Browsing by Subject "NATURAL-KILLER-CELLS"

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  • Honkila, Minna; Niinimaki, Riitta; Taskinen, Mervi; Kuismin, Outi; Kettunen, Kaisa; Saarela, Janna; Turunen, Sami; Renko, Marjo; Tapiainen, Terhi (2019)
    BackgroundSymptomatic primary Epstein-Barr virus infection is a usually self-limiting illness in adolescents. We present a case of an adolescent who had been receiving azathioprine for inflammatory bowel disease for four years and developed a life-threatening primary Epstein-Barr virus infection successfully treated with rituximab.Case presentationAn 11-year-old girl presented with chronic, bloody diarrhea. Endoscopic biopsies confirmed a diagnosis of chronic ulcerative colitis with features of Crohn's disease. Azathioprine was initiated after one year due to active colitis. She responded well and remission was achieved. At the age of 16years she developed a life-threatening Epstein-Barr virus infection including severe multiple organ failure and was critically ill for 4weeks in the intensive care unit. Natural killer cells were virtually absent in the lymphocyte subset analysis. Azathioprine was stopped on admission. She was initially treated with corticosteroids, acyclovir and intravenous immunoglobulin. Approximately 30days after admission, she developed signs of severe hepatitis and pneumonitis and received weekly rituximab infusions for 8weeks. Primary immunodeficiency was excluded by whole exome sequencing in two independent laboratories. Persistent viremia stopped when the natural killer cell count started to rise, approximately 90days after the cessation of azathioprine.ConclusionsWe found 17 comparable cases in the literature. None of the previous cases reported in the literature, who had been treated with azathioprine and developed either a severe or a fatal Epstein-Barr virus infection, underwent full genetic and prospective immunological workup to rule out known primary immunodeficiencies. Recently, azathioprine has been shown to cause rather specific immunosuppression, resulting in natural killer cell depletion. Our case demonstrates that slow recovery from azathioprine-induced natural killer cell depletion, 3months after the stopping of azathioprine, coincided with the clearance of viremia and clinical recovery. Finally, our choice of treating the patient with rituximab, as previously used for patients with a severe immunosuppression and Epstein-Barr virus viremia, appeared to be successful in this case. We suggest testing for Epstein-Barr virus serology before starting azathioprine and measuring natural killer cell counts during the treatment to identify patients at risk of developing an unusually severe primary Epstein-Barr virus infection.
  • Havunen, Riikka; Santos, Joao M.; Sorsa, Suvi; Rantapero, Tommi; Lumen, Dave; Siurala, Mikko; Airaksinen, Anu J.; Cervera-Carrascon, Victor; Tähtinen, Siri; Kanerva, Anna; Hemminki, Akseli (2018)
    Cancer treatment with local administration of armed oncolytic viruses could potentially induce systemic antitumor effects, or the abscopal effect, as they self-amplify in tumors, induce danger signaling, and promote tumor-associated antigen presentation. In this study, oncolytic adenovirus coding for human tumor necrosis factor alpha (TNF-alpha) and interleukin-2 (IL-2) Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 (also known as [a.k.a.] TILT-123) provoked antitumor efficacy in tumors that were injected with Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 and those that were left non-injected in the same animal. Importantly, the virus was able to travel to distant tumors. To dissect the effects of oncolysis and cytokines, we studied replication-incompetent viruses in mice. Systemic antitumor effects were similar in both models, highlighting the importance of the arming device. The cytokines induced positive changes in immune cell infiltrates and induced the expression of several immune-reaction-related genes in tumors. In addition, Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 was able to increase homing of adoptively transferred tumor-infiltrating lymphocytes into both injected and non-injected tumors, possibly mediated through chemokine expression. In summary, local treatment with Ad5/3-E2F-d24-hTNF-alpha-IRES-hIL-2 resulted in systemic antitumor efficacy by inducing immune cell infiltration and trafficking into both treated and untreated tumors. Moreover, the oncolytic adenovirus platform had superior systemic effects over replication-deficient vector through spreading into distant tumors.
  • Kasanen, Henna; Hernberg, Micaela; Mäkelä, Siru; Brück, Oscar; Juteau, Susanna; Kohtamäki, Laura; Ilander, Mette; Mustjoki, Satu; Kreutzman, Anna (2020)
    Anti-PD1 treatment has improved the survival of metastatic melanoma patients, yet it is unknown which patients benefit from the treatment. In this exploratory study, we aimed to understand the effects of anti-PD1 therapy on the patients' immune system and discover the characteristics that would result in successful treatment. We collected peripheral blood (PB) samples from 17 immuno-oncology-naive metastatic melanoma patients before and after 1 and 3 months of anti-PD1 therapy. In addition, matching tumor biopsies at the time of diagnosis were collected for tissue microarray. The complete blood counts, PB immunophenotype, serum cytokine profiles, and tumor-infiltrating lymphocytes were analyzed and correlated with the clinical data. Patients were categorized based on their disease control into responders (complete response, partial response, stable disease > 6 months, N = 11) and non-responders (progressive disease, stable disease
  • Nath, Artika P.; Ritchie, Scott C.; Byars, Sean G.; Fearnley, Liam G.; Havulinna, Aki S.; Joensuu, Anni; Kangas, Antti J.; Soininen, Pasi; Wennerstrom, Annika; Milani, Lili; Metspalu, Andres; Mannisto, Satu; Wurtz, Peter; Kettunen, Johannes; Raitoharju, Emma; Kahonen, Mika; Juonala, Markus; Palotie, Aarno; Ala-Korpela, Mika; Ripatti, Samuli; Lehtimaki, Terho; Abraham, Gad; Raitakari, Olli; Salomaa, Veikko; Perola, Markus; Inouye, Michael (2017)
    Background: Immunometabolism plays a central role in many cardiometabolic diseases. However, a robust map of immune-related gene networks in circulating human cells, their interactions with metabolites, and their genetic control is still lacking. Here, we integrate blood transcriptomic, metabolomic, and genomic profiles from two population-based cohorts (total N = 2168), including a subset of individuals with matched multi-omic data at 7-year follow-up. Results: We identify topologically replicable gene networks enriched for diverse immune functions including cytotoxicity, viral response, B cell, platelet, neutrophil, and mast cell/basophil activity. These immune gene modules show complex patterns of association with 158 circulating metabolites, including lipoprotein subclasses, lipids, fatty acids, amino acids, small molecules, and CRP. Genome-wide scans for module expression quantitative trait loci (mQTLs) reveal five modules with mQTLs that have both cis and trans effects. The strongest mQTL is in ARHGEF3 (rs1354034) and affects a module enriched for platelet function, independent of platelet counts. Modules of mast cell/basophil and neutrophil function show temporally stable metabolite associations over 7-year follow-up, providing evidence that these modules and their constituent gene products may play central roles in metabolic inflammation. Furthermore, the strongest mQTL in ARHGEF3 also displays clear temporal stability, supporting widespread trans effects at this locus. Conclusions: This study provides a detailed map of natural variation at the blood immunometabolic interface and its genetic basis, and may facilitate subsequent studies to explain inter-individual variation in cardiometabolic disease.
  • Jahromi, Leila Pourtalebi; Shahbazi, Mohammad-Ali; Maleki, Aziz; Azadi, Amir; Santos, Helder A. (2021)
    Over the past decades, considerable attention has been dedicated to the exploitation of diverse immune cells as therapeutic and/or diagnostic cell-based microrobots for hard-to-treat disorders. To date, a plethora of therapeutics based on alive immune cells, surface-engineered immune cells, immunocytes' cell membranes, leukocyte-derived extracellular vesicles or exosomes, and artificial immune cells have been investigated and a few have been introduced into the market. These systems take advantage of the unique characteristics and functions of immune cells, including their presence in circulating blood and various tissues, complex crosstalk properties, high affinity to different self and foreign markers, unique potential of their on-demand navigation and activity, production of a variety of chemokines/cytokines, as well as being cytotoxic in particular conditions. Here, the latest progress in the development of engineered therapeutics and diagnostics inspired by immune cells to ameliorate cancer, inflammatory conditions, autoimmune diseases, neurodegenerative disorders, cardiovascular complications, and infectious diseases is reviewed, and finally, the perspective for their clinical application is delineated.
  • Zhang, Jiahui; Ji, Cheng; Zhang, Hongbo; Shi, Hui; Mao, Fei; Qian, Hui; Xu, Wenrong; Wang, Dongqing; Pan, Jianming; Fang, Xinjian; Santos, Helder A.; Zhang, Xu (2022)
    Neutrophils are the most abundant innate immune cells in human circulation; however, their derived exosomes have been rarely studied for tumor treatment. Here, we reported that exosomes from neutrophils (N-Ex) induce tumor cell apoptosis by delivering cytotoxic proteins and activating caspase signaling pathway. In addition, we decorated N-Ex with superparamagnetic iron oxide nanoparticles ( SPIONs) to achieve higher tumor-targeting therapeutic effect. We further fabricated exosome-like nanovesicles from neutrophils (NNVs) at high yield. Compared with liposome-loaded doxorubicin (DOX) and natural NNVs, DOX-loaded NNVs show an improved inhibition of tumor cell proliferation. Moreover, DOX-loaded, SPION-decorated NNVs selectively accumulate at the tumor sites under an external magnetic field, effectively restraining tumor growth and extensively prolonging the survival rate in mice. Overall, a simple and effective method to engineer N-Ex and NNVs at clinical applicable scale was developed, which enables the efficient and safe drug delivery for targeted and combined tumor therapy.
  • Ilander, Mette; Kreutzman, Anna; Rohon, Peter; Melo, Teresa; Faber, Edgar; Porkka, Kimmo; Vakkila, Jukka; Mustjoki, Satu (2014)
  • Eränkö, Elina; Ilander, Mette; Tuomiranta, Mirja; Mäkitie, Antti; Lassila, Tea; Kreutzman, Anna; Klemetti, Paula; Mustjoki, Satu; Hannula-Jouppi, Katariina; Ranki, Annamari (2018)
    BackgroundNetherton syndrome (NS) is a rare life-threatening syndrome caused by SPINK5 mutations leading to a skin barrier defect and a severe atopic diathesis. NS patients are prone to bacterial infections, but the understanding of the underlying immune deficiency is incomplete.ResultsWe analyzed blood lymphocyte phenotypes and function in relation to clinical infections in 11 Finnish NS patients, aged 3 to 17years, and healthy age-matched controls. The proportion of B cells (CD19(+)) and naive B cells (CD27(-), IgD(+)) were high while memory B cells (CD27(+)) and switched memory B cells (CD27(+)IgM(-)IgD(-)), crucial for the secondary response to pathogens, was below or in the lowest quartile of the reference values in 8/11 (73%) and 9/11 (82%) patients, respectively. The proportion of activated non-differentiated B cells (CD21(low), CD38l(ow)) was below or in the lowest quartile of the reference values in 10/11 (91%) patients. Despite normal T cell counts, the proportion of naive CD4(+) T cells was reduced significantly and the proportion of CD8(+) T central memory significantly elevated. An increased proportion of CD57(+) CD8(+) T cells indicated increased differentiation potential of the T cells. The proportion of cytotoxic NK cells was elevated in NS patients in phenotypic analysis based on CD56DIM, CD16(+) and CD27(-) NK cells but in functional analysis, decreased expression of CD107a/b indicated impaired cytotoxicity.The T and NK cell phenotype seen in NS patients also significantly differed from that of age-matched atopic dermatitis (AD) patients, indicating a distinctive profile in NS. The frequency of skin infections correlated with the proportion of CD62L(+) T cells, naive CD4(+) and CD27(+) CD8(+) T cells and with activated B cells. Clinically beneficial intravenous immunoglobulin therapy (IVIG) increased naive T cells and terminal differentiated effector memory CD8(+) cells and decreased the proportion of activated B cells and plasmablasts in three patients studied.ConclusionsThis study shows novel quantitative and functional aberrations in several lymphocyte subpopulations, which correlate with the frequency of infections in patients with Netherton syndrome. IVIG therapy normalized some dysbalancies and was clinically beneficial.
  • Heikkinen, Sanna; Miettinen, Joonas; Pukkala, Eero; Koskenvuo, Markku; Malila, Nea; Pitkaniemi, Janne (2017)
    Background: It has been suggested that long-term activation of the body's stress-response system and subsequent overexposure to stress hormones may be associated with increased morbidity. However, evidence on the impact of major life events on mortality from breast cancer (BC) remains inconclusive. The main aim of this study is to investigate whether major negatively or positively experienced life events before or after diagnosis have an effect on BC-specific mortality in women who have survived with BC for at least 2 years. Methods: We conducted a case fatality study with data on life events from a self-administered survey and data on BC from the Finnish Cancer Registry. Cox models were fitted to estimate BC mortality hazard ratios (MRs) between those who have undergone major life events and those who haven't. Results: None of the pre-diagnostic negative life events had any effect on BC-specific mortality. Regarding post-diagnostic events, the effect was greatest in women with moderate scores of events. As for event-specific scores, increased BC mortality was observed with spouse unemployment, relationship problems, and death of a close friend. By contrast, falling in love and positive developments in hobbies were shown to be associated with lower BC mortality (MRs 0.67, 95% CI: 0.49-0.92 and 0.74, 95% CI: 0.57-0.96, respectively). In an analysis restricted to recently diagnosed cases (2007), also death of a child and of a mother was associated with increased BC mortality. Conclusions: Some major life events regarding close personal relationships may play a role in BC-specific mortality, with certain negative life events increasing BC mortality and positive events decreasing it. The observed favorable associations between positive developments in romantic relationships and hobbies and BC mortality are likely to reflect the importance of social interaction and support. (C) 2017 Elsevier Ltd. All rights reserved.
  • Scharenberg, Marlena; Vangeti, Sindhu; Kekäläinen, Eliisa; Bergman, Per; Al-Ameri, Mamdoh; Johansson, Niclas; Sonden, Klara; Falck-Jones, Sara; Färnert, Anna; Ljunggren, Hans-Gustaf; Michaelsson, Jakob; Smed-Sörensen, Anna; Marquardt, Nicole (2019)
    NK cells in the human lung respond to influenza A virus-(IAV-) infected target cells. However, the detailed functional capacity of human lung and peripheral blood NK cells remains to be determined in IAV and other respiratory viral infections. Here, we investigated the effects of IAV infection on human lung and peripheral blood NK cells in vitro and ex vivo following clinical infection. IAV infection of lung- and peripheral blood-derived mononuclear cells in vitro induced NK cell hyperresponsiveness to K562 target cells, including increased degranulation and cytokine production particularly in the CD56(bright)CD16(-) subset of NK cells. Furthermore, lung CD16(-) NK cells showed increased IAV-mediated but target cell-independent activation compared to CD16(+) lung NK cells or total NK cells in peripheral blood. IAV infection rendered peripheral blood NK cells responsive toward the normally NK cell-resistant lung epithelial cell line A549, indicating that NK cell activation during IAV infection could contribute to killing of surrounding non-infected epithelial cells. In vivo, peripheral blood CD56(dim)CD16(+) and CD56(bright)CD16(-) NK cells were primed during acute IAV infection, and a small subset of CD16(-) CD49a(+)CXCR3(+) NK cells could be identified, with CD49a and CXCR3 potentially promoting homing to and tissue-retention in the lung during acute infection. Together, we show that IAV respiratory viral infections prime otherwise hyporesponsive lung NK cells, indicating that both CD16(+) and CD16(-) NK cells including CD16(-)CD49a(+) tissue-resident NK cells could contribute to host immunity but possibly also tissue damage in clinical IAV infection.
  • Karisola, Piia; Palosuo, Kati; Hinkkanen, Victoria; Wisgrill, Lukas; Savinko, Terhi; Fyhrquist, Nanna; Alenius, Harri; Mäkelä, Mika J. (2021)
    We previously reported the results of a randomized, open-label trial of egg oral immunotherapy (OIT) in 50 children where 44% were desensitized and 46% were partially desensitized after 8 months of treatment. Here we focus on cell-mediated molecular mechanisms driving desensitization during egg OIT. We sought to determine whether changes in genome-wide gene expression in blood cells during egg OIT correlate with humoral responses and the clinical outcome. The blood cell transcriptome of 50 children receiving egg OIT was profiled using peripheral blood mononuclear cell (PBMC) samples obtained at baseline and after 3 and 8 months of OIT. We identified 467 differentially expressed genes (DEGs) after 3 or 8 months of egg OIT. At 8 months, 86% of the DEGs were downregulated and played a role in the signaling of TREM1, IL-6, and IL-17. In correlation analyses, Gal d 1-4-specific IgG4 antibodies associated positively with DEGs playing a role in pathogen recognition and antigen presentation and negatively with DEGs playing a role in the signaling of IL-10, IL-6, and IL-17. Desensitized and partially desensitized patients had differences in their antibody responses, and although most of the transcriptomic changes were shared, both groups had also specific patterns, which suggest slower changes in partially desensitized and activation of NK cells in the desensitized group. OIT for egg allergy in children inhibits inflammation and activates innate immune responses regardless of the clinical outcome at 8 months. Changes in gene expression patterns first appear as posttranslational protein modifications, followed by more sustained epigenetic gene regulatory functions related to successful desensitization.
  • Lopes, Alessandra; Feola, Sara; Ligot, Sophie; Fusciello, Manlio; Vandermeulen, Gaëlle; Préat, Véronique; Cerullo, Vincenzo (2019)
    Background: DNA vaccines against cancer held great promises due to the generation of a specific and long lasting immune response. However, when used as a single therapy, they are not able to drive the generated immune response into the tumor, because of the immunosuppressive microenvironment, thus limiting their use in humans. To enhance DNA vaccine efficacy, we combined a new poly-epitope DNA vaccine encoding melanoma tumor associated antigens and B16F1-specific neoantigens with an oncolytic virus administered intratumorally. Methods: Genomic analysis were performed to find specific mutations in B16F1 melanoma cells. The antigen gene sequences were designed according to these mutations prior to the insertion in the plasmid vector. Mice were injected with B16F1 tumor cells (n = 7-9) and therapeutically vaccinated 2, 9 and 16 days after the tumor injection. The virus was administered intratumorally at day 10, 12 and 14. Immune cell infiltration analysis and cytokine production were performed by flow cytometry, PCR and ELISPOT in the tumor site and in the spleen of animals, 17 days after the tumor injection. Results: The combination of DNA vaccine and oncolytic virus significantly increased the immune activity into the tumor. In particular, the local intratumoral viral therapy increased the NK infiltration, thus increasing the production of different cytokines, chemokines and enzymes involved in the adaptive immune system recruitment and cytotoxic activity. On the other side, the DNA vaccine generated antigen-specific T cells in the spleen, which migrated into the tumor when recalled by the local viral therapy. The complementarity between these strategies explains the dramatic tumor regression observed only in the combination group compared to all the other control groups. Conclusions: This study explores the immunological mechanism of the combination between an oncolytic adenovirus and a DNA vaccine against melanoma. It demonstrates that the use of a rational combination therapy involving DNA vaccination could overcome its poor immunogenicity. In this way, it will be possible to exploit the great potential of DNA vaccination, thus allowing a larger use in the clinic.
  • Teirilä, Laura; Heikkinen-Eloranta, Jenni; Kotimaa, Juha; Meri, Seppo; Lokki, A. Inkeri (2019)
    Preeclampsia is a serious vascular complication of the human pregnancy, whose etiology is still poorly understood. In preeclampsia, exacerbated apoptosis and fragmentation of the placental tissue occurs due to developmental qualities of the placental trophoblast cells and/or mechanical and oxidative distress to the syncytiotrophoblast, which lines the placental villi. Dysregulation of the complement system is recognized as one of the mechanisms of the disease pathology. Complement has the ability to promote inflammation and facilitate phagocytosis of placenta-derived particles and apoptotic cells by macrophages. In preeclampsia, an overload of placental cell damage or dysregulated complement system may lead to insufficient clearance of apoptotic particles and placenta-derived debris. Excess placental damage may lead to sequestration of microparticles, such as placental vesicles, to capillaries in the glomeruli of the kidney and other vulnerable tissues. This phenomenon could contribute to the manifestations of typical diagnostic symptoms of preeclampsia: proteinuria and new-onset hypertension. In this review we propose that the complement system may serve as a regulator of the complex tolerance and clearance processes that are fundamental in healthy pregnancy. It is therefore recommended that further research be conducted to elucidate the interactions between components of the complement system and immune responses in the context of complicated and healthy pregnancy.
  • T. Virtanen, Anniina; Haikarainen, Teemu; Raivola, Juuli; Silvennoinen, Olli (2019)
    Cytokines, many of which signal through the JAK–STAT (Janus kinase–Signal Transducers and Activators of Transcription) pathway, play a central role in the pathogenesis of inflammatory and autoimmune diseases. Currently three JAK inhibitors have been approved for clinical use in USA and/or Europe: tofacitinib for rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, baricitinib for rheumatoid arthritis, and ruxolitinib for myeloproliferative neoplasms. The clinical JAK inhibitors target multiple JAKs at high potency and current research has focused on more selective JAK inhibitors, almost a dozen of which currently are being evaluated in clinical trials. In this narrative review, we summarize the status of the pan-JAK and selective JAK inhibitors approved or in clinical trials, and discuss the rationale for selective targeting of JAKs in inflammatory and autoimmune diseases.
  • Marquardt, Nicole; Kekalainen, Eliisa; Chen, Puran; Lourda, Magda; Wilson, Jennifer N.; Scharenberg, Marlena; Bergman, Per; Al-Ameri, Mamdoh; Hard, Joanna; Mold, Jeffrey E.; Ljunggren, Hans-Gustaf; Michaelsson, Jakob (2019)
    Human lung tissue-resident NK cells (trNK cells) are likely to play an important role in host responses towards viral infections, inflammatory conditions and cancer. However, detailed insights into these cells are still largely lacking. Here we show, using RNA sequencing and flow cytometry-based analyses, that subsets of human lung CD69(-)CD16(-) NK cells display hallmarks of tissue-residency, including high expression of CD49a, CD103, and ZNF683, and reduced expression of SELL, S1PR5, and KLF2/3. CD49a(+)CD16(-) NK cells are functionally competent, and produce IFN-gamma, TNF, MIP-1 beta, and GM-CSF. After stimulation with IL-15, they upregulate perforin, granzyme B, and Ki67 to a similar degree as CD49a(-) CD16(-) NK cells. Comparing datasets from trNK cells in human lung and bone marrow with tissue-resident memory CD8(+) T cells identifies core genes co-regulated either by tissue-residency, cell-type or location. Together, our data indicate that human lung trNK cells have distinct features, likely regulating their function in barrier immunity.