A psoríase (Ps) é uma doença inflamatória crônica-imunomediada da pele, caracterizada por proliferação acentuada e diferenciação anormal de queratinócitos e aumento do infiltrado de células inflamatórias na derme. S100A9 é um alarmina que é produzida por queratinócitos e células mielóides em condições inflamatórias. No entanto, o papel desta molécula no desenvolvimento e manutenção da resposta inflamatória da Ps permanece desconhecida. Nesso objeitvo foi investigar o papel de S100A9 no desenvolvimento da psoríase. Análises de bioinformática de um banco de dados disponível on-line contendo valores de expressão de gênica de humanos mostrou que a expressão de S100A9 está aumentada pele lesionada de pacientes com Ps. Esses dados foram confirmados por imunofluorescência e Western blot onde foi observado um aumento na expressão de S100A9 na pele lesionada de pacientes com Ps, em comparação com amostras de pele não lesionada desses mesmo pacientes. Estes níveis de S100A9 foram positivamente correlacionados com a expressão de queratina-17, um marcador de ativação de queratinócitos. Para investigar o papel do S100A9 no desenvolvimento de Ps, autilizamos o modelo de Ps induzido por aplicação tópica de imiquimode (IMQ) nas costas de de camundongos WT, S100A9 - / - ou camundonos previamente tratados com paquinimod (10mg / kg, vo ), um quelante de S100A9. A exposição ao IMQ induziu o aumento da expresão gênica de S100a9 e proteica de forma rápida e dependente do tempo na pele e nos linfonodos drenantes da pele, e esse aumento permaneceu elevado até o final do experimento (6º dia). Notavelmente, a inflamação, e espessura da pele foram significativamente reduzidas em camundongos tratados com PAQ ou camundongos S100A9 -/- em comparação com camundongos WT. Os parâmetros histológicos confirmam a redução da espessura da epiderme, mostrada por seções histológicas coradas com HE. Para determinar quais células produtoras de S100A9 contribuem para o desenvolvimento de Ps, realizamos uma quimera e mostramos que ambos os queratinócitos e células mieloides são importantes para a produção de s100a9 e contribuem para o desenvolvimento da psoríase. No entanto os queratinócitos parecem ser mais importantes no aumento da espessua e na lesão da pele. Além disso, a expressão de Il23, na pele de animais S100A9 -/- ou tratados com PAQ foi reduzida, o que poderia explicar a redução das linfócitos T gamma-delta IL-17 nos linfonodos desses mesmos camundongos. Nosso trabalho mostrou que o alarmina S100A9 desempenha um papel importante no desenvolvimento da psoríase. Assim, S100A9 poderia ser uma estratégia futura para o tratamento farmacológico da psoríase. Além disso essa proteína poderia ser usada como marcador da atividade da doença / Psoriasis (Ps) is an immune-mediated chronic inflammatory skin disease, characterized by accentuated proliferation and abnormal differentiation of keratinocytes and infiltration of inflammatory cells in the dermis. S100A9 is an alarmin that is produced by keratinocytes and myeloid cells in inflammatory conditions. However, the role of this molecule in the development and maintenance of the inflammatory response in Ps remains not well understood. Herein, we investigated the role of S100A9 in the development of psoriasis. Bioinformatical analysis of an online database containing human gene expression information showed that the s100a9 is overexpressed in lesional skin from Ps patients. These data were confirmed by immunofluorescence and western blot that showed an overexpression of s100a9 in the lesional skin from Ps patients compared with paired samples of nonlesional psoriatic skin. These levels of s100a9 were positively correlated with the expression of keratin-17, a keratinocyte activation marker. To investigate the role of S100A9 in the development of Ps, psoriasis-like skin inflammation was induced by topical application of imiquimod (IMQ) on the back skin of S100A9-deficient mice (S100A9-/-) or paquinimod (10mg/kg, v.o) pretreated mice. IMQ exposure induced s100a9 mRNA and S100A9 protein expression in a rapid and time-dependent manner in the skin and lymph node of mice and remained elevated until the end of the experiment (6th day). Notably, inflammation, assessed by epidermal thickness measurement and H&E-stained histological sections, was significantly reduced in S100A9-/- or paquinimod treated-mice compared with wild-type (WT) control mice. To determine which S100A9- producing cell contributes to the Ps development we performed a chimera and showed that both keratinocytes and myeloid cells are important for the production of s100a9 and contribute to the development of psoriasis. However keratinocytes seems to be most important to development of lesion skin. Moreover, the expression of IL-23, in the skin, was reduced, which might explain the reduction of IL-17-producing gamma-delta T cells in the lymph nodes of S100A9-/- or paquinimod-treated mice. We showed that the alarmin S100a9 plays an important role in the development of psoriasis. Thus, targeting S100A9 could be a future strategy for pharmacological treatment of psoriasis and this protein can be used as a marker of disease activity.

M.Tech. / Psoriasis vulgaris (plaque psoriasis) is a chronic recurring inflammatory skin disease that manifests most commonly as well-circumscribed, erythematous papules and plaques of varying sizes, covered with silvery scales (Beers et al., 2010). The condition itself is considered to be difficult to treat and manage by many types of healthcare practitioners, due in part to its unknown aetiology/trigger and partly due to the nature of the disease itself (Medonça and Burden, 2003). The aim of this study was to ascertain the effects of a Homoeopathic complex remedy on psoriasis. A group of twenty seven participants completed the study. Participants were of both sexes, had to be between the ages of 18 and 65 and had to have been previously diagnosed with plaque psoriasis. The study was conducted over four consultations, two weeks apart, over a six week period. The study followed a double-blind, placebo controlled format. Participants were grouped into matching pairs in terms of age and severity of disease and were then randomly assigned into either the treatment or placebo group for the study duration. Participants were evaluated at each consultation using the three primary assessment tools, namely: the psoriasis area and severity index (PASI) used to assess erythema, thickness and scaling of lesions; the psoriasis disability index questionnaire (PDI), a subjective participant-orientated evaluation of the psychological impact of the disease and the 5-D itch scale used to quantitatively rate the subjective experience of pruritus. The secondary tools used at each consultation were for monitoring purposes only and were used to determine: changes in selected lesion area, as well as the effects of the intervention on the total body surface area (TBSA) affected by psoriasis. The TBSA tool was also used to determine whether new lesions developed during the study period. Using non-parametric analyses, the results of the study demonstrated statistically significant improvement in three of the five variables tested. This includes improvement in: lesion appearance (erythema, scaling and thickness) as determined by PASI; improved psychological experience of the disease quantified by PDI and improvement in the degree of pruritus. It was noted that non-parametric analyses also showed improvement in lesion area. However, lesion area measurement was a secondary tool used for monitoring purposes and it was noted that the use of the tool demonstrated short-comings with regards to consistency and reliability. Parametric analyses showed improvement of statistical significance in one of the five variables tested, namely that of pruritus levels as determined by the 5-D itch scale. It was concluded from this study that the homoeopathic complex remedy was found to be effective in the treatment of certain symptoms of psoriasis and as such should be considered as an adjunct therapy in its treatment.

For more than 100 years dithranol has been successfully used for the treatment of psoriasis . It is still not fully understood, however, how it exerts its antipsoriatic effect. From the information available to date it is clear that the actual process of decomposition is central to the therapeutic action of dithranol. Since there is an obvious parallel between the mechanism of decomposition in solution and that of decomposition/metabolism in skin stability studies were carried out in aqueous buffer (PH 5.5). The effect of various factors such as the presence of various metal ions and surfactants on the decomposition pattern (individual rates of dimer and danthron formation) of dithranol in solution were quantified. The effect of, in particular, surfactants on the skin permeation and decomposition/metabolism of dithranol were then investigated. Because of dithranol's poor water solubility it was necessary to develop an analytical technique capable of the successful quantification of low levels of dithranol and breakdown products in aqueous systems. A previously reported hplc system, which has adequate sensitivity for dithranol and danthron quantification, was used. Improved sensitivity for dimer (3 fold increase), thus allowing the accurate quantification of low levels of dimer in aqueous solutions, was achieved by a modification of the mobile phase. As it was also necessary to establish the amounts of dithranol and breakdown products on and in skin an appropriate extraction method was needed. A procedure whereby skin was first extracted using a mixture of trichloro acetic acid and methanol followed by hplc analysis of the extract was developed. Surfactant solubilisation of dithranol was used to enhance the water solubility of dithranol. Data from the solubilisation studies shows that in sodium lauryl sulphate and tween 80 (above c. m.c in aqueous buffer pH 5.5) the amount of dithranol in solution is directly proportional to the % of surfactant present. In cetrimide, solubilisatiori was observed only at low pH e.g pH 0.4. At pH 5.5, because of the interaction that takes place between dithranol and cetrimide causing dithranol to ionise, dithranol ionisation is responsible for enhanced solubility. About 3 fold more dithranol goes into such cetrimide solutions compared to equivalent concentrations of sodium lauryl sulphate and tween 80. Surfactant presence, however, had implications on dithranol's decomposition pattern. In the sodium lauryl sulphate and tween 80 solutions little change from that seen in buffer pH 5.5 was observed namely - 94 % dimer and - 4 % danthron were produced following complete decomposition. In the presence of cetrimide (PH 5.5) a marked change was seen with - 84% danthron and -14% dimer being formed on complete decomposition. The effect of the inclusion of metal ions i.e Cu2+, Zn2+ and Fe2+ on the kinetics of the decomposition of dithranol to dimer and danthron were quantified. All had a catalytic effect on the rate of dimer formation, while suppressing that of danthron. The catalytic coefficients were in the order of Cu2+ > Fe2+ > Zn2+. Concentration vs time data generated on placing surfactant solutions of dithranol in contact with animal skin (in vitro) and human skin (in vivo) allowed estimates of the amount of dithranol and breakdown products penetrating into the skin, along with the degree of skin surface decomposition taking place during the permeation process. A pronounced deviation was observed for dithranol decomposition in the formulations on the skin and when not in contact with skin. Skin surface decomposition was found to result in the formation of an ,as yet unknown, breakdown product (P4). Using the 12-0-tetradecanoylphorbol-13-acetate/hairless mouse psonasls model it was visually established that the cetrimide-dithranol formulation negated the anti inflammatory effects of dithranol . The tween 80 and sodium lauryl sulphate dithranol formulations reduced the inflammatory response in the psoriasis model to the same degree as an equivalent amount of dithranol delivered in acetone. A preliminary clinical investigation on the influence of cetrimide on the therapeutic outcome of conventional dithranol therapy was carried out using two patients with psoriasis. Cleansing the skin with a solution of cetrimide before and after treatment with dithranol resulted in both a reduction of side effects and a loss in the therapeutic effectiveness of dithranol. The data gathered allowed the discussion of the effect of dithranol's decomposition pathway on its therapeutic outcome.

No description available.

Un important réseau de cytokines serait en grande partie responsable de la formation des lésions psoriasiques. La présence de cellules immunitaires dans des biopsies de peaux psoriasiques suggère une implication majeure de ces dernières dans la maladie. La présente étude tente d'explorer la communication à caractère pro-inflammatoire entre lymphocytes T et kératinocytes psoriasiques. Notre modèle in vitro consiste en une monocouche de kératinocytes sains ou psoriasiques mis en co-culture avec des lymphocytes T sains isolés du sang humain. Les interactions cellulaires ont été étudiées suivant l'analyse de la production de 22 cytokines/chimiokines (technologie du Luminex xMap) et complétées par ELISA. Nos résultats démontrent que les kératinocytes psoriasiques avec les lymphocytes T augmentent leur production de TNF-a, de GM-CSF, de MCP-1, d'IL-6 et d'IL-8 ainsi que celle de lTFN-y, du sIL-2 Ra et de la Fractalkine lorsque 1TL-2 est présente comparativement à la co-culture kératinocytes sains-lymphocytes T. Des tests additionnels avec le neutrophile montrent que la production de cytokines inflammatoires est suffisante pour influencer ce dernier. Ces résultats démontrent l'interaction fonctionnelle entre les kératinocytes et les lymphocytes T ainsi que la persistance des caractéristiques pathologiques des kératinocytes psoriasiques in vitro. Ce modèle expérimental de coculture sera intéressant pour comprendre en profondeur des désordres cutanés auto-immuns comme le psoriasis.

La peau est le plus grand organe du corps humain. Cette enveloppe corporelle, souvent négligée et tenue pour acquise, peut être atteinte de diverses maladies ou d'affectations cutanées. À titre d'exemple, le psoriasis est une dermatose d'évolution chronique et à caractère inflammatoire. Or, cette pathologie est beaucoup plus qu'une condition inesthétique; elle affecte la qualité de vie des patients de manière assez invalidante. En dépit des avancées scientifiques, le psoriasis demeure une dermatose incurable. Conséquemment, l'élaboration de nouveaux produits antipsoriasiques est un enjeu actuel. Inspirés par la contribution substantielle des produits naturels dans cette dermatose, une molécule en particulier a attiré notre attention : le québécol. Ce composé polyphénolique a éveillé notre curiosité scientifique en raison de ses propriétés antiprolifératives et antiinflammatoires. Toutefois, compte tenu de la très faible abondance du québécol dans la nature, cette molécule est synthétisée en laboratoire. Par le fait même, des composés apparentés à ce produit naturel sont également étudiés dans le cadre de ce projet de maîtrise. Ce mémoire présente un outil pharmacologique d'exception : le modèle de peau psoriasique autologue. Élaboré au moyen de l'ingénierie tissulaire, ce modèle reflète avec fidélité les caractéristiques de la peau psoriasique à l'état natif. En considérant son grand potentiel, il demeure le modèle par excellence pour caractériser l'activité antipsoriasique de nouvelles entités chimiques. Les travaux décrits dans ce document portent sur l'évaluation du potentiel antipsoriasique de molécules de source végétale et synthétique. Afin d'approfondir le savoir portant sur ces potentiels candidats, il est envisagé d'investiguer sur leur mécanisme d'action dans la pathologie du psoriasis. Pour ce faire, la peau lésionnelle reconstruite in vitro - un outil cutané unique et innovant - a été mise à profit. / Skin is the largest organ of the human body. Often neglected and taken for granted, this physical envelope can be affected by various diseases or skin disorders. For example, psoriasis is a chronic and inflammatory dermatosis. Yet, this pathology is much more than an unsightly condition; it affects patients' life quality in a disabling way. Despite scientific progress, psoriasis remains an incurable dermatosis. As a result, the development of new antipsoriatic products is an ongoing issue. Inspired by the substantial contribution of natural products in this dermatosis, one molecule in particular caught our attention : the quebecol. This polyphenolic compound has aroused our scientific curiosity because of its antiproliferative and anti-inflammatory properties. However, considering the very low abundance of quebecol in nature, this molecule is produced by chemical synthesis. Thereby, compounds related to this natural product are also studied as a part of this project. This work presents an exceptional pharmacological tool : the autologous psoriatic skin model. Developed using tissue engineering, this model faithfully reflects the characteristics of in vivo psoriatic skin. Considering its great potential, it remains the ultimate model for characterizing the antipsoriatic activity of new chemical entities. The work described in this paper focuses on the antipsoriatic activity evaluation of molecules of plant origin and synthetic origin. In order to deepen the knowledge of these potential candidates, the possibility of investigating their mechanism of action in the pathology of psoriasis is considered. To do so, the in vitro reconstructed lesional skin - a unique and innovative skin tool - was put to contribution.

Le psoriasis est une inflammation chronique assistée du système immunitaire chez l’homme. Dans les lésions psoriasiques, les modifications microanatomiques vasculaires sont un des principaux signes d’une peau psoriasique. Cette étude visait à créer une peau vascularisée reconstruite, bien caractérisée, et facile d’accès pour l’évaluation des candidats au médicament ainsi que pour l’étude de la biologie de l’inflammation et de l’angiogenèse. Les équivalents de peau psoriasique et saine vascularisée ont été produits à l’aide de la méthode par auto-assemblage, qui a été modifiée par l’ajout de cellules endothéliales dermiques microvasculaires humaines. Les similitudes architecturales et caractéristiques des substituts avec l’échantillon in vivo ont été analysées par coloration au trichrome de Masson. Un épiderme bien développé a été observé sur les substituts de peau saine, étant donné qu’un épiderme hyperprolifératif a été observé sur des substituts de peau psoriasique. La nature psoriasique des substituts a été étudiée à l’aide de niveaux d’expression de cytokératine et de marqueurs de différenciation. Les conditions nécessaires à la vascularisation des substituts ont été optimisées. La formation, la différenciation, l’ampleur et la quantité de structures pseudo-capillaires ont été observées dans le cadre d’études par immunofluorescence in toto (IFIT) en utilisant des marqueurs de cellule endothéliale. Les résultats d’études IFIT indiquent que les réseaux pseudo-capillaires à l’intérieur des substituts de peau psoriasique étaient plus ramifiés, denses, chaotiques et nombreux par rapport aux échantillons de contrôle sains, à cause de l’élément de provocation angiogénique du psoriasis. / Psoriasis is an immune-system-mediated chronic inflammation in mankind. In psoriatic skin lesions, vascular microanotomical modifications are one of the important hallmarks of psoriatic skin. The aim of this study was to develop a wellcharacterized and easily accessible reconstructed vascularized psoriatic skin for the evaluation of drug candidates and studying the biology of inflammation and angiogenesis. The vascularized psoriatic and healthy skin equivalents were produced using the self-assembly method, which was modified by the addition of human microvascular dermal endothelial cells. The architectural and characteristic similarities of substitutes to the in vivo condition was analyzed with Masson’s trichrome staining. A well-developed epidermis was observed in healthy skin substitutes, whereas a hyperproliferative epidermis was observed in psoriatic skin substitutes. The psoriatic nature of substitutes was studied with cytokeratin expression levels and differentiation markers. The required conditions for vascularization of substitutes were optimized. The formation, differentiation, extends and the quantity of capillary-like structures were observed with whole-mount immunofluorescence (wmIF) staining studies using endothelial cell markers The results of wmIF studies showed that the capillary-like networks within psoriatic skin substitutes were more branched, dense, chaotic and numerous compared to healthy controls because of the angiogenic provocation feature of psoriasis.

Le psoriasis est une maladie inflammatoire chronique affectant principalement la peau. Au niveau cutané, cette pathologie est caractérisée par une hyperprolifération de l'épiderme ainsi qu'un déséquilibre du métabolisme des acides gras polyinsaturés (AGPIs) contribuant à la boucle d'inflammation chronique. Les AGPIs oméga-3, dont l'acide eicosapentaénoïque (EPA), possèdent des propriétés anti-inflammatoires bénéfiques pour le psoriasis. Toutefois, leur potentiel thérapeutique préserve une faible crédibilité, d'une part parce que certaines observations découlant des études cliniques demeurent contradictoires, et d'une autre part parce que leurs mécanismes d'action dans le psoriasis demeurent peu connus à ce jour. D'une autre part, l'équipe de recherche du Dre Roxane Pouliot a antérieurement démontré le potentiel thérapeutique des oméga-3 sur un modèle de psoriasis *in vitro*. Dans ces travaux, il a été observé que l'EPA était fortement converti en un certain médiateur lipidique anti-inflammatoire, soit l'acide 18-hydroxy-eicosapentaénoïque (18-HEPE). Sur la base de cette observation, il a été suggéré que le 18-HEPE pourrait jouer un rôle pivot dans le mécanisme d'action des oméga-3 dans le psoriasis. C'est pourquoi l'objectif principal de ce projet de recherche était d'évaluer la bio-action du médiateur lipidique 18-HEPE dans le contexte du psoriasis *in vitro*. Pour ce faire, des substituts cutanés sains et psoriasiques ont été produits par génie tissulaire. Les substituts psoriasiques ont reçu des milieux de culture supplémentés ou non avec 0,1 µM de 18-HEPE. Une co-culture de kératinocytes psoriasiques et de lymphocytes T activés a également été réalisée en administrant des milieux de culture supplémentés ou non avec des doses de 18-HEPE allant de 0,1 à 1 µM de 18-HEPE. Les analyses ont révélé que le 18-HEPE ne module pas l'hyperprolifération ni certains marqueurs dérégulés dans l'épiderme des substituts psoriasiques. Également, le 18-HEPE a modulé le profil lipidique des substituts psoriasiques, et ce probablement en s'insérant dans les phospholipides membranaires et en modulant l'activité des enzymes de conversion. De plus, le 18-HEPE a modulé le profil sécrétoire des kératinocytes psoriasiques en présence de lymphocytes T activés, et ce en diminuant la sécrétion des cytokines pro-inflammatoires CXCL10 et IL-8. Finalement, il est suggéré que le 18-HEPE pourrait générer ses effets observés en induisant l'apoptose des lymphocytes T par une hausse d'expression du récepteur Fas à leur surface, puis en diminuant la phosphorylation du récepteur CXCR4. En bref, ce projet de recherche a mis en lumière la bio-action du médiateur lipidique 18-HEPE dans le contexte du psoriasis. Sur la base des observations avec nos modèles *in vitro*, il est conclu que le 18-HEPE ne joue pas un rôle pivot dans le psoriasis, mais qu'il pourrait tout de même contribuer en partie aux effets bénéfiques des oméga-3 dans le psoriasis. / Psoriasis is a chronic inflammatory disease primarily affecting the skin. Psoriatic skin is characterized by hyperproliferation of the epidermis as well as an imbalance in the metabolism of polyunsaturated fatty acids (PUFAs) contributing to the chronic inflammation loop. N-3 PUFAs, including eicosapentaenoic acid (EPA), have beneficial anti-inflammatory properties for psoriasis. However, their therapeutic potential retains low credibility, on the one hand because certain observations resulting from clinical studies remain contradictory, and on the other hand because their mechanisms of action in psoriasis remain little known to date. Dr. Roxane Pouliot's research team previously demonstrated the therapeutic potential of n-3 PUFAs on a model of psoriatic skin reconstructed *in vitro* by tissue engineering. In this work, it was observed that EPA was highly converted into a specific anti-inflammatory lipid mediator, namely 18-hydroxyeicosapentaenoic acid (18-HEPE). Based on these observations, it has been suggested that 18-HEPE may play a pivotal role in the mechanism of action of n-3 PUFAs in psoriasis. Therefore, the main goal of this research project was to evaluate the bio-action of the lipid mediator 18-HEPE in the context of psoriasis *in vitro*. To do this, healthy and psoriatic skin substitutes were produced by tissue engineering. The psoriatic substitutes received culture media supplemented or not with 0.1 µM of 18-HEPE. A co-culture of psoriatic keratinocytes and activated T lymphocytes was also carried out by administering culture media supplemented or not with doses of 18-HEPE ranging from 0.1 to 1 µM of 18-HEPE. Analyzes revealed that 18-HEPE does not modulate hyperproliferation nor some of the dysregulated markers in the epidermis of psoriatic skin substitutes. Also, 18-HEPE modulated the lipid profile of psoriatic substitutes, probably by inserting itself into membrane phospholipids and modulating the activity of converting enzymes. Also, 18-HEPE modulated the secretory profile of psoriatic keratinocytes in the presence of activated T cells, mainly by decreasing the secretion of the pro-inflammatory cytokines CXCL10 and IL-8. Finally, it is suggested that the observed effects of 18-HEPE could be mediated by the induction of T cell apoptosis by an increase in expression of the Fas receptor on their surface and by a decrease in the phosphorylation of the CXCR4 receptor. In summary, this research project shed light on the bio-action of the lipid mediator 18-HEPE in the context of psoriasis. Based on observations with our *in vitro* models, it is concluded that 18-HEPE does not play a pivotal role in psoriasis but may still contribute in part to the beneficial effects of n-3 PUFAs in psoriasis.

Le psoriasis est une dermatose érythémato-squameuse d’évolution chronique. Les patients atteints par la pathologie ont à leur disposition de nombreux traitements qui permettent de contrôler la maladie sans toutefois la guérir. Néanmoins, plusieurs de ces traitements présentent des propriétés toxicologiques et des effets indésirables à court ou long terme. Il devient donc impératif de découvrir de nouvelles molécules thérapeutiques afin d’améliorer considérablement la qualité de vie des patients psoriasiques. Or, l’ingénierie tissulaire permet d’approfondir les connaissances en dermatologie et d’investiguer sur de nouveaux agents thérapeutiques topiques, que ce soit dans le domaine cosméceutique ou pharmaceutique. La culture cellulaire tridimensionnelle (3D) est un modèle pertinent afin d’étudier l’architecture d’un tissu sain ou pathologique. La méthode d’auto-assemblage développée au Laboratoire d’Organogénèse Expérimentale (LOEX) permet l’obtention, entre autre, de substituts cutanés bilamellaires autologues sains ou psoriasiques. L’objectif général de ce projet a été de démontrer, via criblage pharmacologique, le potentiel antipsoriasique d’une gamme de molécules dérivées de la biomasse végétale de la forêt boréale en vue d’une possible utilisation dans le traitement du psoriasis. Des tests de toxicité effectués avec 39 molécules à différentes concentrations ont permis d’identifier 9 molécules inhibitrices de la croissance kératinocytaire et ce, à de faibles concentrations. Parmi ces 9 molécules, toutes testées sur des substituts cutanés 3D sains et psoriasiques, 4 ont démontré des propriétés thérapeutiques prometteuses au niveau de la normalisation de la prolifération et de la différenciation kératinocytaire; il y a une diminution significative de l’épaisseur de l’épiderme vivant des substituts psoriasiques traités avec ces 4 molécules comparativement au contrôle. De plus, ces quatre molécules régulent positivement l’expression de plusieurs protéines impliquées dans la différenciation cellulaire (involucrine, filaggrine, loricrine) ou la prolifération cellulaire (Ki-67). Ainsi, ces molécules novatrices de structure polyphénolique pourraient éventuellement être utilisées en tant que traitement efficace du psoriasis. / Psoriasis is a chronic skin disease characterized by erythematous plaques with loosely adherent silvery-white scales. Psoriatic patients have at their disposal several treatments that control the disease however, no cure has been found yet., Current treatments for psoriasis are associated with toxicological problems and short- and long-term adverse effects. Hence, it is imperative to discover new therapeutic molecules in order to significantly improve the quality of life of psoriatic patients. Tissue engineering of skin is used to deepen our knowledge in dermatology and to investigate on new topical therapeutics for the cosmeceutical or pharmaceutical fields. Three-dimensional (3D) cell culture recapitulates normal and pathological tissue architectures that provide physiologically relevant models to study normal development or diseases of the tissue. The self-assembly method developed at LOEX allows to produce healthy or psoriatic bilamellar skin substitutes. The aim of this project was to demonstrate, using pharmacological screening, the antipsoriatic potential of a range of compounds derived from the plant biomass of the boreal forest. Toxicity assays were used to screen 39 molecules at different concentrations, and a choice of 9 molecules inhibiting the keratinocyte growth at low concentrations was made to pursue this project. Among these 9 molecules, all tested on healthy and psoriatic 3D skin substitutes, 4 of them have shown promising therapeutic properties for the normalization of keratinocyte proliferation and differentiation; these 4 molecules upregulate the expression of several proteins involved in cellular differentiation (involucrin, filaggrin, loricrin) or cellular proliferation (Ki-67). Histological analyses of psoriatic skin substitutes treated with these 4 molecules showed a significant decrease of the epidermis thickness. Thereby, these innovative molecules with a polyphenolic structure could possibly be used as an effective treatment of psoriasis.

L'assurance médicaments au Canada est formée d'une mosaïque de régimes publics et privés. Ce système fait l'objet de critiques depuis plusieurs décennies. En juin 2019, le Conseil consultatif sur la mise en œuvre d'un régime national d'assurance médicaments a recommandé la création d'un régime national public et universel à payeur unique pour la couverture des médicaments d'ordonnance au Canada. Parmi les problématiques invoquées : le coût des agents biologiques est disproportionnellement élevé par rapport au nombre de réclamations correspondantes. En psoriasis, les critères de remboursement basés sur des scores de sévérité et l'échec aux traitements antérieurs sont exigeants. Plusieurs études en maladies auto-immunes ont observé une association entre le régime d'assurance des patients et l'accès aux agents biologiques, plus souvent au détriment des individus assurés au public. Nous avons évalué l'accès aux agents biologiques en psoriasis entre les groupes d'assurance médicaments (public versus privé) en comparant : 1) les scores de sévérité au moment de la prescription; 2) les scores de sévérité au renouvellement; 3) la réponse au traitement; 4) le délai entre la prescription et la première dose du médicament. Cette étude de cohortes rétrospective incluait des patients avec psoriasis traités à l'aide d'un agent biologique prescrit par un dermatologue entre 01/09/2015-31/08/2019. Les données ont été collectées à partir des dossiers médicaux et les analyses réalisées avec SAS® Studio 3.8. Les patients assurés au public (n=78) versus privé (n=93) n'étaient pas différents selon les critères étudiés. Leurs caractéristiques différaient toutefois, notamment : l'âge plus élevé (p<.0001) et la plus forte prévalence d'ordonnance pour compassion (p<.0001) au public. L'étude ne révèle pas d'inégalité dans l'accès aux médicaments entre les groupes. La forte prévalence de compassion au public (42% versus 14%) et de psoriasis sur des sites particuliers (85%) pourrait occulter la présence de différence mesurée sur le PASI. / The Canadian drug insurance consists of a patchwork of public and private plans. This system has been the subject of criticism for decades. In June 2019, the Advisory Council on the Implementation of National Pharmacare recommended the implementation of a national public and universal single-payer plan for prescription drug coverage in Canada. The cost of prescribed biologic agents is disproportionately high compared to the number of corresponding claims. The reimbursement criteria for biological agents in psoriasis are demanding: they are based on validated severity scores and failure to previous therapies. Several studies in autoimmune diseases observed an association between patients' insurance and access to biologic agents, to the detriment of individuals publicly insured. We aimed to compare: 1) psoriasis severity scores at time of biologic prescription in public versus private groups; 2) severity scores at follow-up; 3) treatment response; 4) delay between prescription and first dose of biotherapy. This retrospective cohort study included psoriasis patients with dermatologist-prescribed biologics from 09/01/2015-08/31/2019 in Quebec City, Canada. Data were collected from medical records. Statistical analyses included univariate and multivariate analyses which were conducted using SAS® Studio 3.8. Public (n=78) and private (n=93) patients were not different in outcomes. Patients' characteristics differed between groups. Public patients were older (p<.0001), more socioeconomically deprived (p=.03), and more likely to benefit from compassion prescription (p<.0001) compared to privately insured. Prescribers of biologics can be reassured as our results did not reveal inequality in access or care. The high prevalence of compassionate programs (42% versus 14%) and psoriasis in the face/genitalia/palmoplantar areas (85.4%) observed in the public insurance group may mask differences in PASI response between groups.