A atopia ou dermatite atópica é uma doença inflamatória pruriginosa, crônica e recorrente reconhecida como a segunda alergopatia mais comum, estando aquém apenas da dermatite alérgica à picada de pulgas. Esta doença é caracterizada pela presença exacerbada de prurido corpóreo, infringindo sofrimento ao paciente e desalentando seu proprietário. A busca a uma boa \"qualidade de vida\" está sendo cada vez mais demandada pelos proprietários de animais alergopatas ou portadores de outras doenças crônicas. Por se tratar de uma doença de longo decurso, o tratamento com glicocorticóides pode causar diversos efeitos colaterais, além de doenças mais graves como diabetes melitus e hiperadrenocorticismo iatrogênico. Como alternativa ao tratamento de cães atópicos, a ciclosporina (CsA) acaba tornando-se uma boa opção terapêutica. A CsA inibe as funções das células que iniciam a resposta imunológica (células de Langerhans e linfócitos) e das células que efetuam a resposta alérgica (mastócitos e eosinófilos) e, também, diminui a liberação de histamina e de várias citocinas. Os objetivos do presente estudo incluíram: análise da eficácia da CsA na redução de lesões corpóreas e do prurido com auxílio do CADESI-03 (Olivry et al.,2007) e de duas escalas de prurido corpóreo; detecção de ocorrência de eventuais efeitos adversos (tegumentares ou sistêmicos) decorrentes da terapia imunomodulatória através da realização de hemograma, função renal, função hepática e mensuração da pressão arterial; avaliação e monitoramento da qualidade de vida de 21 animais atópicos tratados com ciclosporina (5 mg/Kg, SID durante 60 dias) com auxílio de uma escala validada para cães. A CsA mostrou-se eficaz no tratamento da dermatite atópica canina pois reduziu as lesões corpóreas em 70% após 60 dias de terapia. Nesse mesmo período ocorreu redução da intensidade do prurido corpóreo em 52,6%, avaliado através da escala numérica verbal; e observou-se redução significativa na escala qualitativa de prurido corpóreo (Hill, 2002; modificada), uma vez que os níveis máximos de prurido (\"três\" e \"quatro\") quase não foram observados após a terapia imunomodulatória. Os efeitos adversos observados foram relacionados a distúrbios gastrintestinais e, ocorreram com maior freqüência nos primeiros 15 dias de tratamento. Alterações laboratoriais não foram observadas. Os animais portadores de dermatite atópica apresentaram melhora no escore de qualidade de vida em 32%. A CsA mostrou-se eficaz no tratamento da dermatite atópica canina. / Atopic dermatitis (AD) is an inflammatory, pruritic and chronic allergic skin disease. It´s recognized as the second most common allergic skin disease of dogs after flea allergy. Pruritus is the predominant sign of canine AD affecting a variety of areas of the body, leading to intense suffering to the animal and its owner. \"Quality of life\" (QL) is being much more requested from owner of animals with allergic skin diseases or with any kind of chronic disease. The long-term use of glucocorticoids therapy can be devastating because of its inumerous adverse effects and secondary diseases like diabetes mellitus and iatrogenic hiperadrenocorticism. Cyclosporine (CsA) has been considered a good therapeutic option in the treatment of canine atopic dermatitis. It inhibits the activation of cells that initiate cutaneous immune response (Langerhans\' cells and lymphocytes) and cells that mediate allergic reactions (mast cell and eosinophils). It also decreases histamine and other citocines release. The objectives of this study included: analysis of the efficacy of CsA in reducing skin lesions and pruritus of 21 atopic dogs using CADESI-03 (Olivry ey al., 2007) and two scales to quantify levels of body itching; detection of any possible adverse effects (dermatologic or systemic) secondary to immunomodulatory therapy, by performing complete blood count, renal and hepatic function and measurement of blood pressure; evaluation and monitoring QL from dogs treated with CsA (5 mg/Kg, SID during 60 days) with a validated scale; This immunomodulatory therapy was considered an effective treatment for atopic dogs because it reduced skin lesions in 70% after 60 days of therapy. During that period there was a reduction of body itching in 52,6% by verbal numeric scale, and there was significant reduction on qualitative scale of body itching (Hill, 2002; modified), since maximum levels of pruritus (\"three\" and \"four\") were hardly observed after immunomodulatory therapy. Gastrointestinal disorders were observed and appeared most often in the first 15 days of therapy. Laboratory abnormalities were not detected. The quality of life of these atopic dogs treated with CsA for 60 days was improved by 32%. CsA was effective and safe in the treatment of canine atopic dermatitis.

Le psoriasis et la dermatite atopique sont des pathologies inflammatoires cutanées chroniques, fréquentes et invalidantes. Dans la peau des patients souffrant de ces pathologies, un dérèglement de la réponse immunitaire aboutissant à une inflammation chronique est toujours observé. Le réseau cytokinique joue un rôle essentiel dans la physiopathologie cutanée en permettant la communication entre les cellules cutanées et les cellules immunitaires. Dans le psoriasis et la dermatite atopique, ce réseau est largement perturbé. En effet, un grand nombre de cytokines proinflammatoires sont surexprimées au détriment des cytokines anti-inflammatoires. Cette inflammation chronique est directement responsable de l'apparition des lésions cutanées. Parmi les cytokines surexprimées dans ces pathologies, des études antérieures du LITEC ont montré in vitro que l'Oncostatine M (OSM) est impliquée dans la production de peptides antimicrobiens et de médiateurs de l'inflammation, ainsi que dans l'inhibition de la différenciation des kératinocytes. Notre objectif était de poursuivre ces travaux en étudiant le rôle de l'OSM dans l'inflammation cutanée in vitro et in vivo chez la souris. Nous avons pour cela, comparé le rôle de l'OSM à celui d'autres cytokines de la famille de l'IL-6, l'IL-6 et l'IL-31, qui présentent également une activité sur le kératinocyte. L'activité de ces cytokines a été étudiée in vitro sur des cultures primaires de kératinocytes murins en monocouche, sur des épidermes reconstruits murins ainsi qu'in vivo dans différents modèles d'inflammation cutanée. Nous montrons que l'OSM est plus active que l'IL-6 et l'IL-31 sur les kératinocytes en culture et que la surexpression de cette cytokine in vivo dans la peau de souris à l'aide d'adénovirus recombinants induit une inflammation cutanée forte, présentant des caractéristiques communes avec le psoriasis et la dermatite atopique. Néanmoins, les souris déficientes pour le gène codant l'OSM ne présente aucune diminution du phénotype inflammatoire cutané dans le modèle de psoriasis induit par application d'Imiquimod et dans un modèle de dermatite atopique induit par application de Calcipotriol, suggérant l'existence de mécanismes de compensation par d'autres cytokines proinflammatoires. En parallèle de cette étude, nous avons mis au point un nouveau modèle d'épidermes reconstruits murins permettant l'étude de l'activité des cytokines sur les kératinocytes. Ce modèle présente l'avantage de reproduire plus finement la physiologie d'un épiderme normal par rapport aux autres modèles préalablement décrits et ouvre la perspective de développer des épidermes reconstruits à partir de kératinocytes de souris transgéniques. En conclusion, ces travaux démontrent le rôle pro-inflammatoire de l’OSM dans l'inflammation cutanée et son activité majeure sur les kératinocytes en comparaison à celles décrites pour l'IL-6 et l'IL-31. Néanmoins, la pertinence du ciblage thérapeutique de cette cytokine dans le psoriasis et la dermatite atopique reste encore à démontrer. / Psoriasis and atopic dermatitis are the most prevalent cutaneous inflammatory disease in worldwide. An imbalance immune response is a characteristic feature of these diseases and through their role in the communication between cutaneous and immune cells; cytokines are key players in these diseases. Indeed, in the psoriatic and atopic lesions, an altered cytokine network is always described and mainly in favor of proinflammatory cytokines. Among them, our laboratory previously described that Oncostatin M, an IL-6 family member is up-regulated in psoriasis and atopic dermatitis lesions. In vitro, we have demonstrated that OSM induces a proinflammatory signature on human keratinocytes including the up-regulation of antimicrobials peptides and proinflammatory mediators as well as inhibiting the epidermal differentiation. The aim of this work was to confirm the role of OSM in cutaneous inflammatory diseases and compare it to others IL-6 family members such as IL-6 and IL-31 also described for their potent activities on keratinocytes. The activity of theses cytokines was study in vitro on normal murine epidermal keratinocytes or in reconstituted murine epidermis and in vivo in inflammatory murine models. Compared to IL-6 and IL-31, OSM is a strong inducer of proinflammatory signature in vitro on keratinocyte and in vivo using recombinant adenovirus overexpressing theses cytokines. The inflammatory phenotype induces by overexpression of OSM in mouse ears mimics key features of psoriatic and atopic skins. However, deficiency mice for the gene encoding OSM dot not demonstrated reduced phenotype in a mouse model of psoriasiform dermatitis induce by imiquimod or in a mouse model of atopic dermatitis induced by calcipotriol suggesting that compensatory cytokines are sufficient to maintain phenotype in the absence of OSM. Concurrent to this study, we also developed a model of reconstituted murine epidermis in order to test the activity of cytokines in a model reproducing more closely the epidermal physiology. The in vitro model could be used to study the function of numerous epidermal proteins of cytokine using transgenic mice and will provide a useful tool in the dermatological research field. Finally this work demonstrated the proinflammatory role of OSM in cutaneous inflammation through its major activities on keratinocytes in comparison to IL-6 and IL-31. However, the relevance of therapeutic strategies to block the activity of this cytokine in inflammatory skin diseases remains to be demonstrated.

The aim of this thesis is to analyze the prevalence of the phenomenon of non-compliance patiens with a diagnosis of atopic dermatitis using the questionnaire survey in two selected dermatology clinics in Prague. The result obtained were tested using standard statistics methods. The results suggest the non-compliance depends mainly on attitude of physisians.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The Atopic Dermatitis (AD) is a chronic inflammatory skin disease that affects patients with disabilities in the skin barrier and low immune response. Tacrolimus ointment for topical use is an immunomodulator that has shown to be a good alternative for the treatment of AD. However, it also has adverse effects such as low and variable bioavailability, burning sensation and itching at the application site. Thus, the development of new dosage forms that overcome these drawbacks is crucial to the success of the therapy. The objective of this study was to obtain lipid nanoparticles (LN) of tacrolimus for future application in AD therapy. The LN were obtained by solvent diffusion method associated with ultrasonication using stearic acid (SA) and beeswax as solid lipid in the solid lipid nanoparticles (SLN) and oleic acid (OA) incorporated into the solid lipid matrix in the carriers lipid nanostructured (NLC). Lipid dispersions were characterized by determining the particle size, Polydispersity Index (PDI), Zeta Potential (ZP) and and drug content in the NL. Evaluation by Transmission Electron Microscopy (TEM), analysis by Differential Scanning Calorimetry (DSC), X-ray diffraction (XRD) and Infrared Spectroscopy in the region Fourier Transform (FT-IR). As results, LN presented nano-sized spherical shape with an average diameter ranging from 139 – 274, 9 nm and IPD from 0.3 - 0.5. PZ of LN was higher than -|25 mV|, which ensures the stability of the dispersion. In the results of DSC, it was observed that the endothermic event in the NLC was shifted to lower temperatures. Drug loading of 2,3 a 3,2%. The results of XRD also showed low crystallinity when NLC was compared with SLN. The results of FTIR was not observed interaction between the drug and the lipid components of the matrix. Then, it can be concluded that NL develop were successfully obtained and may represent promising system for the placement of tacrolimus in topical formulations. / A Dermatite Atópica (DA) é uma doença inflamatória cutânea crônica que acomete principalmente pacientes com deficiência na barreira cutânea e com baixa resposta imunológica. O tacrolimo para uso tópico em pomada é um imunomodulador que tem mostrado ser uma boa alternativa para o tratamento da DA. Porém, ele também apresenta efeitos adversos, tais como baixa e variável biodisponibilidade cutânea, sensação de queimação e prurido no sítio de aplicação. Assim, o desenvolvimento de novas formas farmacêuticas que contornem estas desvantagens é crucial para o sucesso da terapia. Desta forma, o objetivo deste trabalho foi obter nanopartículas lipídicas (NL) contendo tacrolimo para uso tópico. As NL foram obtidas pelo método de difusão do solvente associado a ultrassonicação, utilizando o ácido esteárico (AE) e a cera de abelha (CA) como lipídios sólidos nas nanopartículas lipídicas sólidas (NLS) e ácido oléico (AO) incorporado à matriz lipídica sólida nos carreadores lipídicos nanoestruturados (CLN). As dispersões lipídicas foram caracterizadas através da determinação do tamanho de partícula, Índice de Polidispersidade (IPD), Potencial Zeta (PZ) e teor de fármaco nas NL, avaliação por Microscopia Eletrônica de Transmissão (MET), análises através de Calorimetria Exploratória Diferencial (DSC), Difração de raio-X (DRX) e Espectroscopia na região do Infravermelho com Transformada de Fourier (FTIR). Como resultados, as NL apresentaram tamanho nanométrico, com um diâmetro médio variando de 139 – 274,9 nm e IPD de 0,3 - 0,5. O PZ das NL foi maior do que - |25 mV|. O teor de fármaco encontrado nas NL foi de 2,3 a 3,2 %. Nos resultados de DSC foi observado que o evento endotérmico nas CLN e nas NLS com fármaco foi deslocado para temperaturas menores, sugerindo maior desorganização da estrutura assim como os resultados de DRX, que também revelaram menor cristalinidade. Nos resultados de FTIR não foi observado interação entre o fármaco e os componentes da matriz lipídica. Então, pode ser concluído que as NL desenvolvidas foram obtidas com sucesso e podem representar futuros sistemas promissores para a veiculação do tacrolimo em formulações tópicas.

Staphylococcus aureus is a gram-positive opportunistic pathogen responsible for more deaths every year than HIV/AIDS. Its formidable repertoire of virulence factors, ubiquitous nature, and ability to acquire antibiotic resistance quickly allow S. aureus to colonize and persist in nearly any body site if given the opportunity. S. aureus is the leading cause of many common and severe skin diseases, i.e. atopic dermatitis and surgical site infections, which can result in significant morbidity and mortality due to lack of available treatments and chronic non-healing nature of each infection. The human body is capable of producing many antimicrobial factors, such as defensins in the epidermis, in conjunction with providing a seamless barrier to many environmental threats, i.e. the skin, yet when given the opportunity, S. aureus can overtake these innate defenses, colonize, and cause disease. Despite S. aureus being a prominent organism in skin infections, little has been done to identify critical factors of S. aureus to cause skin infections. This document demonstrates the capacity of specific S. aureus virulence factors, superantigens and cytotoxins, to alter re-epithelialization and wound healing, as indicated by altered keratinocyte migration and proliferation. In an attempt to harness natural occurring host defenses, we have also identified and generated novel antimicrobial peptides capable of ablating toxin production independent of bacterial growth inhibition. Evidence presented should convince the reader that S. aureus exotoxin production is critical in perpetuating chronic wounds through local keratinocyte interaction. This suggests targeting production of these toxins to prevent cell toxicity and inflammatory responses, could allow the host to repair damaged tissue effectively.

Atopic dermatitis (AD) typically develops in patients with a history of allergic ailments, and is characterised by an itchy, inflammatory skin condition with scaling, lichenification, papules, excoriations and pruritus. In AD patients a chronic relapsing inflammatory condition is seen, associated with IgE hyper production. AD flares are largely triggered by environmental factors. However, the exact etiology of AD is unclear and there is a pressing need for new treatment regimens as AD is a chronic condition and requires long term treatment. Historically Aloe has been used to treat skin conditions as well as a variety of other diseases. To further explore the pathogenesis and treatment of AD, Balb/c mice were sensitized and challenged with 2,4-dinitrochlorobenzene (DNCB) for atopic dermatitis induction. Thereafter, mice were treated with either Aloe ferox or Aloe vera applied daily on the dorsal skin for 10 consecutive days. A placebo gel was used for the control mice. Blood was collected at the end of the treatment period and serum IgE levels measured. Serum IgE levels were significantly lowered in the Aloe ferox group than in the Aloe vera group. This study demonstrated Aloe’s immunoregulatory potential for alleviating atopic dermatitis through influencing of Th2 cell activation. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Pharmacology / unrestricted

京都大学 / 0048 / 新制・課程博士 / 博士(薬学) / 甲第17862号 / 薬博第793号 / 新制||薬||236(附属図書館) / 30682 / 京都大学大学院薬学研究科医療薬科学専攻 / (主査)教授 髙倉 喜信, 教授 橋田 充, 教授 佐治 英郎 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Atopische Dermatitis (Atopisches Ekzem) ist die häufigste Erkrankung der Haut, und sie ist mit der Entwicklung anderer schwerwiegenden atopischen Erkrankungen wie Lebensmittelallergien, allergischer Rhinitis, Heuschnupfen und Asthma vergesellschaftet. Inaktivierende Mutationen im Filaggrin (FLG) Gen zeigten die stärkste Assoziation mit dem Krankheitsbild der atopischen Dermatitis. FLG wird fast ausschließlich in der Epidermis der Haut ausgeprägt und trägt maßgeblich zur normalen Differenzierung von Keratinozyten und zur Integrität der Hautbarriere bei. Bi-allelische inaktivierende Mutationen in dem Gen verursachen die Hauterkrankung Ichthyosis vulgaris, bei es zu Ausbildung einer übermäßig trockenen und schuppigen Hautoberfläche kommt. Etwa die Hälfte aller Ichthyosis vulgaris Patienten entwickeln ebenfalls atopische Dermatitis im Laufe Ihres Lebens. Zusätzlich treten in Ichthyosis vulgaris Patienten häufiger atopische Krankheitsbilder auf als in Gesunden. Als Modell zur Erforschung molekularer Grundlagen der Pahtologie des atopischen Ekzemes und von Pathomechanismen der Atopie eignet sich die „flaky tail“ Mauslinie. Diese Mäuse entwickeln typische Merkmale einer systemischen Atopie wie z.B. einen Barriere Defekt der Haut, ein Hautekzem, eine Entzündung der Lunge, sowie erhöhte Mengen an Immunglobulin E im Serum. In diesem Modell wird die Krankheitsentwicklung durch zwei natürlich entstandene Mutationen in den Genen Flg und Tmem79 verursacht. Die das Gen Flg betreffende Mutation bewirkt eine reduzierte Expression, welche einen Ichthyosis vulgairs ähnlichen Phänotyp auslöst, der durch Schuppenartige („flaky“) Haut am Schwanz („tail“) gekennzeichnet ist (Flgft). Die Mutation im Tmem79 Gen bewirkt eine matte Fellfarbe und wird daher als „matted“ Mutation (Tmem79ma) bezeichnet. Obwohl die Mutationen in benachbarten Regionen des Maus Chromosoms 3 zu finden sind, konnten diese genetisch getrennt werden. Dadurch gelang es zu zeigen, dass allein die Tmem79ma Mutation ausreicht, um Ekzeme und systemische Atopie in Mäusen auszulösen. Nach Rückkreuzung der Flgft Mutation auf den pro-allergischen BALB/c genetischen Hintergrund entwickelten die Flgft/ft BALB/c Mäuse eine - Erkrankung ähnlich der atopischen Dermatitis, die ebenfalls von spontanem Asthma und hohen IgE Konzentrationen im Serum gekennzeichnet war. Beides sind Hauptmerkmale des sogenannten atopischen Marsches. Diese Versuche implizierten, dass Filaggrin eine wichtige Funktion im Schutz vor der Entwicklung von Atopie in Mäusen ausübt. Im Gegensatz zu diesen Ergebnissen wurden nach dem Rückkreuzen von Flg knockout (Flg-/-) Mäusen auf den BALB/c Hintergrund nur ein transienter neonataler Ichthyose Phänotyp, aber keine Hautentzündung oder Atopie beobachtet. Um diese Diskrepanz besser zu verstehen, generierten wir Flg knockout Mäuse direkt im BALB/c Hintergrund. Diese genetisch reinen Flg-/-/BALB/c Mäuse rekapitulierten den neonatalen Ichthyose Phänotyp, und sie zeigten einen Barriere Defekt, der die perkutane Sensibilisierung förderte. Spontane Entzündungen der Haut oder systemische Atopie wurden allerdings nicht beobachtet. Um die genetische Ursache der Atopie in Flgft/ft BALB/c Mäusen zu verstehen, sequenzierten wir das Genom mittels PacBio long read sequencing und verglichen es mit dem BALB/c Referenzgenom. Überraschenderweise zeigte die Analyse, dass die kongenen Flgft/ft BALB/c Mäuse ebenfalls die Atopie-verursachende Tmem79ma Mutation im homozygoten Zustand trugen. Zuvor wurde berichtet, dass die Flgft und Tmem79ma Mutationen vor dem Rückkreuzen des Flgft Allels auf den BALB/c Hintergrund voneinander getrennt werden konnten. Unsere Beobachtungen erklären nun die phänotypische Diskrepanz zwischen den Flgft/ft BALB/c und den Flg-/-/BALB/c Mäusen. Die Daten implizieren, dass der alleinige Funktionsverlust von FLG keine Atopie auslöst und werden durch Beobachtungen in einem Teil der FLG-defizienten Ichthyosis vulgaris Patienten gestützt, die ebenfalls keine Atopie zeigen. Es ist trotzdem wahrscheinlich, dass der Verlust von Filaggrin im Zusammenspiel mit weiteren genetischen Barriere Defekten, wie z.B. Mutationen im Tmem79 Gen das Krankheitsbild der Atopie qualitativ beeinflusst.:Abbreviations 6 Summary 9 Zusammenfassung 11 Introduction 13 Skin 13 Epidermis 13 The immune system 15 Adaptive immune response effector mechanisms 17 Allergic diseases 19 Atopic march 19 Atopic dermatitis 19 Metabolics of AD skin 23 Filaggrin and AD 25 Current mouse models of barrier defect and AD 29 Induced AD mouse models 29 Transgenic and knock out (KO) AD mouse models 30 Inbred mouse strains spontaneously developing AD-like disease 31 Mouse models of FLG-deficiency 32 AD and microbiome 34 Aim 37 Material and methods 38 Generation of Flg-/- mice 38 Crispr targeting strategy 38 α-FLG Western Blot 39 Protein extract preparation 39 SDS Electrophoresis 39 α-FLG Immunofluorescence staining 40 PCR Typing 40 Isolation of genomic DNA from mouse tail tips 40 PCR typing strategy 41 H&E staining of neonatal mouse ear skin 42 Ear thickness measurement 44 Quantification of transepidermal water loss (TEWL) 44 Quantification of total and antigen-specific IgE 44 Whole back skin RNA Sequencing (RNA-Seq) 44 Sorting of basal ear skin keratinocytes for RNA extraction, by fluorescence-activated cell sorting (FACS) 45 Quantitative real time PCR (qRT-PCR) 47 Flow cytometric analysis of ear skin 48 Analysis of DO11.10+/4get transgenic T cell response to epicutaneous OVA immunization 49 Skin microbiome analysis 50 S.aureus colonization of Flg mutant mice 51 Long-term epicutaneous OVA treatment 52 Mapping of reads, assembly, annotation and variant calling 53 Statistical analysis 55 Results 56 Generation and validation of Flg-/-/ BALB/c mice 56 Large sequence deletions detected in Flg-mutant mice by PCR 56 Complete loss of FLG protein expression in Flg-/- mice 57 Flg-/-/BALB/c mice show a barrier-defective skin 59 FLG-deficient skin is devoid of inflammation 61 FLG-deficient skin shows age-related inside-out barrier defect 62 Mild T cell expansion and no other changes in the epidermal compartment of the Flg-/-/BALB/c mice 62 γδ T cell expansion in the whole ear skin suspensions of FLG-deficient mice 64 Lack of systemic atopy in FLG-deficient mice, as indicated by IgE quantification 67 S. aureus colonization does not trigger eczema or atopy in FLG-deficient mice 68 Sensitization with a protein Ag does not trigger inflammation in FLG-deficient mice 69 FLG-deficient skin shows age-related outside-in barrier defect 69 Mild inflammatory signature detected in Flg-/-/BALB/c back skin by RNA sequencing 71 Type 2 immune response signalling detected in Flg-/-/BALB/c ear skin keratinocytes by RNA sequencing 72 FLG-deficient ear skin shows elevated IL-1b expression 74 Reduced cutaneous commensal microbial diversity in FLG-deficient mice 75 Presence of atopy-causing Tmem79ma mutation in Flgft/ft BALB/c mouse genome account for phenotypic differences with our Flg-/-/BALB/c mice 76 Discussion 81 FLG-deficiency in mice does not trigger spontaneous atopic disease 81 FLG-deficiency in mice causes mild immunological perturbation 82 Atopic march, observed in Flgft/ft BALB/c congenic strain, can be explained by the presence of the matted mutation 88 Relevance of filaggrin deficiency for the pathogenesis of atopy in mouse and man 89 References 92 Acknowledgments 136 Erklärung zur Eröffnung des Promotionsverfahrens 137 Erklärung über die Einhaltung der gesetzlichen Vorgaben 138

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京都大学 / 新制・課程博士 / 博士(農学) / 甲第23579号 / 農博第2478号 / 新制||農||1088(附属図書館) / 学位論文||R3||N5363(農学部図書室) / 京都大学大学院農学研究科応用生命科学専攻 / (主査)教授 栗原 達夫, 教授 小川 順, 教授 木岡 紀幸 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM