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Impact of the NK Cell Receptor LIR-1 (ILT-2/Cd85j/LILRB1) on Cytotoxicity Against Multiple Myeloma

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Impact of the NK Cell Receptor LIR-1 (ILT-2/Cd85j/LILRB1) on Cytotoxicity Against Multiple Myeloma UNIVERSITÄTSKLINIKUM HAMBURG-EPPENDORF INTERDISZIPLINÄRE KLINIK UND POLIKLINIK FÜR STAMMZELLTRANSPLANTATION Direktor: Prof. Dr. med. N. Kröger Impact of the NK Cell Receptor LIR-1 (ILT-2/CD85j/LILRB1) on Cytotoxicity against Multiple Myeloma Dissertation zur Erlangung des Doktorgrades der Medizin an der Medizinischen Fakultät der Universität Hamburg. Vorgelegt von: Silke Heidenreich aus Essen Hamburg 2012 Angenommen von der Medizinischen Fakultät der Universität Hamburg am: 13.02.2014 Veröffentlicht mit Genehmigung der Medizinischen Fakultät der Universität Hamburg. Prüfungsausschuss, der/die Vorsitzende: Prof. Dr. N. Kröger Prüfungsausschuss, zweite/r Gutachter/in: Prof. Dr. B. Fehse Prüfungsausschuss, dritte/r Gutachter/in: Prof. Dr. M. Trepel I Table of contents Veröffentlichung im Rahmen dieser Dissertation: Heidenreich S, zu Eulenburg C, Hildebrandt Y, et al. Impact of the NK Cell Receptor LIR-1 (ILT-2/CD85j/LILRB1) on Cytotoxicity against Multiple Myeloma. Clinical and Developmental Immunology 2012;2012:13. II Table of contents 1 TABLE OF CONTENTS 1 TABLE OF CONTENTS ..................................................................................................................... III 2 INTRODUCTION ................................................................................................................................. 1 2.1 Hypothesis ................................................................................................................................... 1 2.2 Multiple myeloma ........................................................................................................................ 2 2.2.1 Definition, incidence and prevalence .................................................................................................... 2 2.2.2 Diagnostic criteria and pathogenesis .................................................................................................... 2 2.2.3 Etiology ................................................................................................................................................. 4 2.2.4 Myeloma immune evasion .................................................................................................................... 6 2.2.5 Therapy ................................................................................................................................................ 8 2.3 Natural killer cells........................................................................................................................ 9 2.3.1 Characterization and classification ....................................................................................................... 9 2.3.2 Development ...................................................................................................................................... 12 2.3.3 NK cell signaling pathways ................................................................................................................. 13 2.3.4 NK cell regulation and defense mechanisms ...................................................................................... 14 2.3.4.1 Bacterial defense ................................................................................................................. 17 2.3.4.2 Viral defense ........................................................................................................................ 18 2.3.4.3 Detection of infected or altered cells by MHC expression .................................................... 19 2.3.5 NK cell receptors ................................................................................................................................ 19 2.3.5.1 KIR ....................................................................................................................................... 20 2.3.5.2 LIR-1 / ILT-2 / CD85j ............................................................................................................ 21 2.3.5.3 CD94/NKG2A (CD159a) ...................................................................................................... 26 2.3.5.4 NCR ..................................................................................................................................... 27 2.3.6 Role of NK cells in the treatment of multiple myeloma ....................................................................... 28 3 MATERIAL AND METHODS ............................................................................................................ 29 3.1 Material ....................................................................................................................................... 29 3.1.1 Cells ................................................................................................................................................... 29 3.1.2 Technical equipment .......................................................................................................................... 33 3.1.3 Medium ............................................................................................................................................... 36 3.1.4 Western blot solutions ........................................................................................................................ 37 3.1.5 Antibodies and vectors ....................................................................................................................... 39 3.2 Methods ...................................................................................................................................... 41 3.2.1 Cell culture and isolation of PBMC ..................................................................................................... 41 3.2.2 Flow-cytometric analysis .................................................................................................................... 41 3.2.3 Viability assay ..................................................................................................................................... 43 3.2.4 Transfection of COS-7 with LIR-1 ....................................................................................................... 44 3.2.5 Western blot ....................................................................................................................................... 45 3.2.6 Chromium-release assay .................................................................................................................... 47 3.2.7 Blocking experiments ......................................................................................................................... 48 3.2.8 Statistics ............................................................................................................................................. 51 III Table of contents 4 RESULTS .......................................................................................................................................... 51 4.1 Preliminary studies ................................................................................................................... 51 4.1.1 Expression of LIR-1 and NKG2A on NK-92 and tumor cells ............................................................... 51 4.1.2 Titration of HLA class I antibodies ...................................................................................................... 54 4.1.3 Expression of HLA class I molecules on NK-92 and tumor cells ........................................................ 58 4.1.4 Myeloma cells are highly susceptible to NK-92 mediated killing ......................................................... 60 4.2 Blocking assays ........................................................................................................................ 61 4.2.1 Blocking of neither LIR-1 nor NKG2A on NK-92 cells increases target cell lysis ................................ 61 4.2.2 Blocking of neither LIR-1 nor HLA-I on target cells increases target cell lysis .................................... 66 4.3 Evaluation of reagent-based side effects ............................................................................... 67 4.3.1 Ab or F(ab')2 have no toxic effects on NK-92 under experimental conditions ..................................... 67 4.3.2 F(ab`)2 might balance tumor lysis pattern ........................................................................................... 68 5 DISCUSSION .................................................................................................................................... 70 5.1 Evaluation of the present experiments ................................................................................... 70 5.1.1 Characteristics of the experimental setup ........................................................................................... 70 5.1.2 LIR-1 does not influence cytotoxicity .................................................................................................. 71 5.1.3 Lack of LIR-1 mediated inhibitory influence is in consistency with available data............................... 71 5.1.4 Pre-existing maximum NK cell mediated cytotoxicity is likely to conceal discrete inhibitory effects .... 74 5.1.5 MM evasion mechanism might outweigh approaches of NK cell modulation ..................................... 75 5.2 Functional aspects of LIR-1 according to previous publications ........................................ 75 5.2.1 Modulation of immune functions ........................................................................................................
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