下载此文件-Tumor-specific-Th17-polarized-cells-eradicate-large-

下载此文件-Tumor-specific-Th17-polarized-cells-eradicate-large- From 王华菁20092004 Sunrise Molecular antagonism and plasticity of regulatory and inflammatory T cell programs Immunity29,44-56,July 18,2008 INTRODUCTION ABCD +Naïve CD4 helper T (Th) cells, upon encountering their cognate antigens presented on professional antigen-presenting cells (APCs), differentiate into effector cells that are characterized by their cytokine production profiles and immune regulatory functions. In addition to Th1 and Th2 cells (Dong and Flavell, 2000), a third subset of effector Th cells, Th17, has been identified, which produce IL-17, IL-17F and IL-22 and regulate inflammatory responses by tissue cells (Dong, 2008). Th17 differentiation in mouse is initiated by TGF-β and IL-6. Recently, IL-21 was reported as an autocrine factor induced by IL-6 to regulate Th17 differentiation. STAT3, downstream of IL-6 and IL-21, is essential for RORγt and RORα expression and Th17 differentiation (Laurence et al., 2007; Yang et al., 2007). STAT3 may function by regulating the expression of two orphan nuclear receptors RORγt and RORα in developing Th17 cells (Ivanov et al., 2006; Yang et al., 2008b). Thymus-derived natural regulatory T (nTreg) cells represent a unique subpopulation of CD4+ T cells that inhibit T cell proliferation and autoimmune responses (Wing et al., 2006). The hallmark of nTreg cells is the expression of Foxp3 transcription factor, which is required for maintaining Treg cell function (Williams and Rudensky, 2007). TGF-β has been shown to maintain peripheral nTreg; its deficiency leads to development of early lethal autoimmunity (Marie et al., 2005; Shull et al., 1992). Moreover, in the presence of TGF-β, Foxp3 can be also induced in naive T cells in periphery and the resulting inducible Treg (iTreg) cells exhibit a suppressive phenotype similar to nTreg (Wing et al., 2006). （A）introductionA identifiy, report, showin addition to, moreover As describe above, TGF-β is required for regulation of nTreg and iTreg cells, and it is also involved in Th17 differentiation. Thus, there is not only functional antagonism between Th17 and Treg cells in autoimmunity, as well as reciprocal regulation in the generation of these cells. Although TGF-β induces Foxp3 expression, IL-6 and IL-21 inhibit this regulation and together with TGFβ drive Th17 differentiation. The molecular mechanisms underlying this differential T cell fate decision initiated by cytokines is unclear. （B）introductionB, unclearas describe above, thus, althoughas describe above In the present study, we have analyzed the molecular interaction of Treg and Th17 cell genetic programs in response to cytokine regulation. To better address this question, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) coding sequence inserted into the IL-17F gene. Our data reveal intrinsic association of Th17 and Treg cell differentiation programs in activated T cells in vitro and in vivo. In addition, we have analyzed the genetic programming and re-programming of Treg and Th17 cells. These results thus have revealed the molecular antagonism of Treg and Th17 cell genetic programs and indicated the plasticity of T cell differentiation programs. （C）（D） introductionCD utilize,reveal,analyze, indicate in addition, thusto better address this question， Tumor-specific Th17-polarized cells eradicate large established melanoma Blood, 15 July 2008, Vol. 112, No. 2, pp. 362-373. Introduction BABABCD + 1,2The role of CD4 cells in antitumor immunity remains controversialand poorly understood. They are known to mediate potent therapeuticeffect in the setting of hematopoietic stem cell 3,4 allotransplantationand donor lymphocyte infusion in hematologic malignancy,but antigen-specific T helper (Th) cells have been studied to much lesser extent. A lack of clarity + + regarding CD4 cells isdue, in no small part, to the complexity of their biology. CD4T cells can differentiate into diverse subsets with specificphenotypes that can have self-reinforcing and opposing functions,but these T-cell subsets have not been comprehensively studiedin + tumor-bearing mice.（B）introductionBCD4T cells remain, to much lesser extent, have not been comprehensively studied,but + Historically, CD4 T lymphocytes have been thought of as mereproviders of stimuli to help the + 5–7 putatively more important CD8effectors, which eliminate cancer by direct cytotoxicity.There + are several studies showing that CD4 T helper (Th) cellsare capable of protecting the host against tumor challenge andeven of mediating tumor regression on their own in the settingof either solid 8–13 or hematopoietic disease. Furthermore,protection was maintained against MHC class II–negativemultiple myeloma model and involved cross-presentation by professional antigen-presenting cells (APCs) and activation of tumoricidalactivity mediated by macrophages 14 secreting IFN-. A similarIFN-–dependent mechanism was involved in the rejectionof MHC 15class II–negative tumor in severe combined immunodeficient(SCID) mice. In some cases, the ability to reject antigen-expressingtumor by specific naive Th cells was thought to be substantially +16 +better than the ability of CD8 cells. Classically, effectorCD4 T cells have been categorized 17,18 into T helper 1 (Th1) andT helper 2 (Th2) subsets. Limited studies indicate thatboth subtypes 19–21 elicit antitumor effects, but the Th1-polarizedcells, secreting IFN- and capable of enhancing +22–25 activity of cytotoxicCD8 lymphocytes, have traditionally been regarded as more efficient. + However, it is also clear that CD4 T regulatory cells (T)can efficiently suppress the function regs+5,26–28 of antitumor CD8 T cells.（A） Recently, the novel Th17 lineage, generated in the presenceof TGF-β and IL-6 and expanded 29–31 under the influence of IL-23, has been associated with responses against certain infectionsand implicated in the development of autoimmunity in animalmodels that had been previously linked 32,33 to Th1-type responses(experimental autoimmune encephalitis, collagen-induced arthritis). They also seem to play an important role in the pathogenesisof graft-versus-host disease 34,35 (GVHD). Th17 cells have been found in various tumors, including mycosis fungoides, Sézary 36,37 syndrome, and prostate cancer. Kryczek et al reported thepresence of naturally occurring Th17 cells and T in thetumor microenvironment and tumor-draining lymph nodes in bothregs38 human and mice tumors. Proinflammatory cytokines includingIL-17A, IL-6, and IL-23 have +surveillance by CD8 T cells, and promote de novo 39–45carcinogenesisand neovascularization of tumors via STAT3 signaling and othermechanisms. 46,47been described to impair immuneIn contrast, some publications have reportedantitumor activity of IL-17A or IL-23 that can be 48T-celldependent. （A） Nevertheless, the role of cancer-specific Th17cells in cancer immunity has not been elucidated, （B） but theirability to cause inflamma-tion and destruction of tissues mightbe of interest in the therapy of malignancy. To compare the antitumor efficacy of in vitro–polarizedTCR transgenic Th1, Th17, and nonpolarized Th0 cells, we sought to develop a model that closely resembled human disease.(C) Althoughseveral models have been previously described, one of the mainflaws of currently available systems is that they usually involveusing cancer cells modified to express potentially highly immunogenicforeign or surrogate antigens (eg, OVA or H-Y in female hosts).In other cases, overexpression of potent cytokines, includingIFN-, by the tumor cells was required to observe antitumor effects. Frequently, only very early, small nonvascularized tumors orunrealistic microscopic hepatic or pulmonary "metastases" couldbe treated. In other existing tumor models, treatment is givenbefore the tumor challenge. (A) although, frequentlyin other casesseveral models Tumor protection models may notmimic a clinically relevant scenario, and their relevance tohuman patients with established disease is uncertain. (B) In the clinical setting, solid tumors are large, vascularized,and poorly immunogenic. Immune responses against cancer can be regarded as an autoimmune process where the targets are oftennonmutated self-proteins representing tissue differentiationantigens. As current models of CD4-based anticancer responses,even though valuable, have serious shortcomings and do not approximatea real-life scenario, we sought a novel, more realistic modelthat closely mimicked human disease.(C) We created a transgenicmouse that expresses a MHC class II–restricted TCR recognizingan endogenous melanocyte differentiation antigen called tyrosinase-relatedprotein 1 (TRP-1 or gp75). TRP-1 is present in normal melanocytesas well as in melanoma cells 49and therefore is a potential targetfor immunotherapy in humans. Using + tumor-specific CD4 effectorcells, we characterized in vitro Th1- and Th17-polarized subsetsand compared them with nonpolarized (Th0) cells. We then adoptivelytransferred these cells in an effort to treat large, unmanipulated B16 melanoma. Thus, we describe for the first+ time a CD4, MHC class II–restricted immunotherapy modeltargeting naturally occurring self-antigen.(D) established, Homework from WU Tao Leukemia is the most common malignancy in children especially acute lymphoblastic leukemia (ALL), which accounts for 70% of pediatric leukemia.1 Multiagent chemotherapy is the standard treatment. Acute pancreatitis (AP) is one of the complications that occur during chemotherapy in ALL patients. The main etiology of AP in ALL patients has been reported to be associated with L-asparaginase (L-asp) therapy. (A)The incidence of L-aspassociated AP in children with ALL has been reported to be 2% to 18%.The other reported etiologies include cytosine arabinoside (ara-C) therapy, hypercalcemia, and hypertriglyceridemia. Although there have been many case reports in the literatures highlighting AP after L-asp therapy, only few large case series were reported. The risk factors predisposing for the development of AP have been rarely elucidated(B). AP in children carries a significant morbidity and mortality. It seems therefore essential to identify the risk factors predisposing for AP and early recognition in such high-risk patients. (C) The objectives of this study were to determine the incidence, risk factors, clinical manifestations, and outcome of AP in children with ALL after treatment with chemotherapeutic agents. (D) 注：蓝色部分为stock phrases; 红色部分为Funnel的各个组成部分 INTERMITTENT ANDROGEN SUPPRESSION IN PROSTATE CANCER: THE CANADIAN EXPERIENCE The role of androgen withdrawal is well established in the treatment of advanced prostate cancer. Continuous androgen suppression usually results in a positive response, the pattern of which is highly predictable, and can be accomplished either by surgical or medical castration. In metastatic cancer, the response rate is 70% to 80%, with a median duration of progression-free survival of 12 to 33 months and a median duration of overall survival of 23 to 37 months.1,2 Unfortunately, there are limitations to the continuous use of androgen withdrawal therapy. Early on, treatment results in hot flashes, loss of libido, impotence, and general fatigue. Long-term castration leads to bone demineralization, anemia, lipid disorders, and muscle 3,4wasting. [A]Most importantly, for reasons that remain unknown, the cell death process induced by androgen ablation fails to eliminate the entire malignant cell population, and after a variable period, averaging 24 months, the tumor inevitably recurs and is characterized by androgen-independent 5growth. [B]Treating these androgen-independent clones with systemic therapies has proved difficult, but it may prove possible to modulate the adaptive changes in gene expression that characterize or mediate progression to androgen independence. [C]The concept of intermittent androgen suppression (IAS) is based on the hypothesis that the maintenance of apoptotic potential by successive rounds of androgen withdrawal and replacement might forestall tumor progression. The availability of luteinizing hormone–releasing hormone (LHRH) superagonists and the potential for a full recovery from their action makes it possible to deliver ablative therapy in intermittent pulses. [D] Pain Volume 139, Issue 3, 31 October 2008, Pages 681-687 Behavioral differentiation between itch and pain in mouse , a, aSteven G. Shimadaand Robert H. LaMotte aDepartment of Anesthesiology, Yale University School of Medicine, P.O. Box 208051, 333 Cedar Street, New Haven, Connecticut 06520-8051, USA Introduction (A)The standard model of itch in the mouse has measured scratching in response to pruritic stimuli delivered to the nape of the neck and For such a method to model itch in humans, it would be desirable to meet three criteria. First, the mouse should scratch to stimuli that evoke itch in humans. Second, it should not scratch to stimuli that elicit only pain or other kinds of non-pruritic sensations. Third, it would be desirable if the mouse emitted another type of site-directed behavior, besides scratching, to the non-pruritic stimuli as evidence for sensory detection. In this study we tested the second criterion in the standard model of itch and found that an intradermal injection of the algesic agent, capsaicin, into the nape of the neck does indeed elicit scratching. The third criterion cannot be met if the nape is used as the stimulus site simply because only one type of site-directed behavior is possible, namely scratching with the hind limb. (B)Thus, it was uncertain as to whether scratching to capsaicin delivered to the nape indicated pain or itch, both or neither. (C)This study tested whether the Kuraishi model could be modified in such a way as to allow discrimination between stimuli that humans describe as primarily painful or itchy. (D)Facial wiping with the forelimb has been used in some studies as an indicator of pain in the mouse. It was therefore decided to use the cheek as the site of application of substances of interest. The substances were chosen based on the dominant qualities of sensation they evoke in humans, i.e., capsaicin (pain) and histamine (itch). It was discovered that in response to histamine, the mouse scratched the cheek with its hind limb; in response to capsaicin, the mouse wiped the cheek with its forelimb. Pain 139 (2008) 594–602 Activation of interleukin-1βreceptor suppresses the voltage-gated potassium currents in the small-diameter trigeminal ganglion neurons following peripheral in?ammation Mamoru Takeda *, Junichi Kitagawa, Masayuki Takahashi, Shigeji Matsumoto Department of Physiology, School of Life Dentistry at Tokyo, Nippon Dental University, 1-9-20, Fujimi-cho, Chiyoda-ku, Tokyo 102-8159, Japan Introduction (A) Interleukin-1β(IL-1β) is a proin?ammatory cytokine produced by a variety of cells including immune cells, neurons and glial cells [3]. The release of IL-1βfrom these cells is frequently associated with in?ammation and subsequently hyperalgesia (abnormally intense pain elicited by noxious stimuli) [33]. Glial cells are activated during the in?ammatory response and produce IL-1β[19,45,50,51]. Our recent investigations into mechanical hyperalgesia and neuronal changes in sensitivity after peripheral in?ammation revealed that activation of sensory ganglionic satellite cells in vitro modulates the excitability of nociceptive TRG neuronal cells via IL-1βinduced membrane depolarization and up-regulation of IL-1βreceptors in the neuronal soma [45]. (B)We proposed that these processes contribute to the mechanism underlying trigeminal in?ammatory hyperalgesia [45].Voltage-gated K+ (Kv) channels are important physiological regulators of membrane potential in excitable tissue, including sensory ganglia. (A)TRG neurons express two distinct classes of K+ currents at varying levels including the dominant-sustained K-current (IK) and the fast-inactivating transient A-current (IA) [40,47]. IA is a member of the Kv 1.4 family of Kv channel subunits[29]. Since Kv 1.4 channels are expressed in the small-diameter (Ad-, C-?bers) neurons in the dorsal root ganglia, IA is thought to play a signi?cant role in regulating the activity of nociceptive neurons [32]. Yoshimura et al.[48] demonstrated that in cyclophoshamide-induced chronic cystitis, bladder afferent neurons with tetrodotoxin (TTX) resistant spikes exhibited a lower threshold for spike activation with enhanced ?ring capacity. Temporomandibular joint (TMJ) in?ammation potentiates the excitability of small-diameter TRG neurons innervating TMJ by suppressing IA via a hyperpolarizing shift in the inactivation curve without change in the activation curve [44]. Desson and Ferguson [6] report that IL-1β-induced suppression of IK leads to an increase in membrane excitability of circumventricular organ neurons. The IL-1 β-induced suppression of IK also leads to membrane depolarization in pheochromocytoma-12 (PC12) cells [34]. Taken together, these results suggest that IL-1βpotentiates the excitability of small-diameter TRG neurons by modulation of Kv channels associated with in?ammation-induced up-regulation of IL-1βreceptors. (C) (D)This study investigates the modulation of Kv channels by IL-1βand the relationship between modulation of Kv channels and excitability of small-diameter TRG neurons following in?ammation using perforated patch-clamp techniques. Prospective identification of tumorigenic breast cancer cells Despite advances in detection and treatment of metastatic breast cancer, mortality from this disease remains high because current therapies are limited by the emergence of therapy-resistant cancer cells. As a result, metastatic breast cancer remains an incurable disease by current treatment strategies. Cancers are believed to arise from a series of sequential mutations that occur as a result of genetic instability and/or environmental factors. A better understanding of the consequences of these mutations on the underlying biology of the neoplastic cells may lead to new therapeutic strategies. In solid tumors, it has been demonstrated that only a small proportion of the tumor cells are able to formcolonies in an in vitro clonogenic assay. Furthermore, large numbers of cells must typically be transplanted to form tumors in xenograft models. One possible explanation for these observations is that every cell within a tumor has the ability to proliferate and form new tumors but that the probability of an individual cell completing the necessary steps in these assays is small. An alternative explanation is that only a rare, phenotypically distinct subset of cells has the capacity to significantly proliferate and form new tumors, but that cells within this subset do so very efficiently. To distinguish between these possibilities, it is necessary to identify the clonogenic cells in these tumors with markers that distinguish these cells from other nontumorigenic cells. This identification has been accomplished in acute myelogenous leukemia, where it was demonstrated that a specific subpopulation of leukemia cells (that expressed markers similar to normal hematopoietic stem cells) was consistently enriched for clonogenic activity in nonobese diabeticysevere combined immunodeficient (NOD/SCID) immunocompromised mice, whereas other cancer cells were depleted of clonogenic activity.（A） Such experiments have not been reported in solid cancers. （B） If this model were also true for solid tumors, and only a small subset of cells within a tumor possess the capacity to proliferate and form new tumors, this finding would have significant implications forunderstanding the biology of and developing therapeutic strategies for these neoplasms. （C） To investigate the mechanisms of solid tumor heterogeneity, we developed a modification of the NOD/SCID mouse model in which human breast cancers were efficiently propagated in the mouse mammary fat pad. In the present study, we show that solid tumors contain a distinct population of cells with the exclusive ability to formtumors in mice. We refer to these cells as tumorigenic cells, or cancer-initiating cells, because they consistently formed tumors, whereas other cancer cell populations were depleted of cells capable of tumor formation.Weidentified cell surface markers that can distinguish between these cell populations. Our findings provide a previously uncharacterized model of breast tumor biology in which a defined subset of cells drives tumorigenesis, as well as generating tumor cell heterogeneity. The prospective identification of this tumorigenic population of cancer cells should allow for the identification of molecules expressed in these cells that could serve as targets to eliminate this critical population of cancer cells. （D） 这篇引言为漏斗形结构，见如上A、B、C、D。红色标记为连接词，它们使文章层次清楚，意思明确，上下文连接流畅。 Angiogenin is involved in lung adenocarcinoma cell proliferation and angiogenesis Lung cancer is the most common cause of cancer deaths worldwide. In China, over 20% cancer deaths were caused by lung cancer and it has been considered the most important cancer type in Cancer Prevention and Control by the Ministry of Health of China. The incidence of lung cancer has also increased dramatically in Shanghai, China, and it is ranked as the first and the second malignancy in male and female populations, respectively. According to the WHO classification, lung cancer can be categorized into small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC), which includes adenocarcinoma (AdC), squamous cell carcinoma (SqC), large cell carcinoma (LCC) and other subtypes, of which AdC accounts for more than 40% of all lung cancers. Numerous studies noted that the incidence of lung cancer is increasing worldwide since survival remains poor. Moreover, no better effective therapy cure has been developed for the past 20 years. Angiogenin, a basic heparin-binding protein of 14.4 kDa originally isolated from the conditionedmedium of HT-29 human colon adenocarcinoma cells based on its angiogenic activity, has been shown to play a role in tumor angiogenesis. It interactswith endothelial cells to induce a wide range of cellular responses including migration, proliferation, and tube formation, all of which are essential in the process of angiogenesis. The activity of angiogenin is relatively low as compared with that of vascular endothelial growth factor and basic fibroblast growth factor. However, angiogenin has a comparable angiogenic activity in various in vivo angiogenesis assays. Angiogenin is able to bind to ribosomal RNA (rRNA) gene and stimulate rRNA transcription in endothelial cells. Inhibition of nuclear translocation of angiogenin and mutagenesis at its nuclear localization sequence both potently inhibit the angiogenic activity. Tsuji et al. further demonstrated that angiogenin, in addition to its role in mediating angiogenesis, was constantly translocated to the nucleus of HeLa cells in a cell density-independent manner, and that down-regulation of angiogenin expression by antisense and RNA interference resulted in a decrease in rRNA transcription, ribosome biogenesis, proliferation, and tumorigenesis both in vitro and in vivo. Yoshioka et al. also reported that angiogenin directly stimulated prostate cancer cell proliferation, and that knocking down angiogenin expression in PC-3 human prostate adenocarcinoma cells inhibited ribosomal RNA transcription, in vitro cell proliferation, soft agar colony formation and xenograft growth in athymic mice. （A）However, angiogenin does not exhibit nuclear expression in allhumanmalignancies. Many types ofhumancancer, such as colorectal carcinoma, hepatocellular carcinoma and gastric carcinoma, only present cytoplasm staining. （B） Thus, it is plausible that angiogenin may play distinct roles in different tumor types. （C） In the present study, we demonstrated by immunochemical staining that nuclear expression of angiogenin was present in 100 resected lung AdC tissue specimens and A549 cell line. In addition, we confirmed its biological role by inhibiting angiogenin expression using adenoviral-vector based small interfering RNA (siRNA) technique, and presumed to suggest that angiogenin may be a good candidate for the treatment of lung AdC. （D） 这篇引言为漏斗形结构，见如上A、B、C、D。红色标记为连接词，它们使文章层次清楚，意思明确，上下文连接流畅。