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Toll-like Rezeptoren (TLRs) sind essentielle angeborene Rezeptoren, die konservierte Strukturen von Krankheitserregern oder Gefahrsignale, die von beschädigten Zellen freigesetzt werden, erkennen können. Genetische Variationen in TLRs wie Einzel-Nukleotid-Polymorphismus (SNP) können die Funktion von TLRs beeinträchtigen und erste Studien zeigen, dass dies zu einer erhöhten Anfälligkeit gegenüber Virusinfektionen oder einem erhöhten Krebsrisiko führen kann. In dieser Studie haben wir einen Multicolor-Durchflußzytometrie-Test entwickelt, um die TLR-Funktionen in verschiedenen Subpopulationen unseparierter peripherer mononukleärer Blutzellen (PBMCs) simultan analysieren zu können. Wir konnten beobachten, dass das Ausmaß der TLR-Antworten zwischen den Probanden stark variierte, jedoch über einen Zeitraum von einem Monat gut reproduzierbar war. Zunächst untersuchten wir TLR Reaktionen bei Patienten mit rezidivierenden Herpes labilalis (HL). Im Vergleich zu asymptomatischen Personen war eine HL- Anamnese mit einer signifikant verminderten TLR3-IFN-Gamma-Antwort nach Stimulation mit poly(I:C) in NK Zellen assoziiert. Weitere molekulare Untersuchungen zeigten eine mögliche Beteiligung von TLR3 L412F SNP, welcher die oberflächliche TLR3 Expression und die IFN-Gamma-Antworten in NK-Zellen reduzierte. Einige Studien zeigen, dassTLR1 I602S, ein weiterer sehr verbreiteter SNP, in der Lage ist die TNF-Alpah-Antworten von Monozyten gegen den TLR2/1-Agonisten (Pam3Cys) zu verringern. In der hier vorliegenden Arbeit konnten wir zudem nachweisen, dass TLR1 I602S SNP auch die Funktion von NK-Zellen und CD8+ T-Zellen beeinträchtigt. Wir konnten keine Assoziation zwischen TLR2/1-Defizienz und reaktivierendem HL feststellen. Jedoch konnten wir an einer großen Kohorte von über 326 Patienten zeigen, dass der TLR1 SNP sowohl ein Risikofaktor für Magenkarzinomentstehung als auch für die Metastasierung ist. Zusammenfassend weisen unsere Ergebnisse darauf hin, dass genetische Polymorphismen von TLRs die Funktion von NK-Zellen beeinträchtigen und zu einer erhöhten Anfälligkeit für HSV-1 Erkrankung und Magenkarzinom führen können. / Toll-like Receptors (TLRs) are essential innate receptors which recognize conserved structures of pathogens, or danger signals released from damaged cells. Alterations of TLR responses might result in severe viral infections or a higher risk of cancer. Therefore, development of clinical assays to evaluate TLR functions could provide personalized information about susceptibility to these diseases. Since TLRs are differentially expressed on different subsets of human peripheral blood mononuclear cells (PBMCs), a multi-color flow cytometry-based assay was developed to detect TLR responses of individual cell types simultaneously. We observed that the magnitude of TLR responses largely varied between human subjects, but was highly reproducible over one month. To evaluate the potential role of differences in natural killer (NK) cell TLR response we studied the association of NK cell TLR function and TLR single nucleotide polymorphisms (SNPs) with susceptibility to recurrent herpes labialis (HL) and gastric cancer. Using our assay, impaired TLR3 response of NK cells was found in people with recurrent HL. In addition, we have identified enhanced levels of homozygous TLR3 L412F SNP in people with recurrent HL, which results in lower surface expression and reduced NK cell response to poly(I:C). TLR1 I602S, another common SNP, has been reported to decrease TNF-Alpha responses of monocytes toward TLR2/1 agonist, Pam3CSK4 (Pam3Cys), stimulation. In our study, we found that TLR1 I602S homozygosity also contributes to impaired IFN-Gamma responses of NK cells and CD8+T cells. Although we did not observe an association of TLR2/1 deficiency with recurrent HL, association of TLR1 I602S with risk for primary as well as metastatic gastric cancer was found in a cohort of 326 patients. To sum up, our results suggest that genetic polymorphisms of TLRs can impair TLR function of NK cells, which contribute to the increased susceptibility to HSV-1 diseases and gastric cancer.

Angeborene lymphatische Zellen (ILC) sind wichtige Effektorzellen der angeborenen Immunantwort, deren Entwicklung und Aktivierungswege attraktive therapeutische Ziele darstellen. Sie bestehen aus ILC der Gruppe 1 (Natürliche Killerzellen (NK) und ILC1), ILC2 und ILC3. Neben T-Zellen leisten ILCs einen entscheidenen Beitrag zu den Typ-1-, Typ-2- und Typ-3-Immunantworten. Die Entwicklung von ILCs beim Menschen wurde jedoch noch nicht systematisch untersucht, und frühere in vitro Untersuchungen stützten sich auf die Analyse einiger weniger Marker oder Zytokine, die für die Bestimmung der Identität der verschiedenen ILC-Linien suboptimal sind. Um diese Mängel zu beheben, stellen wir hier eine Plattform vor, die zuverlässig alle menschlichen ILC-Linien aus CD34+ CD45RA+ hämatopoetischen Vorläuferzellen, gewonnen aus Nabelschnurblut und Knochenmark, erzeugt. Mit einem systematischen Ansatz zeigt diese Arbeit, dass eine einzige Kulturbedingung nicht ausreicht, um alle ILC-Untergruppen zu generieren, sondern stattdessen bestimmte Kombinationen von Zytokinen und Notch-Signalen für die Entscheidung über das Schicksal der Linien wesentlich ist. Eine umfangreiche Analyse des Transkriptoms ergab, dass der Erwerb von CD161 robust eine globale ILC-Signatur identifiziert und in vitro ILCs von T-Zell-Signaturen trennt. Die Identität spezifischer in vitro generierter ILC-Linien (NK-Zellen und ILC1, ILC2 und ILC3) wurde durch Proteinexpression, funktionelle Assays und Transkriptomanalysen auf globaler sowie auf Einzelzellebene umfassend validiert. Diese in vitro erzeugten ILC-Linien rekapitulieren die Signaturen und Funktionen ihrer ex vivo isolierten ILC-Pendants. Des Weiteren, behandeln diese Daten die Einschränkungen der Unterscheidung von menschlichen NK Zellen und ILC1 sowohl in vitro als auch ex vivo an. Darüber hinaus löst diese Plattform gängige Probleme bei der Untersuchung menschlicher ILCs, wie z. B. unzureichende Zellzahlen oder die mangelnde Verfügbarkeit von Gewebeproben. Insgesamt stellt diese Arbeit eine Ressource dar, die nicht nur zur Klärung der Biologie und Differenzierung menschlicher ILCs beiträgt, sondern auch als wichtiges Instrument zur Untersuchung der Dysregulation von ILC-Funktionen dient, die bei verschiedenen entzündlichen Erkrankungen des Menschen eine Rolle spielen. / Innate lymphoid cells (ILCs) are critical effectors of innate immunity and inflammation that consist of Group 1 ILCs (natural killer (NK) cells and ILC1), ILC2, and ILC3. As tissue resident lymphocytes, they play a crucial role type 1, type 2 and type 3 immune responses, respectively. Importantly, dysregulated ILC populations have been linked to the pathogenesis of a variety of chronic inflammatory diseases and thus represent attractive therapeutic targets with a potential for autologous cell therapies. However, human ILC generation has not been systematically explored, and previous in vitro investigations have relied on the analysis of few markers or cytokines, which are suboptimal to assign lineage identity and full functional capacity. To address these faults, we present here an effective in vitro platform, which reliably generates the core human ILC lineages from CD34+ CD45RA+ hematopoietic progenitors derived from cord blood and bone marrow. With a systematic approach, this work shows that a single culture condition is insufficient to generate all ILC subsets, and instead, distinct combinations of cytokines and Notch signaling are essential for lineage fate making decisions. In depth transcriptomic analysis revealed that acquisition of CD161 robustly identifies a global ILC signature and separates them from T cell signatures in vitro. The identity of specific ILC subsets, (NK cells and ILC1, ILC2, and ILC3) generated in vitro was validated extensively by protein expression, functional assays, and both global and single-cell transcriptome analysis. These in vitro generated ILC subsets recapitulate the signatures and functions of their ex vivo ILC counterparts. Finally, these data shed light on the limitations in untying the identity of human NK cells and ILC1 in vitro, similarly correlating to lineage identification difficulties ex vivo. Additionally, this platform tackles common problems in human ILC studies such as insufficient cell numbers and scarce availability of tissue samples. Altogether, this work presents a resource not only to aid in clarifying human ILC biology and differentiation, but also to serve as an important tool to study dysregulation of ILC functions, which have been implied in various inflammatory diseases in humans.

Die genaue Implikation natürlicher Killer(NK)-zellen und Neutrophile in Autoimmunerkrankungen des zentralen Nervensystems (ZNS) ist nach wie vor ungeklärt und wurde daher im Mausmodell der multiplen Sklerose (MS), der experimentellen Autoimmunenzephalomyelitis (EAE), sowie bei MS und Neuromyelitis optica (NMO) Patienten untersucht. Bei MS Patienten konnte eine mit der Krankheitsaktivität korrelierende, reduzierte Zahl zirkulierender CX3CR1+NK Zellen festgestellt werden. Daher wurden die NK Zell-Dynamiken und der Einfluss von CX3CR1 auf diese im EAE Mausmodell untersucht. Hierbei konnte in Wildtyp(WT) sowie auch CX3CR1-defizienten EAE Mäusen eine Rekrutierung peripherer NK Zellen in das ZNS beobachtet werden. Anders als bei WT EAE Mäusen wiesen die NK Zellen bei CX3CR1-defizienten Mäusen einen primär unreifen Phänotyp auf, der möglicherweise als ursächlich für die erhöhte Krankheitsaktivität dieser Tiere gemutmaßt werden kann. Der Transfer reifer NK Zellen vor Immunisierung CX3CR1-defizienter Tiere zeigte folglich protektive Effekte und lässt schlussfolgern, dass die CX3CR1-vermittelte Rekrutierung reifer NK Zellen die EAE Neuroinflammation limitiert. Die Diskriminierung der MS von der klinisch ähnlichen NMO stellt nach wie vor eine Herausforderung dar. Neutrophile in ZNS-Läsionen und der Cerebrospinalflüssigkeit(CSF) können bei NMO, nicht aber MS Patienten nachgewiesen werden, weshalb Neutrophile aus dem Blut von NMO und MS Patienten hier vergleichend untersucht wurden. Die Neutrophile beider Patientengruppen wiesen einen aktivierten Phänotyp im Vergleich zu gesunden Kontrollen auf. Im Gegensatz dazu zeigte sich eine von Medikation und neurologischen Defiziten der Patienten unabhängige, kompromittierte Funktionalität der NMO verglichen mit MS Neutrophilen im Hinblick auf Migration, oxidativen Burst und Degranulierung. Die Neutrophilenfunktionalität könnte entsprechend potentiell als diagnostisches Diskriminierungskriterium zwischen der MS und der NMO dienen. / The implication of natural killer (NK) cells and neutrophils in autoimmune disorders of the central nervous system (CNS) remains elusive, and therefore was investigated in a mouse model for multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), and in patients with MS and neuromyelitis optica (NMO), respectively. In MS, a decreased frequency of circulating CX3CR1+NK cells correlating with the patient disease activity has been reported. Therefore, the pattern of NK cell mobilization and the contribution of CX3CR1 to NK cell dynamics in response to neuroinflammatory insult were investigated in the EAE model. Here, NK cells similarly mobilized from the periphery and accumulated in the CNS in both wild-type (WT) and CX3CR1-deficient mice during EAE. However, in mice lacking CX3CR1 the infiltrated NK cells displayed an immature phenotype contrasting with the mature infiltrates in the WT counterparts, apparently contributing to EAE exacerbation in those animals since transfer of mature WT NK cells prior to immunization of CX3CR1-deficient mice exerted a protective effect. Together, these data suggest that the CX3CR1-mediated recruitment of mature CX3CR1+NK cells limits EAE neuroinflammation. Due to clinical similarities, the discrimination between MS and NMO is still challenging. In contrast to MS, neutrophil accumulations were found in CNS lesions and the cerebrospinal fluid (CSF) of NMO patients wherefore a comparative analysis of peripheral blood neutrophils in NMO and MS patients was performed. The results revealed an activated neutrophil phenotype in NMO and MS when compared to healthy individuals. In contrast, analysis of neutrophil migration, oxidative burst activity and degranulation showed a compromised neutrophil functionality in NMO compared to MS, which was not influenced by the treatment regime and clinical parameters of the patients. Thus, neutrophil functionality may represent a new diagnostic tool to discriminate between NMO and MS.

Die spezifische adoptive Immuntherapie ist ein hoffnungsvoller Ansatz zur Behandlung von Tumoren. Die aufwendige individuelle Bereitstellung primärer Effektorlymphozyten könnte durch den Einsatz etablierter tumorantigenspezifischer Effektorzellinien vermieden werden. In dieser Arbeit wurde untersucht, ob sich ein Tumortargeting der humanen Natürlichen Killer-(NK)-Zellinie YT durch den Gentransfer chimärer Immunglobulin-T-Zellrezeptoren (cIgTCRs) erreichen läßt. Die cIgTCR-Konstrukte wurden aus single-chain-Fv-Fragmenten (scFv), dem IgG1-Fc-Teil und der CD3-Zeta-Signalkette erzeugt. Die scFv-Fragmente wurden aus den humanisierten Antikörpern BW431/26 und HuM195, die spezifisch für das karzinoembryonale Antigen (CEA) bzw. CD33 sind, konstruiert und zeigten als scFv-hFc-Fusionsproteine eine spezifische Bindung an Tumorzellen. Die YT-Zellen wurden mit den cIgTCR-Genkonstrukten über Elektroporation transfiziert und über immunologische Verfahren angereichert. In-vitro-Studien ergaben eine spezifische Lyse von CEA+ Kolonkarzinomzellinien durch die scBW431/26-hFcZeta+ YT-Zellen. Die Zytotoxizität korrelierte mit der Expression des cIgTCR-Antigens auf den Tumorzellen und wurde durch zirkulierendes CEA nicht gehemmt. Die scHuM195-hFcZeta+ YT-Zellen zeigten eine spezifische Lyse der CD33+ myeloischen Leukämiezellinie KG1. Die Bestrahlung wurde zur Wachstumsbegrenzung der YT-Zellen eingesetzt. Die spezifische Zytotoxizität der scBW431/26-hFcZeta+ YT-Zellen gegenüber CEA+ Tumorzellen war einen Tag nach Bestrahlung unverändert. Die Koinjektion von CEA+ Tumorzellen mit bestrahlten scBW431/26-hFcZeta+ YT-Zellen führte zu einer signifikanten Hemmung des Tumorwachstums in NOD/SCID-Mäusen. Die cIgTCR+ YT-Zellen zeigten in vitro eine geringe Sensibilität gegenüber allogenen Blutlymphozyten. Die Ergebnisse zeigen, daß die Zytotoxizität der NK-Zellinie YT tumorantigenspezifisch durch cIgTCR-Gentransfer erweitert wird und ein Potential zur Behandlung minimaler Tumorerkrankungen besteht. / The specific adoptive immunotherapy is a promising strategy for cancer treatment. The utilization of established tumor antigen specific effector cell lines could bypass the expendable individual preparation and often limited specificity of primary effector lymphocytes. This study investigated the tumor targeting of the human Natural Killer (NK) cell line YT by gene transfer of chimeric immunoglobulin T cell receptors (cIgTCRs). The cIgTCR constructs were generated of single chain antibody fragments (scFv), the IgG1 Fc part and the CD3 Zeta chain. The scFv fragments were constructed of the humanized antibodies BW431/26 and HuM195 with specificity for the carcinoembryonic antigen (CEA) and CD33, respectively, and showed as scFv-Fc fusion proteins a specific binding to tumor cells. YT cells were transfected with the cIgTCR gene constructs by electroporation and enriched by immunological cell separation. In vitro studies revealed a specific lysis of CEA+ colon carcinoma cell lines by scBW431/26-hFcZeta+ YT cells. The cytotoxicity correlated with the expression of the cIgTCR antigen on the tumor cells and was not inhibited in the presence of soluble CEA. The scHuM195-hFcZeta+ YT cells mediated a specific lysis of the CD33+ myeloic leukemia cell line KG1. The irradiation was used to limit the growth of the YT cell line. The specific cytotoxicity of the scBW431/26-hFcZeta+ YT cells against CEA+ tumor cells was unaltered one day after irradiation. The coinjection of CEA+ tumor cells and irradiated scBW431/26-hFcZeta+ YT cells led to a significant growth inhibition in NOD/SCID mice. The cIgTCR+ YT cells showed a low susceptibility to the cytotoxicity of allogeneic blood lymphocytes in vitro. The results demonstrated that the cytotoxicity of the human NK cell line YT can be specifically extended to tumor antigens by cIgTCR gene transfer. The employment of receptor gene modified YT cells could be a useful tool for the adoptive immunotherapy of minimal tumor diseases.

This study examined the alleged prevalence of Satanism in Zambia, with a particular reference to the Kabwe District during the period 2010-2013. The overall objective was to ascertain the claims and speculations on the alleged prevalence of Satanism in the district of Kabwe. The claims about the alleged prevalence of Satanism and the satanic scare were found by this study to be a reality in Kabwe, with eighty-eight per cent (88%) of the respondents acknowledging the alleged prevalence of the phenomenon. People’s knowledge of Satanism was mainly through rumours, messages from Churches and the electronic media. Studies on rumours (by Stephen Ellis, Gerrie Ter Haar and Jeffrey Victor) have shown that rumours can be investigated in the search for facts, especially rumours that offer plausible explanations for people’s shared anxieties. The above mentioned scholars argue that with efforts at corroboration, such as by interviewing key informants, the researcher can seek credibility on prevailing rumours by verifying or dismissing mere rumours from true stories. The assertions from scholars above justified the use of rumours as a methodological tool in this study. From sources of information the study relied on, claims about the alleged prevalence of Satanism in the district were investigated. The study refuted the satanic claims in a number of cases that were analysed, because they were mostly based on ‘pious legends’ hence lacked objective evidence. From the few incidents that suggested the prevalence of Satanism, there were still two basic problems faced in assessing their credibility: the first being the difficulty in determining the reliability of the confessions from informants who in this case either claimed they were ex-Satanists or served on behalf of Satanists. The second problem consisted in what seemed to be the inconsistency in the explanations of motives behind human killings found in the ritual murders. Some explanations did not suggest satanic motives. One example of refuted claims concerned the two locations within Kabwe district which were highly rumoured to be sites for Satanists, which were found by this study to be Freemasonry Lodges, contrary to what was rumoured.From the findings of this study, it was believed that people joined Satanism either because of the greedy for riches or to avoid poverty. It was also believed that other peoples joined Satanism unconsciously through luring methods used by Satanists. The study also found the satanic scare to have effects on the lives of people in the district. For example, it caused some people to become more committed Christians in their defence against the alleged satanic forces. Because people had associated riches to Satanism, certain individuals avoided getting rich for fear of being labelled ‘Satanists’. / Religious Studies & Arabic / D. Litt. et Phil. (Religious Studies)

行動通訊產業隨著日韓、西歐、亞太、北美和中國大陸陸續啟動B3G行動通訊的商業運轉，全球行動通訊服務和技術的發展進入嶄新的紀元，傳輸速度的大幅提昇，行動通訊服務商積極推動多媒體簡訊、行動音樂、行動影音、行動遊戲、行動訊息和企業數據應用等服務，寄望透過多元應用服務及創新經營模式提升顧客價值與獲利能力；另一方面，行動廣播、無線寬頻、網路電話等新興技術匯流至行動通訊領域，不僅催生行動通訊技術朝IMS和All-IP網路發展，並促使行動通訊服務商在行銷、服務、帳務和網路等層面朝向行動和固網雙網融合與數位匯流的願景佈局。在政府開放營運執照後，行動通訊服務業者皆投入巨額資金經營，期藉由傳輸速度快的優勢，可以發展出更多的行動加值服務內容，以期在語音營收成長飽和之下，創造另一營收來源；但是，行動通訊產業在大規模的投資下，未產生預期的效益，產業間渴望能讓產業創新的殺手級應用(Killer Application)，引導台灣行動通訊產業找到高獲利的藍海市場。本研究期望，透過分析行動通訊產業的價值供應鏈在營運發展過程中碰到的困境，及其面對創新的技術與商業模式如何評估與發展，在面對市場與技術的不確定性下，分析出產業價值鏈的廠商面對創新的競爭所必須思考的關鍵因素，提供台灣行動通訊業者經營業務的一些建議，以便協助台灣在行動通訊市場的產業創新能力，提昇業者對行動加值服務應用與行動通訊設備市場的創新決策正確性，以期推動台灣電信市場的蓬勃發展。 本研究以克雷頓‧克里斯汀生(Clayton M. Christensen)所提出的對突破性科技的看法，利用提出的破壞性創新及資源、流程與價值理論分析模式；以傑佛瑞‧墨爾(Geoffrey A. Moore)提出的技術採用生命周期(Technology Adoption Life Cycle)模式分析五種消費者,探討行動通訊產業如何分析電信業創新的鴻溝,如何邁向康莊大道。在訪談台灣行動通訊產業價值鏈的五家廠商中，就創新的驅動方式、創新的風險評估、如何管理創新與當前產業創新所面臨的問題與解決方案等議題，做充分意見交流，再經由文獻與理論探討、行動通訊產業市場的趨勢與分析、行動通訊產業技術的趨勢與分析，與台灣行動通訊產業個案分析後，最後作成結論與建議，並提出後續研究課題的建議。 經研究與分析台灣行動通訊產業的創新模式，了解行動通訊產業價值鏈創新發展過程中，所碰到過的困境及其後續改善之方案，並對台灣政府與行動通訊業者提出以下的結論與建議： 壹、結論: 一、技術驅動的創新重視程度通常是愈接近產業價值鏈的上游愈高；市場驅動的創新重視程度通常是愈接近產業價值鏈的下游愈高；突破性的創新可能發生於產業鏈中的每一環節。 二、突破性的創新需要同時處理產業鏈中的市場風險與技術風險，兩大天險必須要降低其中一項才容易創新成功；兩種風險都與財務因素息息相關。 三、創新常常來自邊陲，發展創新的組織需要不同於主流產品的績效目標與財務支援。 四、政府正確的產業監理政策常常是行動通訊產業的發展要件；產業生態系的活躍與否常取決於政府對產業的科技政策走向與合宜的法律。 貳、建議： 一、 政府方面: 1.基地台網路: 協調業者以共構的方式及加速整合寬頻接取技術以解決網路品質的問題。 2.技術平台與內容產業:制定適當的產業政策，以協助整合產業上中下游業者，以帶動產業研究與發展。 二、行動通訊營運商: 1.投入研究行動通訊的消費者行為: 行動通訊服務業者應投入資源研究本地消費者行為，以便洞悉創新的殺手級應用。 2.內容與服務平台:積極扮演內容服務開發與技術平台整合角色，以帶動內容產業的蓬勃發展創造「皆贏」的局面。 3.合宜費率: 根據消費者所獲得的行動通訊價值與成本動因計費。 / The mobile telecommunication industry along with Japan, Korea, Western Europe, Asia Pacific, North America and mainland China, it starts the B3G mobile telecommunications commercial subscriber service launch, the global mobile telecommunications service and the technology development enter a brand-new era. Following by the transmission speed of infrastructure network is improved rapidly, the mobile telecommunications service providers are positively to promote the multimedia services, mobile music, mobile video streaming, mobile gaming, mobile messaging and enterprise data service applications. We hope the penetration multi-dimensional applications to serve and innovate the business model to promote the customer value and profit ability. On the other hand, those emerging technologies, such as mobile broadcasting, wireless broadband, IP network telephony are converged to mobile telecommunications domain. Not only expedites the mobile telecommunications technology to IMS and the All-IP network development, but also urges the mobile telecommunications service provider in all aspects of marketing, service, billing and network infrastructures migrate to the wireless and wire-line network fusion and the vision of digital convergences. After the restriction of operation licenses released by government, the mobile telecommunications service providers invest a large amount of funds on new business development. Relying on the quick transmission speed superiority, may develop more mobile value-added service content. We expect to have more another revenue increasing objects while the voice-only service revenue mutuality. Nevertheless, the mobile telecommunications industry under the large-scale investment has not had the anticipated benefit, the industry hope we can let the industrial innovation to produce the “Killer Applications” that guides the Taiwan mobile telecommunications industry to find the high profitable blue sea market. The research expects that, by the penetration analysis mobile telecommunications industry value supply chain the difficult position which bumps into in transport business developing process, and how faces the innovative technology and the business model appraised and development, is facing the indefinite market and the technology, analyzes the industrial innovation the competitive strategy and the key success factors, provides Taiwan the mobile telecommunications entrepreneur to manage the business strategies and suggestions. In order to assist Taiwan in mobile telecommunications market industrial innovation ability, promotes the entrepreneur to the value-added service field and motivates the communication equipment market innovative decision-making accuracy, impels the Taiwan telecommunications market by the time the vigorous development. The research is based on the viewpoint of disruptive technology issued by Clayton M. Christensen to leverage the analysis model of disruptive innovations and resource, process and value theorem; analyzes the five types of consumers by Technology Adoption Life Cycle model issued by Geoffrey A. Moore to investigate how telecommunications industry analyzes the chasm of innovations and how to adopt the early majority of market. In the interview of 5 enterprises across Taiwan mobile telecommunications industrial value chain, we make good communications and share opinions about all the issues of the method of innovation driven, risk assessment on innovations, how to manage innovations, to face problems and resolutions on industrial innovation. By leveraging the entire reference thesis, issued papers and theorem, the trends of market, analysis of market, and technology issues in the mobile telecommunications industry, collaborate with case study of Taiwan mobile telecommunications industry to study and make comments and conclusions on this topic. Also, we provide the suggestions on governing policies, industry strategies, and further research direction. A.Conclusions: 1.Nearby the front end of industry value chain, technology driven innovations methodology is highly enhanced and focused; Nearby the rear end of industry value chain, market driven innovations methodology is highly enhanced and focused. Disruptive technology is possibly occurred in any section of industry value chain. 2.The two major risk factors, market and technology, need to be handled together while manage disruptive innovations. It would make success to assess at least one of two major risk factors and they are all related to financial variables. 3.Innovation is always occurred in the border of organizations which is supported by key performance indicator setting of different major products and necessary financial funding. 4.The mobile telecommunications industry grows by major inferences of correct governing policies and proper regulations issued by technology management department of government. B.Suggestions: 1.For government: a.Base Station System: Coordinate all operators to co-construct the system to speed the integration of broadband wireless access technology to resolve the network quality issues. b.Technology platform and content industry: Collaborate with the enterprises of industry chain to support the research and development by proper industry regulations. 2.For wireless operators: a.Research on wireless consumer behaviors: Coordinate all operators to invest subscriber behaviors and statistic analysis in local market to learn how to produce the killer applications. b.Content and service platform: Proactively involve the content service developing and technology platform integration to develop the content industry as win-win purpose. c.Proper subscriber fare: Charge wireless consumers by the value of requisition and cost driven factor.

L’élimination des cellules sénescentes met en jeu le SASP et les cellules immunitaires de l’immunité innée et adaptative tels que les macrophages (Mφ). Dans le cadre de ce projet, nous rapportons que le SASP a un effet pléiotropique sur l’activité des cellules immunitaires incluant leur recrutement, leur activation et leur différenciation. Nos données montrent que les Mφ humains mis en culture avec le SASP de fibroblastes humains développement un profil inflammatoire spécifique au SASP caractérisé par une sécrétion pro-inflammatoire (M1) (ex : IL- 1β, GM-CSF) et des marqueurs de surface anti-inflammatoires (M2) (cellules CD23+CD206+). Le SASP est aussi capable d’augmenter les capacités d’invasion des Mφ, tel que montré via des essais d’invasion, mais n’a pas d’effet sur la différentiation des monocytes. Nos modèles de co- culture montrent que, quoique les cellules NK sont probablement responsables de l’élimination directe et spécifique des cellules sénescentes, leur activité peut être modulée par d’autres cellules immunitaires tels que les Mφ qui réduisent l’élimination faite par les cellules NK, suggérant un profil M2. Les lymphocytes T CD8+ sont aussi essentiels pour l’élimination des cellules sénescentes puisque leur retrait retarde le processus. De plus, nous démontrons que les cellules T CD4+ mises en culture pendant 48h dans le SASP sécrètent de hauts niveaux d’IL-4, indiquant une polarisation Th2. Somme toute, ces données montrent que le SASP peut moduler l’activité des Mφ tout comme celle d’autres cellules immunitaires impliquées dans l’élimination des cellules sénescentes et peut promouvoir, étonnamment, une réponse immunosuppressive pouvant être importante pendant la réparation tissulaire. / Senescent cell clearance brings into play the senescence-associated secretory phenotype (SASP) and immune cells from the innate and adaptive immunity including macrophages (Mφ). In this study, we report that the SASP has a pleiotropic effect on immune cell activity including recruitment, activation and differentiation. We show that human Mφ exposed to the SASP of human fibroblasts develop a SASP-specific inflammatory profile characterized by pro- inflammatory (M1) secretion (e.g. IL-1β, GM-CSF) and anti-inflammatory (M2) surface markers (CD23 and CD206). The SASP also increases Mφ invasion but has no effect on monocyte differentiation. Co-culture models show that while NK cells are likely the direct effectors of senescent cell specific killing, their activity is modulated by other immune cells including Mφ, which reduced NK-mediated killing, suggesting a M2 profile. Alternatively, CD8+ T lymphocytes are essential for senescent cell killing by NK cells. Finally, CD4+ T cells cultured for 48h in the SASP secrete high-levels of IL-4, indicating a Th2 polarization. Overall, our data reveal that the SASP can modulate Mφ and other immune cells involved in senescent cell clearance and surprisingly promote an immunosuppressive response that could be important in tissue repair.

La leucémie aigüe lymphoblastique de précurseurs des cellules B (pré-B LAL) est le cancer le plus fréquent chez l’enfant. La transplantation de cellules souches hématopoïétiques (TCSH) est nécessaire dans environ 20 à 30 % des enfants ayant une pré-B LAL. Les rechutes après TCSH sont habituellement réfractaires aux thérapies actuelles, et par conséquent, il est important de développer et d’optimiser de nouvelles stratégies thérapeutiques. Dans cette étude, nous nous sommes intéressés aux cellules « cytokine-induced killer » (CIK). En effet, ces cellules ont été montrées comme hautement cytotoxique contre beaucoup de types de cancers. Cependant, leur activité cytotoxique contre les pré-B LAL n’est pas vraiment efficace. Par conséquent, nous avons étudié la possibilité de combiner l’immunothérapie des cellules CIK avec l’interféron alpha (IFN-α) afin d’optimiser l’activité lytique de ces cellules contre les cellules pré-B LAL. De plus, vu qu’il a été démontré que l’activité cytotoxique des cellules CIK provient de la fraction CD56+, plus particulièrement les cellules CD3+CD56+, nous avons décidé d’utiliser la fraction CD56+ (cellules CD56+) dans l’ensemble de nos expériences. Nous avons observé in vitro que les cellules CD56+ lysent mieux les lignées cellulaires pré-B LAL comparativement aux cellules CIK non purifiées. Aussi, leur activité cytotoxique peut être augmentée par le traitement avec l’IFN-α. Par ailleurs, nous avons démontré l’efficacité des cellules CD56+ traitées par l’IFN-α contre les lignées cellulaires pré- B LAL in vivo, dans le modèle de souris NOD/SCID/gamma c- (NSG). La survie des souris est significativement prolongée lorsqu’elles reçoivent les cellules pré-B LAL avec les cellules CD56+ traitées par l’IFN-α. Nous avons par la suite étudié le mécanisme d’action des cellules CD56+ contre les lignées cellulaires pré-B LAL. Nous avons observé que les cellules CD56+ provenant de sang de cordon sont plus efficaces que les cellules CD56+ provenant de sang I périphérique pour tuer les lignées cellulaires pré-B LAL. Nous avons également montré que les cellules CD56+ utilisent seulement la voie NKG2D ou bien les voies NKG2D et TRAIL selon la lignée cellulaire pré-B LAL cible et selon la provenance de la source des cellules CD56+. Par ailleurs, nous avons remarqué que les cellules CIK sont sensibles à l’apoptose par Fas, et que cette sensibilité influence leur activité cytotoxique contre les cellules tumorales. En conclusion, les cellules CD56+ sont cytotoxiques contre les lignées cellulaires pré-B LAL, et leur effet lytique est augmenté par l’IFN-α aussi bien in vitro qu’in vivo dans le modèle de souris NSG. Ces données précliniques sont encourageantes pour tester cette nouvelle approche d’immunothérapie dans le traitement contre la pré-B LAL. / Precursor B-cell acute lymphoblastic leukemia (B-ALL) is the most common form of leukemia in children. Hematopoietic stem cell transplantation (HSCT) is required in around 20 to 30% of children with a B-ALL. The relapses occuring post-HSCT are usually insensitive to current therapy. Therefore, it is important to develop and optimize a new therapeutic strategy. In this study, we were interested to study « cytokine-induced killer » (CIK) cells. These cells have been shown to be very cytotoxic against many types of tumor. However, their cytotoxic activity against B-ALL cells is not very efficient. Consequently, we have studied the effect of combining adoptive immunotherapy of CIK cells with the interferon alpha (IFN-α) to increase their lytic activity against B-ALL cells. In addition, in the literature, the cytotoxic activity of CIK cells has been shown to come from the CD56+ fraction (CD56+ CIK), in particular CD3+CD56+ cells. Therefore, we used the CD56+ fraction in all the experiments. We have observed in vitro that CD56+ CIK cells killed more efficiently B-ALL cell lines than did non-purified CIK cells. Also, their cytotoxic activity could be enhanced with IFN-α. Moreover, we have demonstrated the efficacy of IFN-α-treated-CD56+ CIK cells against B-ALL cell lines in vivo in the model of NOD/SCID/gamma c- (NSG) mice by showing that the survival of mice injected with B-ALL cell lines was significantly increased when they were injected with IFN-α-treated-CD56+ CIK cells. Subsequently, we have studied the lytic mechanism of CD56+ CIK cells against B-ALL cell lines. We have observed that CD56+ CIK cells from cord blood were more efficient than CD56+ CIK cells from peripheral blood to kill B-ALL cell lines. CD56+ CIK cells used only the NKG2D pathway or the both NKG2D and TRAIL pathways depending on the B-ALL cell line and the source of CIK cells. In addition, we showed that CIK cells were sensitive to Fas apoptosis. This sensitivity III influenced the cytotoxic activity of CIK cells against tumor cells. In conclusion, CD56+ CIK cells are cytotoxic against B-ALL cell lines, and their effect can be increased with IFN-α in vitro and in vivo. Taken together, our pre-clinical data are very interesting for testing the potential clinical utility of purified CD56+ CIK cells as an immunotherapeutic strategy for B- ALL patients.