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共278条结果
  • 1.

    【2hr】Adoptive T-cell therapy: adverse events and safety switches

    包量

    机译 过继性T细胞疗法：不良事件和安全开关
    • 作者：Siok-Keen Tey
    • 刊名：Clinical Translational Immunology
    • 2014年第6期
    摘要：The potential of adoptive T-cell therapy in effecting complete and durable responses has been demonstrated in a number of malignant and infectious diseases. Ongoing progress in T-cell engineering has given cause for optimism in the broader clinical applicability of this approach. However, the development of more potent T cells is checked by safety concerns, highlighted by the occurrence of on-target and off-target toxicities that, although uncommon, have been fatal on occasions. Timely pharmacological intervention is effective in the management of a majority of adverse events but adoptively transferred T cells can persist long term, along with any unwanted effects. A recently validated cellular safety switch, inducible caspase 9 (iCasp9), has the potential to mitigate the risks of T-cell therapy by enabling the elimination of transferred T cells if required. In haematopoietic stem cell transplantation, iCasp9-modified donor T cells can be rapidly eliminated in the event of graft-versus-host disease. This review presents an overview of the risks associated with modern T-cell therapy and the development, clinical results and potential future application of the iCasp9 safety switch.
  • 2.

    【2hr】Clinical application of genetically modified T cells in cancer therapy

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    机译 转基因T细胞在癌症治疗中的临床应用
    摘要：Immunotherapies are emerging as highly promising approaches for the treatment of cancer. In these approaches, a variety of materials are used to boost immunity against malignant cells. A key component of many of these approaches is functional tumor-specific T cells, but the existence and activity of sufficient T cells in the immune repertoire is not always the case. Recent methods of generating tumor-specific T cells include the genetic modification of patient lymphocytes with receptors to endow them with tumor specificity. These T cells are then expanded in vitro followed by infusion of the patient in adoptive cell transfer protocols. Genes used to modify T cells include those encoding T-cell receptors and chimeric antigen receptors. In this review, we provide an introduction to the field of genetic engineering of T cells followed by details of their use against cancer in the clinic.
  • 3.

    【2hr】Prognosis in autoimmune and infectious disease: new insights from genetics

    包量

    机译 自身免疫和传染病的预后：遗传学的新见解
    摘要：A well-recognised feature of autoimmune and infectious diseases is that their clinical course and eventual outcome can vary substantially between affected individuals. This variability in disease prognosis critically determines patient well-being, and yet is relatively poorly understood and largely understudied—with many investigators opting instead to study what causes disease development in the first place. Better understanding of what determines prognosis could provide unique insights into disease biology, potentially revealing new therapeutic targets, and will also be essential if prognosis-based ‘personalised medicine' is ever to become a reality. Here, we highlight the previously under-appreciated role that genetics has in determining prognosis in autoimmune and infectious disease, and the common role that FOXO3 has been shown to have as a modulator of inflammatory responses, and thereby of outcome, across several distinct diseases.
  • 4.

    【2hr】Human placenta-derived adherent cells induce tolerogenic immune responses

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    机译 人胎盘来源的贴壁细胞诱导耐受性免疫反应
    摘要：Human placenta-derived adherent cells (PDAC cells) are a culture expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory and anti-inflammatory properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. To elucidate the mechanisms underlying the immunoregulatory properties of PDAC cells, we investigated their effects on immune cell populations, including T cells and dendritic cells (DC) in vitro and in vivo. PDAC cells suppressed T-cell proliferation in an OT-II T-cell adoptive transfer model, reduced the severity of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis and ameliorated inflammation in a delayed type hypersensitivity response model. In vitro, PDAC cells suppressed T-cell proliferation and inhibited Th1 and Th17 differentiation. Analysis of tissues derived from PDAC cell-treated animals revealed diminished CD86 expression on splenic DC, suggesting that they can also modulate DC populations. Furthermore, PDAC cells modulate the differentiation and maturation of mouse bone marrow-derived DC. Similarly, human DC differentiated from CD14+ monocytes in the presence of PDAC cells acquired a tolerogenic phenotype. These tolerogenic DC failed to induce allogeneic T-cell proliferation and differentiation toward Th1, but skewed T-cell differentiation toward Th2. Inhibition of cyclo-oxygenase-2 activity resulted in a significant, but not complete, abrogation of PDAC cells' effects on DC phenotype and function, implying a role for prostaglandin E2 in PDAC-mediated immunomodulation. This study identifies modulation of DC differentiation toward immune tolerance as a key mechanism underlying the immunomodulatory activities of PDAC cells.
  • 5.

    【2hr】Vaccines to prevent leishmaniasis

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    机译 预防利什曼病的疫苗
    摘要：Leishmaniasis is a parasitic disease that encompasses a range of clinical manifestations affecting people in tropical and subtropical regions of the world. Epidemiological and experimental data indicate that protection from disease can be achieved in most people. In addition, we know how the host immune system must respond to infection in order to control parasite growth. However, there is still no vaccine for use in humans. Here, we review our understanding of host immunity following Leishmania infection and also discuss recent advances in the development of vaccines to prevent leishmaniasis, highlighting a new promising approach that targets the parasite hemoglobin receptor.
  • 6.

    【2hr】Interferon-alpha, immune activation and immune dysfunction in treated HIV infection

    包量

    机译 艾滋病毒感染后的干扰素-α，免疫激活和免疫功能障碍
    摘要：Type I interferons (IFNs) exert anti-viral effects through the induction of numerous IFN-stimulated genes and an immunomodulatory effect on innate and adaptive immune responses. This is beneficial in controlling virus infections but prolonged IFN-α activity in persistent virus infections, such as HIV infection, may contribute to immune activation and have a detrimental effect on the function of monocytes and T and B lymphocytes. Activation of monocytes, associated with increased IFN-α activity, contributes to atherosclerotic vascular disease, brain disease and other ‘age-related diseases' in HIV patients treated with long-term antiretroviral therapy (ART). In HIV patients receiving ART, the anti-viral effects of IFN-α therapy have the potential to contribute to eradication of HIV infection while IFN-α inhibitor therapy is under investigation for the treatment of immune activation. The management of HIV patients receiving ART will be improved by understanding more about the opposing effects of IFN-α on HIV infection and disease and by developing methods to assess IFN-α activity in clinical practice.
  • 7.

    【2hr】Accelerating immune reconstitution after hematopoietic stem cell transplantation

    包量

    机译 造血干细胞移植后加速免疫重建
    摘要：Viral infections remain a significant cause of morbidity and mortality after hematopoietic stem cell transplantation. Pharmacologic agents are effective against some pathogens, but they are costly and can be associated with significant toxicities. Thus, many groups have investigated adoptive T-cell transfer as a means of hastening immune reconstitution and preventing and treating viral infections. This review discusses the immunotherapeutic strategies that have been explored.
  • 8.

    【2hr】Clinical immune-monitoring strategies for predicting infection risk in solid organ transplantation

    包量

    机译 预测实体器官移植感染风险的临床免疫监测策略
    摘要：Infectious complications remain a leading cause of morbidity and mortality after solid organ transplantation (SOT), and largely depend on the net state of immunosuppression achieved with current regimens. Cytomegalovirus (CMV) is a major opportunistic viral pathogen in this setting. The application of strategies of immunological monitoring in SOT recipients would allow tailoring of immunosuppression and prophylaxis practices according to the individual's actual risk of infection. Immune monitoring may be pathogen-specific or nonspecific. Nonspecific immune monitoring may rely on either the quantification of peripheral blood biomarkers that reflect the status of a given arm of the immune response (serum immunoglobulins and complement factors, lymphocyte sub-populations, soluble form of CD30), or on the functional assessment of T-cell responsiveness (release of intracellular adenosine triphosphate following a mitogenic stimulus). In addition, various methods are currently available for monitoring pathogen-specific responses, such as CMV-specific T-cell-mediated immune response, based on interferon-γ release assays, intracellular cytokine staining or main histocompatibility complex-tetramer technology. This review summarizes the clinical evidence to date supporting the use of these approaches to the post-transplant immune status, as well as their potential limitations. Intervention studies based on validated strategies for immune monitoring still need to be performed.
  • 9.

    【2hr】Invariant natural killer T-cell neutralization is a possible novel therapy for human eosinophilic esophagitis

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    机译 不变的自然杀伤T细胞中和是人类嗜酸性粒细胞性食管炎的一种可能的新疗法
    摘要：Eosinophilic esophagitis (EoE) is a recently recognized inflammatory disorder that needs a potential therapeutic strategy. We earlier showed that iNKT cell-deficient mice are protected from allergen-induced EoE. Therefore, we now tested the hypothesis that iNKT cells are induced in the human EoE and is a novel possible target for the treatment of human EoE. Accordingly, we examine number of iNKT cells and eosinophils and expression of iNKT-associated cell surface receptors and chemokines by performing immunofluorescence, qPCR and ELISA in the esophageal biopsies and blood samples of normal subjects (comparison control) and EoE patients. Herein, we show that iNKT cell number, their receptor subcomponents Vα24 and Vβ11 expression, and associated chemokine CXCL16 levels (or expression) are induced significantly in EoE patients compared with normal individuals. In addition, we show that CXCL16 levels (or expression) correlate with the mRNA levels of Vα24 receptor but not well with esophageal eosinophilia in human EoE. Of note, we show that in vivo activation of iNKT cells is sufficient to induce EoE in mice. Furthermore, we show that anti-mCD1d- and anti-hVα24Jα18-neutralizing antibody treatment protects allergen-induced experimental EoE. Taken together, we have shown first time that iNKT cells have a critical pathogenic role in human and experimental EoE. iNKT cell neutralization by humanized anti-CD1d and anti-Vα24Jα18 antibodies might be a novel and potential therapy for human EoE.
  • 10.

    【2hr】Post-traumatic stress disorder: revisiting adrenergics, glucocorticoids, immune system effects and homeostasis.

    包量

    机译 创伤后应激障碍：重新审视肾上腺素能，糖皮质激素，免疫系统作用和体内平衡。
    摘要：This review focuses on post-traumatic stress disorder (PTSD). Several sequelae of PTSD are partially attributed to glucocorticoid-induced neuronal loss in the hippocampus and amygdala. Glucocorticoids and adrenergic agents cause both immediate and late sequelae and are considered from the perspective of their actions on the expression of cytokines as well as some of their physiological and psychological effects. A shift in immune system balance from Th1 to Th2 dominance is thought to result from the actions of both molecular groups. The secretion of glucocorticoids and adrenergic agents is commonly induced by trauma or stress, and synergy between these two parallel but separate pathways can produce long- and short-term sequelae in individuals with PTSD. Potential therapies are suggested, and older therapies that involve the early effects of adrenergics or glucocorticoids are reviewed for their control of acute symptoms. These therapies may also be useful for acute flashback therapy. Timely and more precise glucocorticoid and adrenergic control is recommended for maintaining these molecular groups within acceptable homeostatic limits and thus managing immune and brain sequelae. Psychotherapy should supplement the above therapeutic measures; however, psychotherapy is not the focus of this paper. Instead, this review focuses on the probable molecular basis of PTSD. Integrating historical findings regarding glucocorticoids and adrenergic agents into current research and clinical applications returns the focus to potentially life-changing treatments. Autologous adoptive immune therapy may also offer utility. This paper reports clinical and translational research that connects and challenges separate fields of study, current and classical, in an attempt to better understand and ameliorate the effects of PTSD.
  • 11.

    【2hr】Bacterial lipodipeptide, Lipid 654, is a microbiome-associated biomarker for multiple sclerosis

    包量

    机译 细菌脂肽脂654是一种与微生物组相关的多发性硬化症生物标志物
    摘要：Multiple sclerosis (MS) is an autoimmune disease of unknown etiology. Infectious agents have been suggested to have a role as environmental factors in MS, but this concept remains controversial. Recently, gastrointestinal commensal bacteria have been implicated in the pathogenesis of autoimmune diseases, but mechanisms underlying the relationship of human systemic autoimmunity with the commensal microbiome have yet to be identified. Consistent with the lack of understanding of pathogenic mechanisms and relevant environmental factors in MS, no blood biomarkers have been identified that distinguish MS patients from healthy individuals. We recently identified a unique gastrointestinal and oral bacteria-derived lipodipeptide, Lipid 654, which is produced by commensal bacteria and functions as a human and mouse Toll-like receptor 2 ligand. Using multiple-reaction-monitoring mass spectrometry, a critical approach in targeted lipidomics, we now report that Lipid 654 can be recovered in the serum of healthy individuals. Most interestingly, we find that Lipid 654 is expressed at significantly lower levels in the serum of patients with MS compared with both healthy individuals and patients with Alzheimer's disease. These results thus identify for the first time a potential mechanism relating the gastrointestinal and oral commensal microbiome to a human systemic autoimmune disease. In addition, these results also identify a potential etiologic environmental factor and novel clinically relevant serum biomarker for MS.
  • 12.

    【2hr】IL-21 Modulates Activation of NKT Cells in Patients with Stage IV Malignant Melanoma

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    机译 IL-21调节IV期恶性黑色素瘤患者NKT细胞的活化
    摘要：Interleukin-21 (IL-21) is a common γ-chain cytokine produced by T helper and natural killer T (NKT) cells. It has been shown to regulate the response of various lymphocyte subsets including NK, NKT, T and B cells. Owing to its potent anti-tumor function in preclinical studies and its ability to induce cytotoxicity and interferon-γ (IFN-γ) production in NK and CD8 T cells, recombinant IL-21 (rIL-21) was fast-tracked into early-phase clinical trials of patients with various malignancies. In a phase 2a trial of patients with metastatic melanoma, we analyzed the frequency and function of NKT cells in patients receiving rIL-21. NKT cells were present at a low frequency, but their levels were relatively stable in patients administered rIL-21. Unlike our observations in NK and CD8 T cells, rIL-21 appeared to reduce IFN-γ and TNF production by NKT cells, whereas it enhanced IL-4 production. It also modulated the expression of cell surface markers, specifically on CD4− NKT cells. In addition, an increase in CD3+CD56+ NKT-like cells was observed over the course of rIL-21 administration. These results highlight that IL-21 is a potent regulator of NKT cell function in vivo.
  • 13.

    【2hr】Pollen-induced antigen presentation by mesenchymal stem cells and T cells from allergic rhinitis

    包量

    机译 花粉诱导的变应性鼻炎的间充质干细胞和T细胞抗原呈递
    摘要：Mesenchymal stem cells (MSCs) are promising cellular suppressor of inflammation. This function of MSCs is partly due to their licensing by inflammatory mediators. In cases with reduced inflammation, MSCs could become immune-enhancer cells. MSCs can suppress the inflammatory response of antigen-challenged lymphocytes from allergic asthma. Although allergic rhinitis (AR) is also an inflammatory response, it is unclear if MSCs can exert similar suppression. This study investigated the immune effects (suppressor vs enhancer) of MSCs on allergen-stimulated lymphocytes from AR subjects (grass or weed allergy). In contrast to subjects with allergic asthma, MSCs caused a significant (P<0.05) increase in the proliferation of antigen-challenged lymphocytes from AR subjects. The increase in lymphocyte proliferation was caused by the MSCs presenting the allergens to CD4+ T cells (antigen-presenting cells (APCs)). This correlated with increased production of inflammatory cytokines from T cells, and increased expressions of major histocompatibility complex (MHC)-II and CD86 on MSCs. The specificity of APC function was demonstrated in APC assay using MSCs that were knocked down for the master regulator of MHC-II transcription, CIITA. The difference in the effects of MSCs on allergic asthma and AR could not be explained by the sensitivity to the allergen, based on skin tests. Thus, we deduced that the contrasting immune effects of MSCs for antigen-challenged lymphocytes on AR and allergic asthma could be disease specific. It is possible that the enhanced inflammation from asthma might be required to license the MSCs to become suppressor cells. This study underscores the need for robust preclinical studies to effectively translate MSCs for any inflammatory disorder.
  • 14.

    【2hr】The delicate balance of melanoma immunotherapy

    包量

    机译 黑色素瘤免疫疗法的微妙平衡
    摘要：The strategy of immune modulation for the treatment of cancer is being refined with the introduction of multiple new therapeutic agents into the clinic. Melanoma is a disease where many of these agents have demonstrated efficacy. The mechanisms of action of these agents exploit the counter-regulatory mechanisms of the immune response. However, these agents are also associated with immune-related adverse events (IRAEs), which represent tissue-specific inflammatory responses. These IRAEs highlight the delicate balance of immunologic homeostasis and, with some interventions, may occur more frequently in patients who sustain a therapeutic response. This review will discuss melanoma immunogenicity and immunotherapy. Furthermore, the spectrum and distinction between a reversible immune adverse event and autoimmunity will be highlighted.
  • 15.

    【2hr】Interleukin-6: a new therapeutic target in systemic sclerosis?

    包量

    机译 白细胞介素6：系统性硬化症的新治疗靶点？
    摘要：Interleukin-6 (IL-6) is a classic pro-inflammatory cytokine critical in mounting an effective immune response. It is secreted by a wide array of cell types; however, its effector cells are more restricted, owing to the fact that very few cells, except lymphocytes and hepatocytes, express the functional membrane IL-6 receptor thus reducing the number of IL-6-responsive cells. Trans-signalling, the shedding of the membrane-bound form of the IL-6 receptor into the local microenvironment, greatly increases the range of cells that can respond. IL-6 has been demonstrated to have a pivotal role in the pathogenesis of rheumatoid arthritis, Castleman's disease and Crohn's disease exemplified by the use of an anti-IL-6 biological therapy. However, IL-6 is also associated with the autoimmune disease systemic sclerosis (SSc) and has been shown to be directly fibrotic. Elevated levels of IL-6 are found in SSc patients and this correlates with skin thickness, suggesting a causal effect. This review focuses on the role of IL-6 in SSc, a chronic autoimmune disease with fibrosis. In particular, we will examine the evidence base of the role of IL-6 in fibrosis in this condition, especially the downstream effector pathways. We will then argue why molecular targeting of IL-6 is a promising therapeutic target in this fibrosing disease.
  • 16.

    【2hr】Maternal and infant infections stimulate a rapid leukocyte response in breastmilk

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    机译 母婴感染会刺激母乳中的白细胞快速反应
    摘要：Breastmilk protects infants against infections; however, specific responses of breastmilk immune factors to different infections of either the mother or the infant are not well understood. Here, we examined the baseline range of breastmilk leukocytes and immunomodulatory biomolecules in healthy mother/infant dyads and how they are influenced by infections of the dyad. Consistent with a greater immunological need in the early postpartum period, colostrum contained considerable numbers of leukocytes (13–70% out of total cells) and high levels of immunoglobulins and lactoferrin. Within the first 1–2 weeks postpartum, leukocyte numbers decreased significantly to a low baseline level in mature breastmilk (0–2%) (P<0.001). This baseline level was maintained throughout lactation unless the mother and/or her infant became infected, when leukocyte numbers significantly increased up to 94% leukocytes out of total cells (P<0.001). Upon recovery from the infection, baseline values were restored. The strong leukocyte response to infection was accompanied by a more variable humoral immune response. Exclusive breastfeeding was associated with a greater baseline level of leukocytes in mature breastmilk. Collectively, our results suggest a strong association between the health status of the mother/infant dyad and breastmilk leukocyte levels. This could be used as a diagnostic tool for assessment of the health status of the lactating breast as well as the breastfeeding mother and infant.
  • 17.

    【2hr】A new ICB sister journal focuses on clinical and translational immunology

    包量

    机译 ICB的新姊妹期刊着重于临床和转化免疫学
    摘要：
  • 18.

    【2hr】Monocyte-derived macrophages do not explain susceptibility to pulmonary non-tuberculous mycobacterial disease

    包量

    机译 单核细胞衍生的巨噬细胞不能解释肺非结核分枝杆菌疾病的易感性
    摘要：Pulmonary infections with non-tuberculous mycobacteria (NTM) affect a subset of older individuals (mostly women) with no known immunological defects. As NTMs are intracellular pathogens, it is important to establish whether NTM disease is associated with defective production of Th1 cytokines or poor responses by host macrophage/monocytes. We have shown that patients display vigorous production of interferon gamma (IFNγ) when CD4 T cells are stimulated with mycobacterial antigens. This implicated the macrophage response to IFNγ. Blood monocytes are poorly representative of lung macrophages, so monocyte-derived macrophages (MDMs) were created and then stimulated with lipomannan (a Toll-like receptor (TLR)2 agonist), lipopolysaccharide (LPS; a TLR4 agonist) or recombinant human IFNγ. MDMs from NTM patients, their offspring and healthy donors expressed similar amounts of IFNγR1, and cellular responses to IFNγ were similar, so there is no evidence of a genetic defect in this pathway. MDMs from NTM patients produced less interleukin-6 in response to LPS (P<0.01) than cells from controls, but other cytokine responses were normal. This warrants further study.
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