espaciales y la correlación cruzada entre las variables corregionalizadas a simular. Sin embargo, el principal inconveniente proviene de la pérdida de información en la presencia de muestreos heterotópicos, cuando no todas las variables son conocidas en las mismas ubicaciones. La información en las ubicaciones donde no se conoce alguna variable se pierde por completo, por lo que la cosimulación vía MAF no está condicionada a todos los datos originales. En cambio, la cosimulación tradicional no sufre de este inconveniente, por lo que resulta ser más versátil en cuanto al manejo de bases de datos heterotópicos.

<p>Helminth exposure, allergy and asthma each induce cellular responses in lymphoid and peripheral tissues that give rise to type-2 inflammation. Essential molecular mediators of this response are type-2 cytokines interleukin(IL)-4 and IL-13 derived from various subsets of immune cells. In lymphoid tissues, CD4+ Tfh cells make IL-4 to elicit IgE and high-affinity IgG1 production. In peripheral sites of infection, group 2 innate lymphoid (ILC2) cells make IL-13 and Th2 cells make both IL-13 and IL-4. Together, these cells mediate smooth muscle contraction, mucus production and recruitment of other innate effector cells, all of which are hallmarks of type-2 inflammation. As central mediators of type-2 inflammation, understanding the cell-specific expression and molecular regulation of type-2 cytokines in CD4+ T cells and ILC2 cells may lead to new therapies that ameliorate allergic disease and helminth infections. </p><p>The AP-1 factor basic leucine zipper transcription factor ATF-like (BATF) has been identified as a pioneer factor in in vitro-generated Th17 cells. BATF facilitates chromatin remodeling at the IL-17 locus as well as loci of key Th17-associated lineage specifying factors. It has also been deemed essential to the generation of functional humoral immunity through the development of follicular helper T (Tfh) cells and germinal center B cells. However, the role of BATF in the development and function of other CD4+ T helper subsets and innate immune cells in vivo has remained unclear. I show here that mice deficient in BATF do not develop type-2 inflammation after exposure to the parasitic helminth Nippostongylus brasiliensis. Since type-2 cytokine expression by Th2 and ILC2 cells is essential for expedient helminth expulsion, I hypothesized that BATF likely has a role in the development and/or induction of cytokine expression in CD4+ Th2 cells and ILC2 cells. Consistent with this hypothesis, I found that BATF utilizes a novel mechanism to control Th2 cytokine expression in Th2 cells. Specifically, BATF promotes permissive epigenetic modifications to alter the chromatin landscape early during Th2 cell differentiation. In addition, my data show that BATF deficiency inhibits the activation of ILC2 cells, preventing ILC2-mediated helminth clearance. </p><p>In addition to uncovering BATF-mediated regulations of type-2 inflammation, my work has revealed new insight into the role of a second bZIP transcription factor, cMaf, during type-2 immunity. As mentioned above, helminth exposure elicits IL-4 production by both CD4+ Tfh and Th2 cells. Although type-2 cytokine transcription has been well characterized in Th2 cells, Tfh cell-mediated IL-4 production has yet to be fully defined. Importantly, I show that IL-4 production by Tfh cells is sustained upon deletion of classical IL-4 regulatory factors signal transducer and activator of transcription 6 (STAT6) and STAT5 and is not dependent on high GATA-3 expression. In sum, Tfh-driven IL-4 production is induced independent of classical pathways in Th2 cells. </p><p>Presently, the non-canonical transcription factors involved in IL-4 production by Tfh cells remain unclear. C-Maf works with BCL6, the master regulator of Tfh cells, to elicit Tfh formation. However, the precise role of c-Maf in Tfh cell fate and function remains unclear. So far, it has been shown that in Th2 cells, c-Maf binds to the IL-4 promoter and in Tfh cells, c-Maf binds to the CNS2 enhancer of the IL-4 locus to regulate IL-4 expression. Therefore, I hypothesized that c-Maf is important in non-canonical, GATA-3-independent IL-4 production by Tfh cells. </p><p>Here, I show that Tfh cells lacking canonical Th2 pathways for IL-4 expression express high levels of c-Maf and IL-4 transcript. Deletion of c-Maf in CD4+ T cells resulted in normal induction of BCL6 expression. Thus the initial stages of Tfh cell generation were induced. However, cMaf-deficient CD4+ T cells did not express important molecules associated with Tfh cell migration. Immunohistochemistry also confirmed that c-Maf deficiency inhibited CD4+ T cell migration from the paracortex into the B cell follicle. </p><p>These defects did not inhibit cMaf-deficient CD4+ T cells from making IL-4 transcript; however, IL-4 protein production was significantly impaired. Together, these results demonstrate that c-Maf is essential for Tfh cell-mediated immunity by promoting CD4+ T cell migration to the B cell follicles and the production of IL-4 protein in the germinal centers. </p><p>Collectively, the objective of my thesis research is to define the roles of the bZIP transcription factors BATF and c-Maf in type-2 inflammation. My data demonstrate that BATF is essential for the differentiation and function of Tfh, Th2, and ILC2 cells during helminth infection. Additionally, I have shown that c-Maf is required for Tfh function and CD4+ T cell migration to the B cell follicle. Thus, BATF and c-Maf are central to the development of humoral and peripheral type-2 inflammatory responses against helminth infection. Given the wide spectrum of disorders associated with type-2 inflammation, the identification of factors relevant to the development and function of Th2-, ILC2- and Tfh-driven allergic pathologies is broadly relevant. A comprehensive characterization of core factors like BATF and c-Maf provide new avenues in which to explore novel therapies to modulate type-2 inflammatory responses.</p> / Dissertation