The effects of toll-like receptor ligand-activated dendritic cells on human CD4⁺T cell responses

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Title from PDF of title page (University of Missouri--Columbia, viewed on November 19, 2010).Includes bibliographical referencesVita.Thesis advisor: David R. Lee."December 2008"Ph. D. University of Missouri-Columbia 2008.Dissertations, Academic -- University of Missouri--Columbia -- microbiology (Medicine).Dendritic cells (DCs) play an important role as a link between innate and adaptive immunity through their abilities to detect infection and to prime naïve T cells (signal 1 and 2). They not only activate naïve T cells, but also direct differentiation of CD4+ T cells to induce appropriate immune responses against pathogens via cytokine production (signal 3). In this study, human monocyte-derived dendritic cells (moDCs) as a model for myeloid DCs were activated in vitro with an array of Toll-like receptor (TLR) ligands derived from or mimicking various pathogens, to determine their cytokine profiles, as well as the ability of these differentially TLR ligand-activated DCs to induce differentiation of naïve CD4+ T cells. moDCs activated with a viral TLR ligand (TLR3 ligand) induced more heavily skewed Th1 responses, whereas bacterial TLR ligand (TLR1/2, 4 and 5 ligand)-activated moDCs induced more balanced Th1/Th2/Th17 responses in CD4+ T cells. Unexpectedly, moDCs activated with another viral TLR ligand (TLR7/8 ligand) also induced more balanced Th1/Th2/Th17 CD4+ T cell responses. These results provide a framework for the use of these TLR ligands in tailoring T cell responses in vaccines and other immunotherapeutic approaches

Supportive intervention using a mobile phone in behavior modification

The authors previously developed a mobile ecological momentary assessment (EMA) system as a real-time data collection device using a mobile phone. In this study, a real-time advice function and real-time reporting function were added to the previous system as a supportive intervention. The improved system was found to work effectively and was applied to several clinical cases, including patients with depressive disorder, dizziness, smoking habit, and bronchial asthma. The average patient compliance rate was high (89%) without the real-time advice and higher (93%) with the advice. The trends in clinical data for patients using a mobile EMA with/without the new function were analyzed for up to several months. In the case of dizziness, an improving trend in its clinical data was observed after applying the real-time advice, and in the case of depressive disorder, a stabilizing trend was observed. The mobile EMA system with the real-time advice function could be useful as a supportive intervention in behavior modification and for motivating patients in self-management of their disease.</p

Analysis of faecal sludge collection efficiency for improvement in developing countries

In most developing countries on-site sanitation, and more specifically septic tanks, will remain the primary sanitation system used for human waste management for many years to come, as the cost of installing sewerage infrastructure remains prohibitive. However, studies have shown that septic tanks are rarely desludged, which reduces their wastewater treatment performance and greatly increases the risk of tanks becoming pollution sources. Furthermore, the systems in place for faecal sludge collection often lack efficiency and the existing services tend to be outside of public sector control and not regulated. To ameliorate this situation, the development of new analysis methods for faecal sludge collection systems is crucial. This paper presents an analysis method adapted from “time and motion studies” in solid waste management and a mathematical model which allows for precise analysis of faecal sludge collection and recommendations to be made to dramatically improve the efficiency of existing collection systems

Willingness to pay/use for water supply and sanitation

This paper is a sociocultural case study of Dhaka, the capital city of Bangladesh, on the willingness to pay/use for water supply and sanitation. “Willingness to use” is a relatively new concept which can be defined as the maximum amount of desire one can willingly express for a certain commodity or service. Many technical, institutional, financial and legal factors determine the willingness to use. Affordability combined with willingness to use leads to willingness to pay. The low “willingness to pay/use” is one of the reasons behind the unproportional success rate of much of the national and international efforts undertaken for safe water supply and sanitation. However safe water supply and sanitation is an urgent need in Bangladesh where the number of water borne diseases cases per 100,000 persons is 51,000, much higher than other developing countries (WHO, 1992). One of the causes behind this alarming situation is low willingness to pay/use. Along with a brief description of the present situation in Dhaka city, efforts are taken to identify the problems behind the low willingness to pay/use for water supply and sanitation in light of the sociocultural aspects. This may provide useful information for other developing countries. Some improvement strategies are also proposed

Requiring factors in structural model of the blood vesselfor the principle analysis of measurement of blood pressure waveform by applanation tonometry.

生体内の血圧脈波を非侵襲的に計測する手法として,｢トノメトリ法｣が知られており,近年,この計測手法を用いて得られた血圧脈波波形から,動脈硬化などの循環器系疾患のスクリーニングや予防診断に役立てようという動きが活発である｡しかしながら,組織内の血管を圧迫した場合の血管の変形挙動については,十分な解析は行われていない｡そこで本研究では,生体中のトノメトリ状態を解析可能な数値解析モデルを構築することを目的とした｡この結果, トノメトリ法による血圧脈波計測の原理解析を行うための血管断面構造の応力解析モデルには,以下の要件が求められることが明らかとなった｡・センサ部と皮膚表面はそれぞれ独立な要素としてモデル化し,これらの接触部においては摩擦を考慮しなければならない｡・応力の定量的な解析を行うためには,素材の非線形的な機械的特性を考慮する必要がある｡さらに,実験結果と計算結果を一致させるためには,初期形状を正確にモデル化することが必要であることがわかった｡"Applanation tonometry" is well known method as the technique which measures blood pressure waveform in vivo non-invasively. Recently, utilizing for screening and prevention diagnosis of circulatory system diseases such as the arteriosclerosis from the blood pressure waveform gotten by this measurement technique is very actively being investigated. However, the sufficient analysis is not carried out on the deformation behavior of the blood vessel in real human body. Consequently, the purpose of this paper is to construct the analyzable numerical model in respect of the applanation tonometry. As this result, following factors are necessary in the numerical analysis model of cross sectional structure of blood vessel for the principle analysis of the blood pressure waveform measurement for applanation tonometry. 1) Sensor block and skin surface must have the independent structure, and it must consider the friction in the contact area. 2) For the quantitative analysis, it is necessary to consider the hyper-elasticity which is a nonlinear material property. In addition, it is necessary to accurately model the initial shapes of the material

Recent Advance in Antigen-Specific Immunotherapy for Acute Myeloid Leukemia

Relapse after chemotherapy is inevitable in the majority of patients with acute myeloid leukemia (AML). Thus, it is necessary to develop novel therapies that have different antileukemic mechanisms. Recent advances in immunology and identification of promising leukemia-associated antigens open the possibilities for eradicating minimal residual diseases by antigen-specific immunotherapy after chemotherapy. Several methods have been pursued as immunotherapies for AML: peptide vaccines, granulocyte-macrophage colony-stimulating factor-secreting tumor vaccines, dendritic cell vaccines, and adoptive T cell therapy. Whereas immunogenicity and clinical outcomes are improving in these trials, severe adverse events were observed in highly avid engineered T cell therapies, indicating the importance of the balance between effectiveness and side effects in advanced immunotherapy. Such progress in inducing antitumor immune responses, together with strategies to attenuate immunosuppressive factors, will establish immunotherapy as an important armament to combat AML

The EZH2 inhibitor tazemetostat upregulates the expression of CCL17/TARC in B‐cell lymphoma and enhances T‐cell recruitment

An inhibitor of the histone methyltransferase enhancer of zeste homologue 2 (EZH2), tazemetostat, has been developed for the treatment of B-cell lymphoma, but its mechanisms of action are not fully elucidated. We screened for genes targeted by tazemetostat in eleven B-cell lymphoma cell lines and found that tazemetostat significantly increased the expression of chemokine (C-C motif) ligand 17 (CCL17)/thymus- and activation-regulated chemokine (TARC) in all, which codes for a chemokine that is a hallmark of Hodgkin/Reed-Sternberg (H/RS) cells in Hodgkin lymphoma. Notably, gene set enrichment analysis demonstrated a positive correlation between the genes upregulated by tazemetostat in five follicular lymphoma (FL) cell lines and those reported to be overexpressed in H/RS cells. The CCL17 promoter region was enriched in repressive histone modification H3K27me3, and tazemetostat induced H3K27 demethylation and activated gene transcription. CCL17 protein secretion was also induced by EZH2 inhibition, which was further enhanced by concurrent CpG stimulation. In vitro transwell migration assay demonstrated that CCL17 produced by tazemetostat-treated B cells enhanced the recruitment of T cells, which had the potential to exert antilymphoma response. Analysis of publicly available human lymphoma databases showed that CCL17 gene expression was inversely correlated with the EZH2 activation signature and significantly paralleled the CD4⁺ and CD8⁺ T-cell–rich signature in FL and germinal center B-cell–like diffuse large B-cell lymphoma. Our findings indicate that tazemetostat can potentially activate antilymphoma response by upregulating CCL17 expression in B-cell lymphoma cells and promote T-cell recruitment, which provides a rationale for its combination with immunotherapy

Programmed cell death 1‐expressing CD56‐negative natural killer (NK) cell expansion is a hallmark of chronic NK cell activation during dasatinib treatment

Dasatinib treatment markedly increases the number of large granular lymphocytes including natural killer (NK) cells in a proportion of Ph+ leukemia patients, which associates with a better prognosis. In-depth immune profiling of NK cells can predict therapeutic response in these patients. In the present study, we showed that CD56-negative (CD56neg) NK cells increased exclusively in cytomegalovirus-seropositive (CMV+) patients treated with dasatinib. The increase longitudinally paralleled with progressive differentiation of CD56dim NK cells during dasatinib therapy driven by CMV reactivation as shown by principal component analysis on 19 NK cell markers. The CD56neg NK cells showed downregulation of NK-activating receptors, upregulation of PD-1, and lower cytotoxicity and cytokine production, indicating that these cells are anergic and dysfunctional as seen in chronic infections with HIV-1 or hepatitis C virus. Moreover, cytolytic activity of CD56dim and CD56neg NK cells against leukemia cells was partially restored by nivolumab in proportion to the frequency of PD-1+ NK cells. The proportion of patients who achieved deep molecular responses at 2 years was significantly higher in dasatinib-treated patients with ≥3% CD56neg NK cells than in those with fewer CD56neg NK cells (54.5% vs 15.8%, P = .0419). These findings suggest that CD56neg NK cells may be an exhausted population induced by chronic activation through CMV reactivation during dasatinib therapy. Expansion of CD56neg NK cells is a hallmark of chronic NK cell activation in patients treated with dasatinib and may predict a better clinical outcome. Furthermore, PD-1 blockade may enhance anti-leukemia responses of such NK cells