T and NK Cell Mediated Immunity in Chronic Myeloid Leukaemia

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dissertationes scholae doctoralis ad sanitatem investigandam universitatis helsinkiensis 30/2016 METTE ILANDER T and NK Cell Mediated Immunity in Chronic Myeloid Leukaemia HEMATOLOGY RESEARCH UNIT

1 dissertationes scholae doctoralis ad sanitatem investigandam universitatis helsinkiensis 30/2016 METTE ILANDER T and NK Cell Mediated Immunity in Chronic Myeloid Leukaemia HEMATOLOGY RESEARCH UNIT DEPARTMENT OF CLINICAL CHEMISTRY AND HEMATOLOGY FACULTY OF MEDICINE AND HELSINKI UNIVERSITY HOSPITAL COMPREHENSIVE CANCER CENTER DEPARTMENT OF HEMATOLOGY DOCTORAL PROGRAMME IN CLINICAL RESEARCH UNIVERSITY OF HELSINKI

8 α

10 γ γ

16 , βω. γ

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# " " $ " " " ) #.)!! ( " #! "! "" ' " #!'!" )! '! # " )!! + '! "! -, # " " * ""!) " $ #!

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

42 CD45 CD3 CD16 CD56 CD56 unstimulated CD107a/b K562 stimulated

43 CD3 CD45 CD56 CD16 CD56 unstimulated K562 stimulated Granzyme B TNF-α/IFN-γ In study I,

46 International scale (%) MMR (IRIS) IFN Start IFN Stop IFN Immune cell analyses IM

49 A NK cell proportion p= % of lymphocytes Study III Study I Study II B % of CD56 DIM NK cells 0 Non-relapsingEarly RelapseLate Relapse IFN-ON IFN-OFF Healthy T315I Study III Study I Study II CD57 CD56 DIM NK cells p= Non-relapsingEarly RelapseLate Relapse IFN-ON IFN-OFF Healthy T315I εγ

50 εγ εγ

51 Adaptive markers Baseline % of lymphocytes A 10 5 EAT2- NK cells p= p= p= p= B % of lymphocytes month EAT2- p= p= p= p= Non-relapsing Early Relapse Late Relapse 0 Non-relapsing Early Relapse Late Relapse % of lymphocytes C PLZF- NK cells p= p= p= p= D % of lymphocytes PLZF- p= p= p= p= Non-relapsing Early Relapse Late Relapse 0 Non-relapsing Early Relapse Late Relapse % of lymphocytes E FCER1G- NK cells p= p= p= p= F % of lymphocytes FCERG1- p= p= p= p= % of lymphocytes G Non-relapsing Early Relapse Late Relapse SYK- NK cells p= p= p= p= H % of lymphocytes Non-relapsing Early Relapse Late Relapse SYK- p= p= p= p= Non-relapsing Early Relapse Late Relapse Non-relapsing Early Relapse Late Relapse εγ 0

53 A Unstimulated K562 stimulation 8.6% 12.6% CD56DIMCD16neg CD56DIMCD16neg CD56 B % of CD56DIMCD16- NK cells CD CD56DIMCD16- TNFα/IFNγ secretion p < Non-relapsing Early Relapse Late Relapse IFN-ON IFN-OFF Healthy

54 A C % CCR7 + CD45RA - of CD4 + T-cells p= T EM CD4 + T-cells healthy IFN-OFF IFN-ON % CCR7 - CD45RA + of CD4 + T-cells B D p= T EMRA CD4 + T-cells healthy IFN-OFF IFN-ON % CCR7 + CD45RA + of CD4 + T-cells p= Naive CD4 + T-cells healthy IFN-OFF IFN-ON % CCR7 + CD45RA - of CD4 + T-cells p= T CM CD4 + T-cells healthy IFN-OFF IFN-ON

57 Cytokine secretion of CD4+ T-cells non-relapsing relapsing NK-cell %

A 1500000 Granzyme B + CD4 + T cells p= 0.

0145 /ml 1000000 500000 % TNF-α / IFN-γ+

58 A Granzyme B + CD4 + T cells p= B Granzyme B + T-cells p= /ml % TNF-α / IFN-γ DA 6m IM 6m NI 6m 0 Healthy DA IM NI

60 B16.OVA alive Näive OT-1 dasatinib pretreated Näive dasatinib pretreated OT-I B16.OVA only 5:1 10:1 E:T

62 Dasatinib concentration A 100 nm 0 M 10 µm 1 µm 100 nm 10 nm 1 nm 0 M Dasatinib cytotoxicity K562 B16.OVA B Cell viability (%) Tumor sizes C 11 7 ** Days of treatment Days of treatment Tumor size (mm 2) Tumor size (mm 2 ) Control Dasatinib Control + CD8, CD4, NK1.1 Dasatinib + CD8, CD4, NK1.1 Dasatinib + CD8, CD4 Control + IgG Dasatinib + IgG

63 PD-1 expressing CD8+ T cells Blood Dasatinib Control Dasatinib Tumor Control p= % of CD8+ T cells

65 εγ

69 γα

93 Recent Publications in this Series 10/2016 Tarja Pääkkönen (Jokinen) Benign Familial Juvenile Epilepsy in Lagotto Romagnolo Dogs 11/2016 Nora Hiivala Patient Safety Incidents, Their Contributing and Mitigating Factors in Dentistry 12/2016 Juho Heinonen Intravenous Lipid Emulsion for Treatment of Local Anaesthetic and Tricyclic Antidepressant Toxicity 13/2016 Riikka Jokinen Genetic Studies of Tissue-Specific Mitochondrial DNA Segregation in Mammals 14/2016 Sanna Mäkelä Activation of Innate Immune Responses by Toll-like Receptors and Influenza Viruses 15/2016 Mari Hirvinen Immunological Boosting and Personalization of Oncolytic Virotherapies for Cancer Treatment 16/2016 Sofia Montalvão Screening of Marine Natural Products and Their Synthetic Derivatives for Antimicrobial and Antiproliferative Properties 17/2016 Mpindi John Patrick Bioinformatic Tools for Analysis, Mining and Modelling Large-Scale Gene Expression and Drug Testing Datasets 18/2016 Hilla Sumanen Work Disability among Young Employees Changes over Time and Socioeconomic Differences 19/2016 Oyediran Olulana Akinrinade Bioinformatic and Genomic Approaches to Study Cardiovascular Diseases 20/2016 Prasanna Sakha Development of Microfluidic Applications to Study the Role of Kainate Receptors in Synaptogenesis 21/2016 Neha Shrestha Mesoporous Silicon Systems for Oral Protein/Peptide-Based Diabetes Mellitus Therapy 22/2016 Tanja Holopainen Targeting Endothelial Tyrosine Kinase Pathways in Tumor Growth and Metastasis 23/2016 Jussi Leppilahti Variability of Gingival Crevicular Fluid Matrix Metalloproteinase -8 Levels in Respect to Pointof-Care Diagnostics in Periodontal Diseases 24/2016 Niina Markkula Prevalence, Predictors and Prognosis of Depressive Disorders in the General Population 25/2016 Katri Kallio The Roles of Template RNA and Replication Proteins in the Formation of Semliki Forest Virus Replication Spherules 26/2015 Hanna Paatela Role of Dehydroepiandrosterone in High-Density Lipoprotein-Mediated Vasodilation and in Adipose Tissue Steroid Biosynthesis 27/2016 Johanna Mäkelä Neuroprotective Effects of PGC-1α Activators in Dopaminergic Neurons 28/2016 Sandra Söderholm Phosphoproteomic Characterization of Viral Infection 29/2016 Mariann Lassenius Bacterial Endotoxins in Type 1 Diabetes Helsinki 2016 ISSN ISBN

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