Serial imaging of human embryonic stem-cell engraftment and teratoma formation in live mouse models

Two new types of lentiviral vectors expressing a reporter transgene encoding either firefly luciferase （fLuc） for bioluminescence imaging or the HSV1 thymidine kinase （HSV1-TK） for radiopharmaceutical-based imaging were constructed to monitor human embryonic stem cell （hESC） engraftment and proliferation in live mice after trans- plantation. The constitutive expression of either transgene did not alter the properties of hESCs in the culture. We next monitored the formation of teratomas in SCID mice to test （1） whether the gene-modified hESCs maintain their developmental pluripotency, and （2） whether sustained reporter gene expression allows noninvasive, whole-body imaging of hESC derivatives in a live mouse model. We observed teratoma formation from both types of gene-modified cells as well as wild-type hESCs 2-4 months after inoculation. Using an optical imaging system, bioluminescence from the fLuc-transduced hESCs was easily detected in mice bearing teratomas long before palpable tumors could be detected. To develop a noninvasive imaging method more readily translatable to the clinic, we also utilized HSV1-TK and its specific substrate, 1-（2＇-deoxy-2＇-fluoro-β-D-arabinofuranosyl）-5-[^125I]iodouracil（[^125I]FIAU）, as a reporter/ probe pair. After systemic administration, [^125I]FIAU is phosphorylated only by the transgene-encoded HSV1-TK enzyme and retained within transduced （and transplanted） cells, allowing sensitive and quantitative imaging by single-photon emission computed tomography. Noninvasive imaging methods such as these may enable us to monitor the presence and distribution of transplanted human stem cells repetitively within live recipients over a long term through the expression of a reporter gene.

Metabolic checkpoints in neurodegenerative T helper 17（TH17） and neuroregenerative regulatory T(Treg) cells as new therapeutic targets for multiple sclerosis

The central nervous system (CNS) is an immune-privileged site with tightly-regulated immune responses, a concept proposed by Nobel Laureate Sir Peter Medawar in 1960. Under physiological conditions, only a few T lymphocytes conducting immunosurveillance can infiltrate the CNS.

Reduced Locomotor Activity Correlates with Increased Severity of Arthritis in a Mouse Model of Antibody-Induced Arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial hyperplasia and progressive cartilage and bone destruction that leads to a substantial loss of general functions and/or a decline in physical activities such as walking speed in humans. The K/BxN serum transfer arthritis in mice shares many immunological and pathological features with human RA. Very few studies are available in mice that investigate the changes in physical activity in relation to arthritis development. In this study we investigate the effect of arthritis on the locomotor activity of mice during K/BxN sera transfer arthritis. Methods: Arthritis was induced in Balb/c mice by injecting intraperitoneally with 200 μl of K/BxN sera;Balb/c mice injected with phosphate buffered saline (PBS) served as control. Progress of arthritis was estimated by daily measurements of joint thickness. Each mouse’s locomotor activity (travel distance and travel time) was assessed every day for duration of 20 minute period using the SmartCageTM platform. Data were analyzed using the SmartCageTM analysis software (CageScoreTM). Results: Arthritic Balb/c mice showed a reduction in distance covered and travel speed when compared to arthritis-free, control Balb/c mice. Maximum decline in locomotor activity was observed during the peak period of the disease and correlated to the increase in joint thickness in the arthritic mice. Conclusion: This report demonstrates that measuring locomotor activity of mice during progression of K/BxN sera-induced arthritis using the SmartCageTM platform offers a quantitative method to assess physical activity in mice during arthritis.

Regulation of immune-related diseases by multiple factors: a meeting report of 2017 International Workshop of the Chinese Academy of Medical Sciences Initiative for Innovative Medicine on Tumor Immunology

Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Academy of Medical Sciences Initiative for Innovative Medicine on Tumor Immunology held in Beijing, China, on May 12, 2017, a number of speakers reported new findings and ongoing studies on immune-related diseases such as cancer, fibrotic disease, diabetes, and others. A considerably insightful overview was provided on cancer immunity, tumor microenvironments,and new immunotherapy for cancer. In addition, chronic inflammatory diseases were discussed. These findings may offer new insights into targeted immunotherapy.

You had me at PELO:a"Ribosome Rescuer"induces NLR inflammasome assembly

Pyroptosis,an inflammatory form of programmed cell death,eliminates a niche where pathogens replicate,providing overall benefits to a host.When left uncontrolled,pyroptosis can lead to severe pathology.Overactive pyroptotic activation has been implicated in neuroinflammation,cardiovascular disease,acute respiratory distress syndrome(ARDS),and many other diseases[1,2,3].Because of its multiple and permanent consequences,pyroptosis is a highly regulated signaling pathway.Major regulators of pyroptosis are NLR inflammasomes,which are activated by various“danger”signals such as ATP.

nflammasomes in cancer： a double-edgecl sword

Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent induc- ers of interleukin （IL）-I~ and IL-18 during infammation, are large protein complexes typically consisting of a Nod-like receptor （NLR）, the adapter protein ASC, and Caspase-1. During malignant transformation or cancer therapy, the inflammasomes are postulated to become activated in response to danger signals arising from the tumors or from therapy-induced damage to the tumor or healthy tissue. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy depending on the specific con- text. Here we summarize the role of different inflamma- some complexes in cancer progression and therapy. Inflammasome components and pathways may provide novel targets to treat certain types of cancer; however, using such agents should be cautiously evaluated due to the complex roles that inflammasomes and pro- inflammatory cytokines play in immunity.

“Autoinflammatory psoriasis”-genetics and biology of pustular psoriasis

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations.Plaque psoriasis,which is the most common manifestation of psoriasis,is located on one end of the spectrum,dominated by adaptive immune responses,whereas the rarer pustular psoriasis lies on the opposite end,dominated by innate and autoinflammatory immune responses.In recent years,genetic studies have identified six genetic variants that predispose to pustular psoriasis,and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis.In this review,we discuss the presentation and clinical subtypes of pustular psoriasis,contribution of genetic predisposing variants,critical role of the IL-36 family of cytokines in disease pathophysiology,and treatment perspectives for pustular psoriasis.We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.

IFNγsignaling integrity in colorectal cancer immunity and immunotherapy

The majority of colorectal cancer patients are not responsive to immune checkpoint blockade(ICB).The interferon gamma(IFNγ)signaling pathway drives spontaneous and ICB-induced antitumor immunity.In this review,we summarize recent advances in the epigenetic,genetic,and functional integrity of the IFNγsignaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB.Moreover,we discuss how to target IFNγsignaling to inform novel clinical trials to treat patients with colorectal cancer.

Mechanistic insights into cancer immunity and immunotherapy

While immunotherapy has had an important impact on cancer treatment,only approximately a quarter of patients respond to these treatments.Why does it work in some patients but not in other patients?How can we improve the therapeutic efficacy of current immunotherapy?Are there potential new strategies to tackle this problem?The answers to these questions may rely on our in-depth understanding of the basic mechanisms of the cancer immune response,immunotherapeutic efficacy,and resistance.

RBP-J is required for M2 macrophage polarization in response to chitin and mediates expression of a subset of M2 genes

Development of alternatively activated （M2） macrophage phenotypes is a complex process that is coordinately regulated by a plethora of pathways and factors. Here, we report that RBP-J, a DNA-binding protein that integrates signals from multiple pathways including the Notch pathway, is critically involved in polarization of M2 macrophages. Mice deficient in RBP-J in the myeloid compartment exhibited impaired M2 phenotypes in vivo in a chitin-induced model of M2 polarization. Consistent with the in vivo findings, M2 polarization was partially compromised in vitro in Rbpj-deficient macrophages as demonstrated by reduced expression of a subset of M2 effector molecules including arginase 1. Functionally, myeloid Rbpj deficiency impaired M2 effector functions including recruitment of eosinophils and suppression of T cell proliferation. Collectively, we have identified RBP- Jas an essential regulator of differentiation and function of alternatively activated macrophages.

Predictive biomarkers for immune checkpoint blockade and opportunities for combination therapies

Immune checkpoint blockade therapies(ICBs)are a prominent breakthrough in cancer immunotherapy in recent years(named the 2013“Breakthrough of the Year”by the Science magazine).Thus far,FDA-approved ICBs primarily target immune checkpoints CTLA-4,PD-1,and PD-L1.Notwithstanding their impressive long-term therapeutic benefits,their efficacy is limited to a small subset of cancer patients.In addition,ICBs induce inadvertent immune-related adverse events(irAEs)and can be costly for long-term use.To overcome these limitations,two strategies are actively being pursued:identification of predictive biomarkers for clinical response to ICBs and multi-pronged combination therapies.Biomarkers will allow clinicians to practice a precision medicine approach in ICBs(biomarker-based patient selection)such as treating triple-negative breast cancer patients that exhibit PD-L1 staining of tumor-infiltrating immune cells in
1%of the tumor area with nanoparticle albumin-bound(nab)epaclitaxel plus anti-PD-L1 and treating patients of MSI-H or MMR deficient unresectable or metastatic solid tumors with pembrolizumab(anti-PD-1).Importantly,the insights gained from these biomarker studies can guide rational combinatorial strategies such as CDK4/6 inhibitor/fractionated radiotherapy/HDACi in conjunction with ICBs to maximize therapeutic benefits.Further,with the rapid technological advents(e.g.,ATCT-Seq),we predict more reliable biomarkers will be identified,which in turn will inspire more promising combination therapies.

Immune regulation in the tumor microenvironment and its relevance in cancer therapy

Cancer immunotherapy,including immune checkpoint blockade and CAR-T cell therapy,has introduced revolutionary approaches to treating patients with cancer.The success and hope of cancer immunotherapy have continuously stimulated high interest in dissecting immunotherapy resistance mechanisms,researching previously unknown therapeutic targets,and informing novel clinical trials in cancer therapy.The notion that the tumor microenvironment holds the key to understanding tumor immunity and developing novel immunotherapy has been well established in the field of tumor immunology and medical oncology[1].This special issue of Cellular&Molecular Immunology(CMI)compiles a series of review articles,presenting state-ofthe-art literature and concepts focused on several important aspects concerning the most recent advancement in immune sensitive and resistant mechanisms in the tumor microenvironment,and their relevance in cancer therapy.

Reflections on COPD comorbidities

To the Editor:Chronic obstructive pulmonary disease(COPD)is a common disease among the elderly,affecting over one-third of the elderly population worldwide.The progressive decline in lung function characteristic of COPD significantly impacts the quality of life and employability of affected individuals,resulting in a substantial direct and indirect socioeconomic burden.COPD frequently has comorbidities involving other organ systems.Virtually all elderly COPD patients present with one or more comorbid conditions,collectively exacerbating health and economic burdens.While viral and bacterial infections remain the most common triggers for COPD exacerbations(ECOPD).

Bone marrow and the control of immunity

Bone marrow is thought to be a primary hematopoietic organ. However, accumulated evidences demonstrate that active function and trafficking of immune cells, including regulatory T cells, conventional T cells, B cells, dendritic cells, natural killer T (NKT) cells, neutrophils, myeloid-derived suppressor cells and mesenchymal stem cells, are observed in the bone marrow. Furthermore, bone marrow is a predetermined metastatic location for multiple human tumors. In this review, we discuss the immune network in the bone marrow. We suggest that bone marrow is an immune regulatory organ capable of fine tuning immunity and may be a potential therapeutic target for immunotherapy and immune vaccination.