Bei der Aufrechterhaltung des homeostatischen Gleichgewichts und der peripheren Selbst-Toleranz spielen CD4+CD25+ regulatorische T-Zellen (Tregs) eine wichtige Rolle. In Vorarbeiten wurden Subpopulationen von murinen CD4+ Tregs identifiziert, die sich durch die Expression des Integrins alphaE auszeichnen. Diese alphaE+ Treg Subpopulationen weisen einen Effektor/Memory-ähnlichen Phänotyp auf. In der vorliegenden Dissertation wurde untersucht, welche Bedingungen zur Entwicklung von alphaE+ Effektor/Memory Tregs in vivo führen und aus welchen Vorläuferzellen sie entstehen. Dabei zeigte sich, dass es sich bei den alphaE+ Tregs um Effektor/Memory T-Zellen handelt, die unter physiologischen Bedingungen in vivo ein hohes Maß an Zellteilung aufweisen, welche zum Teil abhängig von der bakteriellen Besiedelung des Darms ist. Darüber hinaus wurde beobachtet, dass alphaE+ Tregs nach oraler, antigen-spezifischer Aktivierung in den darm-assozierten lymphoiden Geweben sowohl aus konventionellen naiven CD4+ T-Zellen, als auch aus thymus-generierten naiven CD4+CD25+ Tregs entstehen können. Zusammenfassend deuten die erzielten Ergebnisse darauf hin, dass das spezifische mukosale Mikroenvironment sowohl die Expansion als auch Konvertierung von Tregs fördert und so eine wichtige Rolle für die Aufrechterhaltung der Homeostase von alphaE+Foxp3+ Tregs spielt. Zudem wurde in dieser Arbeit die Ausbildung von gewebespezifischen Homingrezeptor-Phänotypen von naiven CD4+CD25+ Tregs untersucht. In in vitro Kultur-Systemen zeigte sich, dass selektive Modulation von Tregs, ähnlich wie bei konventionellen T-Zellen, die Induktion von organspezifischen Migrationseigenschaften ermöglicht. So konnte eine effiziente Wanderung von Tregs in den Darm ausgelöst werden. Diese Daten legen den Schluss nahe, dass die Herstellung von Tregs mit spezifischen Wanderungseigenschaften eine Option für therapeutische Anwendungen in der adoptiven T-Zell Therapie sein könnte. / Regulatory CD4+CD25+ T cells (Tregs) play an important role in immune homeostasis and in the maintenance of self-tolerance. Previously, subsets of murine CD4+ Tregs characterised by expression of the integrin alphaE had been identified. These alphaE+ Treg subsets display an effector/memory-like phenotype. In the present study the circumstances favouring in vivo generation of effector/memory-like alphaE+ Tregs were analysed. The results presented here show that alphaE+ effector/memory-like Treg subsets contain a large fraction of cycling cells under physiologic conditions in healthy mice. This in vivo proliferation depended, at least in part, on intestinal commensal microflora. Furthermore, it was observed that alphaE+ Tregs not only developed by differentiation of naive-like CD4+CD25+ Tregs, but were also generated de novo from naive CD4+ T cells in the gut-associated lymphoid tissue upon oral antigen delivery. Taken together, these results indicate that the mucosal microenvironment favours both expansion and conversion of Tregs and thereby represents an important mechanism for the homeostatic maintenance of alphaE+Foxp3+ Tregs. In addition, susceptibility of naive CD4+CD25+ Tregs to acquire tissue-specific homing receptor phenotypes was investigated. In vitro culture systems demonstrated that Tregs, similarly to conventional T cells, could be configured with organ-selective homing properties allowing efficient targeting into the gut. These results suggest that generation of Tregs with specific homing properties for therapeutic purposes in adoptive T cell therapy might be a feasible option.

<p>U ovoj doktorskoj disertaciji predstavljena je radiolo&scaron;ka i strukturna karakterizacija građevinskih materijala koji se mogu naći u upotrebi u Srbiji. Izvr&scaron;ena je radiolo&scaron;ka karakterizaicija ukupno 348 uzoraka: granita,&nbsp; fosfogipsa,&nbsp; sirovina&nbsp; u&nbsp; keramičkoj&nbsp; industriji,&nbsp; keramičkih pločica,&nbsp; betona,&nbsp; opeke,&nbsp; maltera,&nbsp; siporeksa,&nbsp; crepa&nbsp; i&nbsp; drugih<br />građevinskih materijala op&scaron;te upotrebe.&nbsp; Radiolo&scaron;ka karakterizacija je&nbsp; sprovedena&nbsp; merenjem&nbsp; koncentracija&nbsp; aktivnosti 226 Ra,232 Th&nbsp; i 40 K metodom&nbsp; gama&nbsp; spektrometrije,&nbsp; kao&nbsp; i&nbsp; ekshalacije&nbsp; radona&nbsp; iz selektovanih&nbsp; građevinskih&nbsp; materijala&nbsp; kori&scaron;ćenjem&nbsp; aktivnih&nbsp; uređaja RAD7,&nbsp; RTM&nbsp; 1688-2,&nbsp; AlphaGUard&nbsp; i&nbsp; AlphaE.&nbsp; Kori&scaron;ćenjem&nbsp; Monte Karlo&nbsp; simulacija&nbsp; izvr&scaron;ena&nbsp; je&nbsp; procena&nbsp; jačina&nbsp; apsorbovanih&nbsp; doza<br />gama&nbsp; zračenja,&nbsp; uočena&nbsp; su&nbsp; odstupanja&nbsp; od&nbsp; teorijski&nbsp; procenjenih vrednosti&nbsp; i&nbsp; dati&nbsp; predlozi&nbsp; za&nbsp; korekciju.&nbsp; Izvr&scaron;ena&nbsp; je&nbsp; procena radijacionog&nbsp; rizika&nbsp; od&nbsp; kori&scaron;ćenja&nbsp; analiziranih&nbsp; građevinskih materijala&nbsp; u&nbsp; enterijeru,&nbsp; kao&nbsp; i&nbsp; za&nbsp; profesionalna&nbsp; lica&nbsp; pri&nbsp; radu&nbsp; sa sirovinskim&nbsp; materijalima.&nbsp; Ispitivane&nbsp; su&nbsp; mogućnosti&nbsp; upotrebe fosfogipsa&nbsp; kao&nbsp; NORM&nbsp; materijala&nbsp; u&nbsp; proizvodnji gips-karton&nbsp; ploča&nbsp; i opeke&nbsp; uz procenu radijacionog rizika od upotrebe.&nbsp; Napravljeno je 8 uzoraka&nbsp; opeke&nbsp; sa&nbsp; različitim&nbsp; udelog&nbsp; fosfogipsa&nbsp; i&nbsp; izvr&scaron;ena&nbsp; je<br />radiolo&scaron;ka&nbsp; i&nbsp; strukturna&nbsp; karakterizacija&nbsp; dobijenih&nbsp; materijala. Ispitivane&nbsp; su&nbsp; varijacije&nbsp; koeficijenata&nbsp; emanacije&nbsp; radona&nbsp; iz građevinskih materijala tokom vremena, kao i uticaj efekata curenja i povratne difuzije koji dovode do tih varijacija. Ispitivan je takođe i uticaj strukture materijala u smislu mineralo&scaron;kog i hemijskog satava i&nbsp; poroznosti&nbsp; na&nbsp; vrednosti&nbsp; koeficijenta&nbsp; emanacije&nbsp; radona. Meneralo&scaron;ka&nbsp; karakterizacija&nbsp; uzoraka&nbsp; izvr&scaron;ena&nbsp; je&nbsp; metodom rendgenske&nbsp; strukturne&nbsp; analize&nbsp; (XRD),&nbsp; a&nbsp; hemijska&nbsp; metodom rendgenske&nbsp; fluorescentne&nbsp; analize&nbsp; (XRF).&nbsp; Merenje&nbsp; ukupne&nbsp; efektivne poroznosti izvr&scaron;eno je metodama apsorpcije vode i metodom živine porozimetrije.&nbsp; Na&nbsp; osnovu&nbsp; dobijenih&nbsp; rezultata&nbsp; uspostavljene&nbsp; su značajne&nbsp; korelacije&nbsp; između&nbsp; pojedinih&nbsp; radiolo&scaron;kih&nbsp; i&nbsp; strukturnih parametara za analizirane uzorke građevinskih materijala.</p> / <p>In&nbsp; this&nbsp; doctoral&nbsp; dissertation,&nbsp; the&nbsp; results&nbsp; of&nbsp; the&nbsp; radiological&nbsp; and structural characterization of building materials used in Serbia were presented.&nbsp; Radiological&nbsp; characterization&nbsp; of&nbsp; a&nbsp; total&nbsp; of&nbsp; 348&nbsp; samples was performed, including granite, phosphogypsum, raw&nbsp; materials&nbsp; in the ceramic industry, ceramic tiles, concrete, brick, mortar, siporex, tiles,&nbsp; and&nbsp; other&nbsp; materials&nbsp; frequently&nbsp; used&nbsp; as&nbsp; building&nbsp; materials.Radiological characterization was performed by measuring activity concentrations&nbsp; of 226 Ra,232 Th,&nbsp; and 40 K&nbsp; by&nbsp; gamma&nbsp; spectrometry method, as well&nbsp; as radon exhalation from selected building materials using active devices RAD7, RTM 1688-2, AlphaGuard and AlphaE.Using&nbsp; Monte&nbsp; Carlo&nbsp; simulations,&nbsp; the&nbsp; absorbed&nbsp; gamma&nbsp; dose&nbsp; rates were&nbsp; estimated.&nbsp; Furthermore,&nbsp; the&nbsp; deviations&nbsp; from&nbsp; the&nbsp; theoretically estimated&nbsp; absorbed&nbsp; dose&nbsp; rates&nbsp; were&nbsp; observed,&nbsp; and&nbsp; suggestions&nbsp; for correction were given. An assessment of the radiation risk from the use&nbsp; of&nbsp; analyzed&nbsp; building&nbsp; materials&nbsp; in&nbsp; the&nbsp; interior,&nbsp; as&nbsp; well&nbsp; as&nbsp; for occupational&nbsp; workers&nbsp; working&nbsp; with&nbsp; raw&nbsp; materials&nbsp; was&nbsp; conducted.The possibilities of using phosphogypsum as a NORM material in the production&nbsp; of&nbsp; gypsum&nbsp; plasterboard&nbsp; and&nbsp; bricks&nbsp; were&nbsp; investigated, with&nbsp; an&nbsp; assessment&nbsp; of&nbsp; the&nbsp; radiation&nbsp; risk&nbsp; due&nbsp; to&nbsp; use&nbsp; of&nbsp; phosphogypsum as a component in the building materials. 8 samples of&nbsp; bricks&nbsp; with&nbsp; different&nbsp; proportions&nbsp; of&nbsp; phosphogypsum&nbsp; were&nbsp; made and&nbsp; radiological&nbsp; and&nbsp; structural&nbsp; characterization&nbsp; of&nbsp; the&nbsp; obtained materials was performed. Variations of radon emanation coefficients from building materials over time, as well as the influence of leakage and&nbsp; back&nbsp; diffusion&nbsp; effects&nbsp; leading&nbsp; to&nbsp; these&nbsp; variations,&nbsp; were investigated. The influence of the structure of the material in terms of mineral and chemical composition and porosity on the values of the radon&nbsp; emanation&nbsp; coefficient&nbsp; was&nbsp; also&nbsp; investigated.&nbsp; The mineralogical characterization of the samples was performed by the method&nbsp; of&nbsp; X-ray&nbsp; structural&nbsp; analysis&nbsp; (XRD),&nbsp; and&nbsp; the&nbsp; chemical characterization&nbsp; by&nbsp; the&nbsp; method&nbsp; of&nbsp; X-ray&nbsp; fluorescence&nbsp; analysis (XRF). The measurement of total effective porosity was performed by water absorption methods and mercury porosimetry method. Based on&nbsp; the&nbsp; obtained&nbsp; results,&nbsp; significant&nbsp; correlations&nbsp; were&nbsp; establishedbetween&nbsp; individual&nbsp; radiological&nbsp; and&nbsp; structural&nbsp; parameters&nbsp; for&nbsp; the analyzed samples of construction materials.</p>