Bullous pemphigoid (BP) is a common autoimmune blistering disease in the adult population, but extremely rare in the pediatric population. Childhood BP usually has a favorable prognosis and responds well to topical and oral steroids. However, for patients that do not respond to corticosteroids, therapeutic alternatives are scarce. We report a case of a toddler with recalcitrant BP who was successfully treated with mycophenolate mofetil (MMF).

No description available.

No description available.

La protéine IL4I1 est une enzyme sécrétée dont l’activité L-amino acide oxydase vis-à-visde la phénylalanine inhibe la prolifération des lymphocytes T in vitro (Boulland et al, Blood 2007).Comme d’autres enzymes immunosuppressives, elle est exprimée dans les tumeurs au niveau descellules myéloïdes et/ou des cellules tumorales (Carbonnelle-Puscian et al, Leukemia 2009). Le but decette thèse a été de caractériser les conditions d’expression d’IL4I1 et de comprendre son rôle dans lecancer.Nous avons montré que les macrophages et les cellules dendritiques représentent la principalesource d’IL4I1 in vitro et dans des lésions inflammatoires chroniques. L’expression d’IL4I1 dans lesphagocytes mononucléés est induite par les interférons ou les ligands de TLR, activant respectivementSTAT1 et NF-kB, tandis que les lymphocytes B expriment des niveaux nettement plus faibles d’IL4I1sous le contrôle de la voie IL-4/STAT6 et de la voie CD40/NFkB. L’expression d’IL4I1 par des cellulesmonocytaires inhibe la production de cytokines Th1 et pourrait donc contribuer à la régulation del’inflammation Th1 in vivo.Dans un modèle murin de cancer, l’expression d’IL4I1 facilite le développement tumoral endiminuant la réponse T cytotoxique spécifique de la tumeur. Ceci est observé à des niveaux d’activitéIL4I1 proches de ceux mesurés dans des tumeurs humaines, suggérant qu’IL4I1 puisse contribuer àl’échappement des tumeurs au système immunitaire chez l’homme. Nous avons développé plusieursmutants d’IL4I1, afin d’évaluer l’impact de l’activité enzymatique versus celui de l’éventuelle liaison del’enzyme à un récepteur, dans l’effet protumoral observé. Un de ces mutants est actuellementdisponible pour une étude chez la souris.Nos résultats installent définitivement IL4I1 dans le panorama des enzymesimmunosuppressives associées au cancer et ouvrent la voie au développement d’inhibiteursspécifiques comme outils thérapeutiques / The IL4I1 protein is a secreted L-amino acid oxidase, which inhibits T cell proliferationthrough phenylalanine degradation in vitro (Boulland et al, Blood 2007). Similar to previously describedimmunosuppressive enzymes, IL4I1 is expressed in cancer by myeloid cells and/or tumor cells(Carbonnelle-Puscian et al, Leukemia 2009). The aim of this work was to characterize the cells andstimuli associated with IL4I1 expression and to decipher its role in cancer.We showed that macrophages and dendritic cells are the main source of IL4I1 in vitro and inchronic inflammatory lesions. IL4I1 expression in mononuclear phagocytes is induced by interferons orTLR ligands, which act through STAT1 and NFkB respectively. Conversely, B cells express dramaticallylower levels of IL4I1 under the control of IL-4/STAT6 and CD40/NFkB. IL4I1 expression by monocyticcells inhibits the production of Th1 cytokines and may thus contribute to Th1 inflammation control invivo.In a murine model of cancer, IL4I1 expression facilitates tumor development by depressing thetumor specific cytotoxic T cell response. This is observed for IL4I1 activity levels in the range of thosemeasured in human tumors, suggesting that IL4I1 may contribute to tumor immune escape in humans.We developed several IL4I1 mutants to discriminate the role of the enzymatic activity versus the bindingto a putative cell surface receptor in the protumor effect observed. One of these mutants is currentlyavailable for in vivo testing.Our results definitively establish IL4I1 in the family of immunosuppressive enzymes associatedwith cancer and pave the way for the development of specific inhibitors as therapeutic tools

Les travaux de l'équipe ont permis de montrer qu'IL4I1 est une L-amino acide oxydase sécrétée par les cellules d'origine myéloïde dégradant la phénylalanine en H2O2, NH3 et phénylpyruvate. Elle est fortement exprimée au sein des tumeurs humaines et facilite l'échappement tumoral dans un modèle de mélanome murin. Cette enzyme inhibe l'expression de la chaîne ζ du TCR ainsi que la prolifération des lymphocytes T effecteurs/mémoires via la production d'H2O2. IL4I1 appartient donc à une famille d'enzymes régulatrices des réponses immunitaires impliquées dans la défaillance de la réponse anti-tumorale.Au cours de ma thèse, j'ai montré qu'IL4I1 induit la différenciation des lymphocytes T CD4+ naïfs conventionnels en cellules CD25fortFoxP3+ chez l'Homme et la souris. Ces cellules exercent une action suppressive in vitro équivalente à celle de cellules régulatrices obtenues sans IL4I1 et leur phénotype est similaire. La promotion de la différenciation Treg par IL4I1 a pu être observée dans différentes conditions in vitro et s'avère particulièrement importante lorsque les cellules sont cultivées sans ajout d'IL2 et de TGFβ. Le mécanisme impliqué reposerait en partie sur la consommation de Phe par l'activité enzymatique qui serait responsable de l'inhibition de la voie mTORC1 observée.En conclusion, nous avons démontré un nouveau rôle d'IL4I1 sur les lymphocytes T. Ainsi, en inhibant la prolifération des lymphocytes T et en induisant la polarisation Treg, IL4I1 pourrait jouer un rôle important dans l'échappement tumoral. IL4I1 étant sécrétée et peu exprimée à l'état physiologique, elle pourrait être la cible de traitements adjuvants dans le cancer. / Our team has shown that IL4I1 is a secreted L-amino acid oxidase which degrades phenylalanine into H2O2, NH3 and phenylpyruvate.. This enzyme is produced by myeloid cells and expressed within human cancers. IL4I1 expression facilitates tumor growth in a mouse model. IL4I1 inhibits TCRζ chain expression and T lymphocyte proliferation via H2O2 production. Therefore IL4I1 belongs to a family of enzymes endowed with immune regulatory functions involved in the anti-tumor response failure.During my PhD, I showed that IL4I1 induces CD25highFoxP3+ cells differentiation from conventional naïve CD4+ T cells, both in humans and mice in vitro systems. These cells exert similar in vitro suppressive activity than those obtained without IL4I1 with a similar phenotype. Treg differentiation promotion by L4I1 is observed in various in vitro conditions and is particularly important when cells are cultured without addition of IL2 and TGFβ. The involved mechanism would partially depend on the phenylalanine consumption by the enzymatic activity which would be responsible for the mTORC1 pathway inhibition observed.In conclusion, we have demonstrated a new mechanism of IL4I1 action on T lymphocytes. Thus, by inhibiting T lymphocytes proliferation and by inducing Treg polarization, IL4I1 could play an important role in tumor escape. Since IL4I1 is secreted and weakly expressed under physiological conditions, it could be the target of adjuvant therapy in cancer.

Myelin and oligodendrocytes (OLGs) are the apparent targets of the immune-mediated injury that underlies the development of multiple sclerosis (M8). Recovery from M8 clinical relapses likely reflects remyelination attributed to recruitment and differentiation of oligodendrocyte progenitor cells (OPCs), rather than to new process formation by previously myelinating OLGs. Newly emerging M8-directed immuno-modulatory therapies (statins and FTY720) can readily cross the blood-brain barrier and have been shown to impact signaling pathways implicated in cytoskeletal regulation, differentiation, migration, and survival; these are cellular events presumably important for myelin integrity and remyelination. / Statins inhibit the production of cholesterol (concentrated in the myelin membrane) and isoprenoids (post-translational attachments regulating the functions of proteins such as the Rho GTPases). We showed that treatment of human and rodent-derived OPCs with lipophilic statins induced an initial process extension associated with enhanced differentiation and impaired spontaneous migration, whereas prolonged treatment induced process retraction and cell death. Rodent and human mature OLGs demonstrated similar cytoskeletal and survival responses. Chronic simvastatin therapy of mice inhibited remyelination following demyelination induced by the OLG toxin, cuprizone, attributed to a block in OPC differentiation and consequent decrease in mature OLGs. Even fully myelinated animals treated with simvastatin over the long-term demonstrated a decrease in myelin in the brain by maintaining oligodendroglial cells in the pre-OLG state and preventing continual replacement of mature OLGs. / FTY720 is an agonist of G-protein-coupled receptors S1P1, 3, 4, and 5, that are associated with distinct receptor isotype-selective activation of Rho GTPases. In human OPCs, FTY720 could induce initial S1P3/5-dependent process retraction associated with an inhibition of differentiation, and subsequent S1P1-dependent process extension. Mature OLGs showed a dose-dependent cyclic modulation of process extension and retraction was observed over time. Both human OPCs and OLGs were rescued by FTY720 under death-promoting environments. Both cell types also demonstrated a cyclic and reciprocal modulation of S1P1 and S1P5 mRNA levels, reflected in the recurring receptor isotype-dependent functional responses over time. Studies using organotypic cerebellar slice cultures demonstrated that FTY720 did not impact myelin integrity under basal conditions, yet accelerated remyelination following lysolecithin-induced demyelination. Both treatment regimens were associated with an extension of OPC and mature OLG processes. / Our observations demonstrate that drug concentrations used to modulate immune function can have differential dose and time-dependent effects on OPCs, OLGs, as well as on myelin and remyelination processes. Our findings indicate the need to monitor the effects of putative immuno-modulatory therapies on myelin-related processes in MS patients.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

No description available.

Myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) play an essential role in the immunosuppressive networks that contribute to tumor immune evasion. The mechanisms by which tumors promote the expansion and/or function of these suppressive cells and the cross-regulation between MDSC and Treg remain incompletely defined. The current work evaluates the influence of MDSC, expanded in two mouse cancer models, on immunosuppressive Treg. We demonstrate that tumor-induced MDSC endowed with the potential of suppressing conventional T lymphocytes surprisingly impair TGF-β1-mediated generation of induced Treg (iTreg) from naïve CD4⁺ T lymphocytes. Suppression of iTreg generation by MDSC occurs early in the differentiation process, and is cell contact dependent. This inhibition of FoxP3-expressing T lymphocyte differentiation by MDSC does not depend on arginase 1, cystine/cysteine depletion, iNOS/NO, or PD-1/PD-L1 signaling. These findings therefore indicate that MDSC from tumor-bearing hosts have the heretofore unreported ability to restrict some immunosuppressive Treg subpopulations.

Cyclophosphamide (CY) was injected intraperitoneally into mice at varying dosage levels 48 hours prior to intravenous inoculation of constant amounts of dialysable leucocytic transfer factor (TF). Bovine TF to coccidioidin and Brucella abortus and porcine TF to Mycobacterium avium were used. Twenty-four hours after TF injections, mice were tested for delayed hypersensitivity by footpad inoculation with specific antigens. The results show that CY slightly enhanced the delayed hypersensitivity response to the specific test antigens in all three systems. This was not true at every CY dose level, however, since there was a correlation between the dosage of CY and the time of peak footpad swelling. Cyclophosphamide at a low level (20 mg/kg body wt) caused the maximal reading at 24 hours after test, whereas the high level dose (200 mg/kg) showed greatest thickening of the footpad at 48 hours. Transfer factor dosage differences appeared to change the response relatively little, if at all. The cyclophosphamide dose response, on the other hand, showed disparities among various antigen systems and at the different observation times. Under these conditions, no consistent, striking effects of CY on transfer could be noted.