Les polynucléaires éosinophiles sont des leucocytes multifonctionnels qui participent aux réponses innées et adaptatives par l’expression et la sécrétion de nombreux récepteurs et médiateurs. De plus en plus d’études, épidémiologiques, in vivo ou in vitro, suggèrent la participation des éosinophiles dans l’immunité anti-tumorale, et notamment dans le contexte du cancer du côlon. En effet, la présence d’une TATE (Tumor-Associated Tissue Eosinophilia) chez les sujets atteints de cancers est, en général, associée à un pronostic favorable. De même, notre laboratoire ainsi que d’autres équipes ont montré que les éosinophiles humains expriment des récepteurs et médiateurs, communs aux lymphocytes et connus pour être impliqués dans l’immunité anti-tumorale, tels que le 2B4, le complexe CD3/TCRγδ ou le granzyme A. La stimulation des éosinophiles in vitro, via ces récepteurs, conduit à la mort de cellules cancéreuses. Cet effet nécessitant un contact entre les cellules impliquant LFA-1 sur les éosinophiles. L’interleukine-18 est un membre de la famille des cytokines de l’IL-1. Elle fut initialement identifiée comme un facteur induisant la production d’IFNγ, basé sur sa capacité à promouvoir une réponse de type Th1 chez les lymphocytes et les cellules NK. Aujourd’hui, l’IL-18 est considérée comme une cytokine immuno-régulatrice capable de stimuler de nombreux types cellulaires. Son implication dans la réponse anti-tumorale est de plus en plus reconnue, notamment en favorisant la cytotoxicité de cellules NK. Nous avons donc étudié si cette cytokine pouvait également être impliquée dans la cytotoxicité des éosinophiles. Dans ce travail, nous avons démontré que les éosinophiles humains exercent une cytotoxicité vis-à-vis de plusieurs lignées cellulaires tumorales avec cependant une certaine hétérogénéité. L’IL-18 est non seulement capable d’activer in vitro les éosinophiles mais elle participe également à leur activité anti-tumorale vis-à-vis d’une lignée de carcinome du côlon, en favorisant notamment le contact entre les deux types cellulaires. Nos résultats proposent l’IL-18 comme un nouveau médiateur dans l'activité anti-tumorale des éosinophiles et apportent également un nouvel argument en faveur du rôle bénéfique que les éosinophiles peuvent exercer, notamment dans le contexte du cancer du colon. / Eosinophils are multifunctional leukocytes which participate in innate and adaptive immune response though the expression and secretion of various receptors and mediators. Numerous epidemiological, as well as in vivo and in vitro studies suggest the involvement of eosinophils in antitumor immunity, notably in context of colon cancer. In fact, a TATE (Tumor-associated tissue eosinophilia) is associated with a good prognostic value. Recently, we and others have shown that human eosinophils expressed receptors and mediators shared with lymphocytes and involved in anti-tumor defense, such as 2B4, TCRγδ/CD3 complex, and granzyme A (8–10). Eosinophil stimulation through these receptors induced tumor cell death in vitro. This activity required cell-cell contact involving LFA-1 on eosinophils. IL-18 is a member of the IL-1 family of cytokines. IL-18 was first identified as an IFNγ-inducing factor, based on its ability to enhance the Th1-type immune response by stimulating NK cells and T cells. IL-18 is actually considered as an immunoregulatory cytokine able to stimulate various cell types. IL-18 participates in antitumor responses notably by enhancing NK cell-mediated cytotoxicity. In this context, we have studied whether this cytokine may be also involved in eosinophil-mediated cytotoxicity. In this study, we show that human eosinophils exert cytotoxicity against tumor cells in vitro, with heterogeneity according to the type of target cells. IL-18 increases eosinophil-mediated cytotoxicity towards a carcinoma cell line in vitro by promoting cell-cell contact between these two cell types. Our results propose IL-18 as a new mediator in antitumor properties of human eosinophils and support further evidence that eosinophils could exert a beneficial role, notably in the context of colon cancer.

L’hypoxie est connue pour être responsable d’une propagation tumorale accrue. En conséquence, les tumeurs hypoxiques nécessitent un diagnostic rapide et précis. L’accès à toutes les localisations tumorales par l’imagerie nucléaire est devenu un intérêt majeur pour l’orientation thérapeutique. Dans la première partie de ce manuscrit, un nouveau traceur de l’hypoxie tumorale marqué au technétium 99m a été développé avec succès. De nouveaux traceurs organosilylés marqués au fluor 18 ont également été étudiés. Un second travail a porté sur le développement d’une nouvelle stratégie de fluoration nucléophile pour la préparation de traceurs TEP. Des essais synthèse du Fluorodésoxyglucose ont été réalisés. L’élaboration de cette stratégie a également conduit au développement d’une nouvelle méthodologie de synthèse de dérivés d’acides sulfoniques par déprotection de thiols au moyen d’hypochlorite de tert-butyle. / It has been recognized that hypoxia plays a major negative role in overall tumor progression. The identification and quantitative estimation of tumor hypoxia by means of nuclear imaging is an important factor in planning the therapeutic strategy for a better clinical outcome. In the present work, a new 99mTc tracer for imaging tumor hypoxia has been successfully developed. New organosilicon fluorinated derivatives were also studied. Every synthesized compounds incorporated a nitroimidazole moiety, which is selectively trapped in hypoxic cells. The second part of this work, led to the development of a new nucleophilic fluorination strategy for the preparation of PET tracers. The new strategy was attempted for the preparation of Fluorodeoxyglucose. In the course of this study, a novel oxidative deprotection method of thiols was developed. Herein was described, the synthesis of sulfonic acid derivatives by oxidative deprotection of thiols using tert-butyl hypochlorite.

The Court of Appeal in Bohemia between 1749 and 1790 (1850) This thesis describes the development of The Court of Appeal in Bohemia between the years 1749 and 1850. The main aim of this thesis is the description of the role of this court in the system of justice in the second half of the eighteen century and the description of the effects of reforms of Maria Theresa and Joseph II on the constitution, structure and function of the court. In the form, which the court acquired at the time of the rule of Joseph II, the court remained for another sixty years. The Court of Appeal in Bohemia was founded in the year 1548. From the beginning it was a royal court and was empowered to hear appeals of municipal courts. Its competence was extended during the ages. On the contrary the district of the court was limited during the eighteen century only to Bohemia. In the year 1850 the court was transformed into Higher Regional Court in Prague.

Experiments were conducted to investigate: 1) production of trans-18:1 and cis/trans-18:2 isomers due to input of forage and corn grain in continuous culture fermenters, 2) concentrations of trans-18:1 and cis/trans-18:2 isomers in blood and milk fat of grazing cows fed a grain supplement containing solvent- or mechanically-extracted soybean meal, 3) plasma and milk fatty acid profiles of lactating cows in response to a conjugated linoleic acid (CLA) mixture infused into the rumen, and 4) effects of cis9,trans11-18:2 (9/11CLA) or trans10,cis12-18:2 (10/12CLA) on de novo synthesis and desaturation of milk fatty acids in lactating cows fed unsaturated oils. In the first study, rumen fermenters were fed (50 g DM/d) orchardgrass or red clover with 0, 8, or 16 g/d corn replacing equal portions of forage DM. Outflow of trans11,cis15-18:2 (11/15LA) in effluents was greater when DM input was clover or grass only. With each increment of corn, output of 9/11CLA increased until it was 205% greater compared with forage alone. Trans11-18:1 (TVA), an intermediate in 18:2n6 (LA) and 18:3n3 (LN) hydrogenation, output increased by 28% with corn addition. Outputs of trans10-18:1 and 10/12CLA nearly doubled as corn increment increased. In the second experiment, Holstein cows grazing mixed clover-grass pastures were fed a grain supplement (6.7 kg/d) containing 1.7 kg solvent-extracted soybean meal (SES, 15 mg LA/g of DM), 1.9 kg mechanically-extracted soybean meal (MES, 24 mg LA/g of DM), or 1.9 kg MES plus 30 g of liquid methionine hydroxy analog (MESM). Cows fed MES or MESM had greater concentrations of LA, TVA, 9/11CLA, and 11/15LA in blood compared with cows fed SES. Daily yields of 18:0 (SA), LA, LN, TVA, and 9/11CLA in milk fat also were greater for cows fed MES or MESM compared with SES. In experiment 3, four Holstein cows were used in a 4 x 4 Latin square to determine plasma and milk fatty acid profiles during infusion of a CLA mixture at 0, 45, 90, or 180 g/d for 48 h into the rumen. Relative to the control, infusion of 180 g CLA/d decreased milk fat percentage and yield. Lower milk fat yield resulted from depressed concentrations of saturated 6:0 to 16:0 medium-chain fatty acids (MCFA). Concentrations of TVA, trans10-18:1, and 10/12CLA in blood plasma, and yields in milk fat increased in response to each dose of CLA. Stearic acid yield also increased as dose of CLA increased. Yield of cis9-18:1 (OA) in milk fat, however, was lower at 180 g CLA/d. In experiment 4, four cows were fed high-oleic (HO) or high-linoleic (HL) (2.5% of DM) oil for 11 d prior to abomasal infusion (15 g/d) of 9/11CLA or 10/12CLA for 48 h (2 x 2 factorial). Milk fat percentage and yield decreased 25% due to infusion of 10/12CLA compared with 9/11CLA, regardless of diet. Lower fat yields resulted from lower MCFA concentrations and yields. Regardless of diet, concentration (but not yield) of SA increased 40% when 10/12CLA was infused compared with 9/11CLA. Concentrations and yields of OA, 9/11CLA, and 20:4n6 also were reduced by infusing 10/12CLA compared with 9/11CLA regardless of diet. Thus, in addition to inhibiting de novo fatty acid synthesis, 10/12CLA appeared to inhibit desaturation via delta-6 and delta-9 desaturases. Significant implications from the above studies include: 1) 11/15LA and TVA are the primary intermediates flowing out of the rumen during hydrogenation of pasture lipids, 2) replacing forage DM with starch, OA, and LA increases synthesis of trans10-18:1 and 10/12CLA in the rumen, 3) desaturation of TVA produced in the rumen provides an alternate source for 9/11CLA in milk fat, and 4) 10/12CLA decreases de novo synthesis and desaturation of milk fatty acids. / Ph. D.

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