Thesis (Selection of subject)Thesis (Selection of subject)(version: 348)
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NK cells and their receptors in immune regulation – possible targets for immunomodulation
Thesis title in Czech: NK buňky a jejich receptory v imunitní regulaci - možné cíle pro imunomodulaci
Thesis title in English: NK cells and their receptors in immune regulation – possible targets for immunomodulation
Key words: Imunomodulace, NK buňky, receptory, cytotoxicita, efektorová funkce, průtoková cytometrie
English key words: Immunomodulation, NK cells, receptors, cytotoxicity, effector function, flow cytometry
Academic year of topic announcement: 2012/2013
Type of assignment: dissertation
Thesis language: angličtina
Department: Czech Academy of Sciences (11-00048)
Supervisor: MUDr. Anna Fišerová, CSc.
Author: hidden - assigned and confirmed by the Study Dept.
Date of registration: 27.02.2009
Date of assignment: 27.02.2009
Date and time of defence: 16.09.2013 10:00
Venue of defence: Fyziologický ústav AV ČR, v.v.i.
Date of electronic submission:23.05.2013
Date of proceeded defence: 16.09.2013
Course: Defence of the dissertation (B90002)
Reviewers: doc. RNDr. Jana Pěknicová, CSc.
  doc. RNDr. Zuzana Kročová, Ph.D.
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Preliminary scope of work
Abstrakt (česky)

Přirození zabíječi - buňky NK hrají důležitou roli v imunitním dohledu a regulaci jednak přímým cytotoxickým působením na infikované, transformované či jinak poškozené buňky, ale také produkcí cytokínů a chemokínů. Výsledná odpověď je dána převahou stimulačních nebo inhibičních signálů, přenášených širokou paletou membránových receptorů. Zabíječské s Ig–příbuzné molekuly KIR2DL4 a LILRB1, které rozpoznávají vlastní HLA–G molekuly během těhotenství stejně jako NKR–P1 receptory lišící se ve funkci a počtu izotypů jsou druhově závislé a redukované v průběhu fylogeneze, zatímco NKG2D, reagující na stresem indukované proteiny a adenozínové receptory (AR) potlačující zánětovou reakci, zůstávají evolučně konzervované.
Cílem této práce bylo studium zapojení NK buněk a jejich receptorů v několika modelech imunitních poruch a u různých savčích druhů, za účelem získání nového náhledu na jejich funkci a možnost imunitní modulace.
Ukázali jsme zde, že výběr druhu ve studiu ovlivnění NK buněčné funkce může být v některých případech kritický. Reakce na glykany, s využitím syntetického GlcNAc terminovaného glykomimetika GN8P, měla protichůdné účinky na NK buněčnou funkci u lidí a C57Bl/6 myší. U lidí byla snížena cytotoxická aktivita NK buněk s vysokou expresí NKR–P1A, zatímco u myší podání GN8P aktivalo NK buňky a B16F10 specifickou tvorbu protilátek IgG2a izotypu, která následně zvýšila na protilátkách závislou cytotoxicitu (ADCC). Tento účinek byl pozorován pouze u myší nesoucích Nkr-p1(T) gen (kódující NK1.1 receptor). Endogenní hormon lidský chorionický gonadotropin (hCG), projevil jako většina hormonů, míru pleiotropie ve svém účinku. Pozorovali jsme posílení CD8 T buněk na úkor Th lymfocytů a zvýšenou expresi KIR2DL4 receptoru na NK buňkách, která podporuje produkci cytokinů. Navíc je tento účinek protichůdný k zamýšlenému užití hCG, tj. zlepšení výsledku postupů asistované reprodukce, protože takový profil byl pozorován u neúspěšných implantací. Evoluční konzervovanost adenozínových receptorů byla ověřena pomocí agonisty A2AAR – CPCA, který měl srovnatelné tlumící účinky na NK buněčnou cytotoxicitu u všech sledovaných savčích druhů (člověk, prase, koza, potkan, myš) u zdravých i nádorových jedinců. Lokální mikrovlnná hypertermie (HT) in vivo do místa nádoru vykázala pozitivní účinek nejen na redukci nádorových buněk, ale také na NK buněčnou cytotoxicitu, přesto že celkové zastoupení NK buněk ve slezině nebylo ovlivněno. Tento postup je však omezen pouze na lokalizované, primární nádory. Pro další optimalizaci HT byly vyvinuty multifunkční nanočástice založené na lidském feritinu a nádorově specifických cílících struktur. Tato nanoplatforma může zvýšit efektivitu HT terapie i na cirkulující nádorové buňky nebo metastatická ložiska.
Naše výsledky prokázaly klíčové zapojení NK buněk v rozvoji a regulaci imunitní odpovědi v průběhu autoimunitních a reprodukčních poruch, nádorové transformaci nebo teplotního šoku. Tato práce přináší nové možnosti imunitní modulace prostřednictvím NK buněk, ale další výzkum je nutný k jejich plnému využití.
Zde poskytujeme základy k těmto výzkumům a následně možným budoucím klinickým aplikacím. V dalším studiu bude perspektivní sledovat vliv hormonálních hladin nebo autoimunitních změn u myších kmenů v závislosti na NKR–P1 a Ly49 fenotypu.
Preliminary scope of work in English
Abstract (english)

Natural Killers – NK cells play an important role in immune surveilance and regulation either by direct cytotoxicity towards infected, transformed or otherwise damaged cells, or by production of cytokines and chemokines. The resulting response of NK cells is given by the sum of stimulating and inhibiting signals, tranduced by a wide array of receptors. Killer Ig–like receptors KIR2DL4 and LILRB1, which recognize self HLA–G molecules in pregnancy, as well as NKR–P1 receptors, which differ in the number of isotypes, are species–dependent and reduced during phylogenesis. NKG2D, reacting to stress–inducible proteins, and adenosine receptors (AR), which supress the inflamatory reaction, remain evolutionary conserved.
The aim of this work was to study the involvement of NK cells and their receptors in several immune disorders and in various species, to provide new insights into their function and posisible immune modulation.
We have shown here, that the choice of species in the study of NK cell effector functions may be crucial in some cases. The reaction to glycans, using synthetic GlcNAc–terminated glycomimetics GN8P, exerted opposing effects on NK cell function in humans and C57Bl/6 mice. In humans, the glycomimetic decreased cytotoxic activity of high NKR–P1A expressing NK cells, while in mice it mounted an NK cell–mediated antibody formation and tumor–specific IgG2a production with subsequent increase in antibody dependent cellular cytotoxicity (ADCC). This effect was observed only in C57BL/6 mice expressing Nkr–p1c(T) gene (coding NK1.1 receptor). Endogenous hormone human chorionic gonadotropin (hCG), exerted as most other hormones a degree of pleiotropy in its effect. We observed a preference of cytotoxic over helper T cells and increased KIR2DL4 expression on NK cells, which renders them more prone toward cytokine production. Moreover, this effect proved to be antagonistic to the original intent of the hCG use – that is to improve the outcome of assisted reproduction courses, since such profile was observed during failed embryotransfers. A2A adenosine receptor agonist CPCA on the other hand, was used to prove the evolutionary conserved mechanisms in its function, by thwarting NK cell cytotoxicity in healthy and immunocompromised subjects equally (human, pig, goat, rat, mouse). In vivo tumor–localized hyperthermia (LHT) proved to have beneficial effect on NK cell–mediated lytic activity, despite the NK cell distribution remained unchanged. This procedure is however limited to localized, primary tumors. For further optimization of LHT, multifunctional ferritin–based nanoparticles with tumor targeting structures were developed. This nanoplatform may increase the efficacy of LHT therapy onto circulating cancer cells or metastatic foci.
Our results proved the key involvement of NK cells in the development and regulation of immune response in autoimmune and reproductive disorders, tumor transformation or heat–induced stress. This work brings new options for NK cell–mediated immune modulation, but further research is needed to achieve their full potential. We here provide the basis for this research and its possible clinical applications in the future. It would be perspective in future studies to observe the hormonal levels or autoimmune changes in murine strains with varying NKR–P1 and Ly49 phenotypes.
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