Spontaneous Rejection Research Articles

Quasi-waffle solar distiller for durable desalination of seawater.

Water purification via interfacial solar steam generation exhibits promising potential. However, salt crystallization on evaporators reduces solar absorption and obstructs water supply. To address it, a waffle-shaped solar evaporator (WSE) has been designed. WSE is fabricated via a zinc-assisted pyrolysis route, combining low-cost biomass carbon sources, recyclable zinc, and die-stamping process. This route enables cost-effective production without the need of sophisticated processing. As compared to conventional plane-shaped evaporators, WSE is featured by extra sidewalls for triggering the convection with the synergistic solute and thermal Marangoni effects. Consequently, WSE achieves spontaneous salt rejection and durable evaporation stability. It has demonstrated continuous operation for more than 60 days in brine without fouling.

Solar Desalination with Monolithic Foams Containing a Combination of Graphite and SnSe Featured with a Hierarchical Structure and Bimodal Pores for Spontaneous Salt Rejection

The increasing interest in solar water evaporation technology is due to its potential to replace conventional desalination systems. In this study, we suggest a new solar desalination system that has a hierarchical photothermal structure and is structurally monolithic. The overall membrane is made up of a macroscale porous melamine foam frame that acts as a porous insulator and a mass transfer layer. The mass transfer layer is designed with a bimodal porous structure of melamine foam, with large pores coated with a composite of graphite and SnSe (G-SnSe) and small pores. This simple structure provides many benefits. First, it combines two photothermal mechanisms, thermal vibration in graphite and non-radiative relaxation in SnSe, to achieve synergies in the conversion of light to heat energy. Second, compared to the single materials, graphite or SnSe alone, the nanocomposite of G-SnSe has a higher effective surface area, resulting in increased solar absorption. Finally, the melamine foam structure with bimodal pores enhances seawater wicking and has a high salt rejection capacity due to its volumetric porosity bimodal configuration of up to 35%. The monolithic melamine foam with a hierarchical photothermal structure minimizes interference with water transport due to the resistance-free presence of a continuous interfacial layer.The monolithic structure evaporaters (MSE) achieved a high evaporation rate of 1.303 kg m-2h-1 under 1 sun condition due to increased capillarity by the small-scale pores in the photothermal layer. Furthermore, spontaneous salt rejection was observed during solar desalination, attributed to the presence of intrinsic large-scale pores in melamine foam for draining the concentrated salt water from the surface. The feasibility of outdoor solar desalination was established, with a high evaporation rate of 1.259 kg m-2h-1. The mechanical stability of MSE was achieved by incorporating a small amount of binder (less than 3% of total photothermal materials), maintaining efficient performance for up to 30 days without degradation. The proposed strategy in the simple monolithic structure with bimodal porosity provides a general toolkit for designing high-performance solar desalination devices due to high evaporation rate and spontaneous salt rejection capability.In summary, the solar water evaporation technology is becoming increasingly popular as a possible replacement for traditional desalination systems. We propose a novel monolithic solar desalination system with a hierarchical photothermal structure, which is composed of a macroscale porous melamine foam as a skeleton which has both roles : an insulator and a mass transfer layer. The bimodal porous structure of melamine foam with large pores coated with a composite of graphite and SnSe provides many benefits, including increased solar absorption and a high salt rejection capacity. The MSE structure achieves a high evaporation rate and spontaneous salt rejection, making it a feasible option for outdoor solar desalination. The proposed strategy provides a general toolkit for designing high-performance solar desalination devices.

In situ tumour arrays reveal early environmental control of cancer immunity

The immune phenotype of a tumour is a key predictor of its response to immunotherapy1–4. Patients who respond to checkpoint blockade generally present with immune-inflamed5–7 tumours that are highly infiltrated by T cells. However, not all inflamed tumours respond to therapy, and even lower response rates occur among tumours that lack T cells (immune desert) or that spatially exclude T cells to the periphery of the tumour lesion (immune excluded)8. Despite the importance of these tumour immune phenotypes in patients, little is known about their development, heterogeneity or dynamics owing to the technical difficulty of tracking these features in situ. Here we introduce skin tumour array by microporation (STAMP)—a preclinical approach that combines high-throughput time-lapse imaging with next-generation sequencing of tumour arrays. Using STAMP, we followed the development of thousands of arrayed tumours in vivo to show that tumour immune phenotypes and outcomes vary between adjacent tumours and are controlled by local factors within the tumour microenvironment. Particularly, the recruitment of T cells by fibroblasts and monocytes into the tumour core was supportive of T cell cytotoxic activity and tumour rejection. Tumour immune phenotypes were dynamic over time and an early conversion to an immune-inflamed phenotype was predictive of spontaneous or therapy-induced tumour rejection. Thus, STAMP captures the dynamic relationships of the spatial, cellular and molecular components of tumour rejection and has the potential to translate therapeutic concepts into successful clinical strategies.

Boosting In-Vivo Anti-Tumor Immunity with an Oral Microparticulate Breast Cancer Vaccine and Low-Dose Cyclophosphamide.

Tumor cells express antigens that should induce immune-mediated rejection; however, spontaneous rejection of established tumors is rare. Recent evidence suggests that patients suffering from cancer exhibit an elevation in regulatory T cells population, a subset of CD4+ T cells, which suppress tumor recognition and elimination by cytotoxic T cells. This study investigates immunotherapeutic strategies to overcome the immunosuppressive effects exerted by regulatory T cells. A novel immunotherapeutic strategy was developed by simultaneous administration of oral microparticulate breast cancer vaccines and cyclophosphamide, a regulatory T cell inhibitor. Breast cancer vaccine microparticles were prepared by spray drying, and administered orally to female mice inoculated with 4TO7 murine breast cancer cells in combination with a low dose of intraperitoneally administered cyclophosphamide. Mice receiving the combination of vaccine microparticles and cyclophosphamide exhibited maximal tumor regression and the highest survival rate compared with the control groups. This study highlights the importance of cancer vaccination along with regulatory T cell depletion in cancer therapy, and suggests that a low dose of cyclophosphamide that specifically and significantly depletes regulatory T cells may be a highly effective immunotherapeutic strategy for the treatment of cancer.

Graphite/SnSe hybrid-embedded monolithic foams with hierarchical and bimodal pores for high performance solar desalination membranes with spontaneous salt rejection

Solar water evaporation techniques have attracted considerable interest due to their strong potential to disrupt existing desalination systems. As the interfaical solar steam generation has been heavily studied to explore the strategies to increase light absorption, recent effort has been focused on the development of mass transfer-based interfacial layer. Here, we propose monolithic solar evaporator (MSE) having a hierarchical mass transfer layer made of a melamine foam skeleton coated with graphite and tin selenide photothermal materials (G-SnSe). Unlike conventional solar evaporator structures consisting of double or three layers, the MSE has a monolithic configuration on top of wihch G-SnSe forms the bimodal porous structure (50–60% porosity) for enhancing the mass transfer. Due to the reinforced capillarity at the small-scale pores in the bimodal structure, the MSE structure achieves a high evaporation rate of 1.303 kg m-2h−1 when exposed to 1 sun irradiation. Furthermore, large-scale pores in the bimodal structures would simultaneously promote the autonomous rejection of salts at the MSE surface during solar desalination. We show that optimizing the bimodally porous structure and the interfacial properties significantly improves the solar evaporation efficiency, demonstrating the intricated structure for the next generation solar evaporation and desalination systems.

The role of education in the accumulation and transmission of social experience

It is demonstrated that social experience is accumulated in the process of real joint life activity of people in the course of satisfying their group and individual interests and needs, in which there is a constant spontaneous rejection of those forms (technologies and results) of their actions, conduct, communicative acts, the used means, ideological and value foundations, etc. that are recognized as harmful or potentially dangerous for the existing level of social integration of the team and turn out to be unacceptable in terms of their social cost and consequences. Some of these undesirable forms eventually fall under institutional taboo (legislative, religious and other prohibitions, sanctions, etc.), while others remain condemned within the framework of customs (morality, virtue). The forms that in the short term, and especially in the long term, prove to be quite acceptable or even desirable from the point of view of maintaining, reproducing, and sometimes increasing the level of social consolidation of community members, their tolerance, the quality of their mutual understanding and interaction, both spontaneously and over time institutionally selected as recommended, are accumulated and consolidated in social norms, standards, values, rules, laws, and ideological principles. Education is one of these most effective forms. The article shows what functions are performed by education at all levels and stages.

MHC genotype, immune repertoire, and tumor immunity all influence spontaneous cancer development and metastasis in spontaneous breast cancer models

Abstract 20 to 30% of breast cancers overexpress ERRB2, encoding the human epidermal growth factor-2 receptor (HER2). Overexpression of HER2 is associated with poorer prognosis, particularly in metastatic disease. Although HER2 therapeutics exists many patients eventually develop uncontrolled tumor growth. The BALB/c-neuT mouse has been a popular model for investigating HER2-positive breast cancer. We have found that immune responsiveness and MHC genotype are important factors in spontaneous tumor development and tumor rejection in the neuT model. To assess the influence of immune response potential on tumor biology we introduced the skg ZAP-70 mutation or the H-2b MHC haplotype into the neuT model. Spontaneous tumors appeared with decreased frequency and metastasis or increased frequency and metastasis, respectively, in comparison to the BALB/c model. H-2b tumors were readily transplantable into the breast fat pads of syngeneic BALB.B-neuT hosts which developed systemic immune abnormalities very similar to those observed in BALB/c - neuT or BALB/c WT mice bearing neuT tumors. However, BALB.B WT hosts initially accepted the grafts, but subsequently rejected them after they were established. Adoptive transfer of splenocytes from BALB.B WT mice which had rejected tumor conferred resistance to the tumor grafts, as well as to spontaneous tumors developing in BALB.B neuT littermates. The strong H-2b-mediated antitumor response in WT mice indicates efficient antigen presentation, and presumably leads to strong tolerance in neuT+ animals. The importance of an intact T cell signaling and MHC genotype indicate a critical role for T cell-mediated immunity and tolerance in the biology of the spontaneously developing tumor and metastasis.

Plastic Bronchitis in Children with Asthma

Plastic bronchitis (BP) is usually an evolutionary complication of respiratory condi-tions such as asthma and / or pre-existing cardiac, and its occurrence in a patient without chronic respiratory pathology remains exceptional.?We report the observation of a seven-year-old child, followed for asthma, who presented with a pneumatic appearance of commonplace, massive atelectasis of the entire left lung. Endoscopic exploration of the tracheobronchial tree confirmed the extensive obstruction of the left tree by bronchial mussels. The evolution was favorable after the extraction and spontaneous rejection of intrabronchial mussels.

Knowledge and Distrust May Go a Long Way in the Battle With Disinformation: Mental Processes of Spontaneous Disbelief

A common claim is that people have an easier time accepting information than rejecting it, resulting in gullibility. In this article, I review empirical research demonstrating how the human mind is equipped with successful and spontaneous rejection processes that may protect us from disinformation.

Are Conventional Type 1 Dendritic Cells Critical for Protective Antitumor Immunity and How?

Dendritic cells (DCs) are endowed with a unique potency to prime T cells, as well as to orchestrate their expansion, functional polarization and effector activity in non-lymphoid tissues or in their draining lymph nodes. The concept of harnessing DC immunogenicity to induce protective responses in cancer patients was put forward about 25 years ago and has led to a multitude of DC-based vaccine trials. However, until very recently, objective clinical responses were below expectations. Conventional type 1 DCs (cDC1) excel in the activation of cytotoxic lymphocytes including CD8+ T cells (CTLs), natural killer (NK) cells, and NKT cells, which are all critical effector cell types in antitumor immunity. Efforts to investigate whether cDC1 might orchestrate immune defenses against cancer are ongoing, thanks to the recent blossoming of tools allowing their manipulation in vivo. Here we are reporting on these studies. We discuss the mouse models used to genetically deplete or manipulate cDC1, and their main caveats. We present current knowledge on the role of cDC1 in the spontaneous immune rejection of tumors engrafted in syngeneic mouse recipients, as a surrogate model to cancer immunosurveillance, and how this process is promoted by type I interferon (IFN-I) effects on cDC1. We also discuss cDC1 implication in promoting the protective effects of immunotherapies in mouse preclinical models, especially for adoptive cell transfer (ACT) and immune checkpoint blockers (ICB). We elaborate on how to improve this process by in vivo reprogramming of certain cDC1 functions with off-the-shelf compounds. We also summarize and discuss basic research and clinical data supporting the hypothesis that the protective antitumor functions of cDC1 inferred from mouse preclinical models are conserved in humans. This analysis supports potential applicability to cancer patients of the cDC1-targeting adjuvant immunotherapies showing promising results in mouse models. Nonetheless, further investigations on cDC1 and their implications in anti-cancer mechanisms are needed to determine whether they are the missing key that will ultimately help switching cold tumors into therapeutically responsive hot tumors, and how precisely they mediate their protective effects.

Abstract A021: Vaccination with autologous, nonattenuated, live glioblastoma cells induces potent peripheral and intratumoral anti-tumoral responses: A first-in-human study

Abstract Glioblastoma (GBM), which grows uninhibited in the brain, almost never metastasizes outside of it. The rare occurrence (<0.5%) of overt GBM extracranial metastasis is paradoxically associated with significantly enhanced patient survival. We previously reported that the highly malignant F98 Fischer-rat GBM model, which grows aggressively in the brain, spontaneously regresses when injected subcutaneously as live unattenuated cells. The peripheral growth and regression of live glioma cells markedly enhanced the survival of all rats, and cured (survival >9 months) approximately 50% of rats challenged with F98 cells intracranially. The results in the F98 model were corroborated in the CNS1 astrocytoma model in Lewis rats. The fraction of cured rats in both models were the highest reported in published literature. We found that the spontaneous rejection of live glioma cells inoculated in peripheral sites was immune-mediated. This location-biased immune response was termed “Split Immunity”—a tumor that thrives in an immune-privileged site (e.g., the brain) may be inhibited by injecting live unmodified tumor cells in a site that is not privileged, generating protective immunity that spreads back to the privileged site.To evaluate the applicability of the “Split Immunity” approach in humans, we ran a first-in-human (FIH) study on two recurrent GBM patients. The patients were vaccinated subcutaneously, initially with autologous irradiated tumor cells, and then with autologous, non-attenuated, live tumor cells. The treatment caused no serious adverse events. The injected live tumor cells did not grow at the inoculation site, nor did they spread metastatically, as evaluated by choline 18F PET-CT. Standard biochemical and hematologic blood tests showed no treatment-related adverse effects. Both patients’ quality of life (QoL) questionnaires demonstrated subjective improvements in self-evaluated “global health status.” The treatment had demonstrated several signs indicative of efficacy. MRI evaluation using “treatment response assessment maps” (TRAM) demonstrated strong increases in the “treatment-response” component following live-cell vaccination, compatible with “pseudo-progression-like” responses in both patients. Using elaborate 8-color flow cytometric panels, we detected potent tumor-cell specific polyfunctional activation in 2.5% and 5% of peripheral cytotoxic T-cell (CTL) and T helper cells (Th), respectively, 3 days following live-cell vaccination. Flow cytometric immune mapping of all intratumoral immune cell subsets showed major changes from baseline that had occurred shortly after live-cell vaccinations. We observed major increases (8 to 200 fold) in both patients of all monitored intratumoral dendritic cell (DC) subsets (CD1c+ and CD141+ myeloid DC, CD123+ plasmacytoid DC). Patient-1 showed the highest frequency of intratumoral CD56brt natural killer (NK) cells from all previously fully mapped brain tumor patients. Patient-2’s intratumoral CTL and Th were increase by 6- and 17-fold, respectively. Patient-2’s CD141+ and CD1c+ myeloid DC had exhibited upregulated CD86 maturation marker following treatment. Overall, the immune infiltrate following treatment in Patient-2 exceeded the immune infiltrates found in 42 previously fully-mapped brain tumor patients. The flow cytometric results were corroborated by the patients’ immunohistochemistry data. Patient-2, who had been treated by a tighter vaccination protocol than Patient-1, had survived 19 months after GBM recurrence, which is considerably longer than the median 6- to 8-month survival of recurrent GBM patients. Taken together, the accumulated FIH results are suggestive of safety and efficacy of the “Split Immunity” approach. Based on the these results, we have recently received an ethical approval for a phase IIa clinical trial on 8 recurrent- and 4 newly-diagnosed GBM patients. Citation Format: Ilan Volovitz, Nati Shapira, Rachel Grossman, Zvi Ram. Vaccination with autologous, nonattenuated, live glioblastoma cells induces potent peripheral and intratumoral anti-tumoral responses: A first-in-human study [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A021.

Power-Decoupling of a Multiport Isolated Converter for an Electrolytic-Capacitorless Multilevel Inverter

This paper presents a generalized power-decoupling control scheme using a multiport isolated bidirectional converter for a multilevel inverter, which has multiple dc links inside. In the proposed method, a single power-decoupling capacitor is needed for all the dc links in the multilevel inverter cell. First, a prototype of the power-decoupling concept of individual H-bridge cells in the multilevel inverter is proposed, using a separate power-decoupling circuit. Then, a more advanced one-step power-decoupling method is proposed. The lifetime and reliability of the multilevel inverter is improved as film capacitors replace the large capacitance electrolyte capacitors. A multi-input ports/single output voltage-fed dual half-bridge converter (MDHB) is used for the power-decoupling circuit. A steady-state analysis for the peak and root mean square of the MDHB current is carried out for the loss breakdown. The currents are functions of the switching frequency, phase shift, leakage inductance, turn ratio, and output voltage, which make the multiport transformer design complex. A design methodology is proposed, which takes into account the design of the copper and core losses as functions of the switching frequency and number of turns. Furthermore, a special winding method for the input port is illustrated to obtain identical leakage inductances for the uniform current distribution in the multiport transformer. The proposed MDHB employs a current-sensorless power-decoupling control that contributes to the spontaneous ripple rejection of all the dc links without individual link current information, as well as to the cost and size reduction. Hence, the ripple-rejection controller is independent of the control configuration of the multilevel inverter, and also available for universal applications of various inverter topologies. Since the primary-input ports of MDHB share a single magnetic core for interfacing the ripple power to the unified secondary ripple capacitor, the controller design becomes difficult in considering the dynamic interaction among the ports, along with the average-voltage control loop design. In this paper, the dynamic analysis and controller design procedure of the circuit is also presented. The power decoupling is achieved even when the ripple frequency is other than the double frequency of the inverter output, since the single-pole transfer function of the small-signal model of the MDHB allows sufficient phase margin, along with high bandwidth. The proposed power-decoupling method for the multilevel inverter is validated with the help of simulation and 1.2-kW hardware prototype experimental results.

S100A4 Protects Myeloid-Derived Suppressor Cells from Intrinsic Apoptosis via TLR4-ERK1/2 Signaling.

Myeloid-derived suppressor cells (MDSCs) often expand during cancer or chronic inflammation and dampen immune responses. However, mechanisms underlying their capacity to escape intrinsic apoptosis in the inflammatory environment are still largely unknown. In this study, we investigated this in mouse tumor models with MDSC accumulation. Spontaneous rejection of tumors implanted into mice deficient for the small Ca2+-binding protein S100A4 (S100A4−/−) was accompanied by low numbers of peripheral MDSCs. This was independent of S100A4 expression on tumor cells. In contrast, MDSCs from S100A4−/− tumor-bearing mice showed a diminished resistance to the induction of intrinsic apoptosis. Further studies demonstrated that S100A4 protects MDSCs from apoptosis through toll-like receptor-4/extracellular signal-regulated kinase-dependent caspase-9 inhibition. The finding that S100A4 is critical for MDSC survival in inflammatory environments might have important implications for the clinical treatment of cancer or inflammation-related diseases.

A Flagellin-Derived Toll-Like Receptor 5 Agonist Stimulates Cytotoxic Lymphocyte-Mediated Tumor Immunity

Toll-like receptor (TLR) mediated recognition of pathogen associated molecular patterns allows the immune system to rapidly respond to a pathogenic insult. The “danger context” elicited by TLR agonists allows an initially non-immunogenic antigen to become immunogenic. This ability to alter environment is highly relevant in tumor immunity, since it is inherently difficult for the immune system to recognize host-derived tumors as immunogenic. However, immune cells may have encountered certain TLR ligands associated with tumor development, yet the endogenous stimulation is typically not sufficient to induce spontaneous tumor rejection. Of special interest are TLR5 agonists, because there are no endogenous ligands that bind TLR5. CBLB502 is a pharmacologically optimized TLR5 agonist derived from Salmonella enterica flagellin. We examined the effect of CBLB502 on tumor immunity using two syngeneic lymphoma models, both of which do not express TLR5, and thus do not directly respond to CBLB502. Upon challenge with the T-cell lymphoma RMAS, CBLB502 treatment after tumor inoculation protects C57BL/6 mice from death caused by tumor growth. This protective effect is both natural killer (NK) cell- and perforin-dependent. In addition, CBLB502 stimulates clearance of the B-cell lymphoma A20 in BALB/c mice in a CD8+ T cell-dependent fashion. Analysis on the cellular level via ImageStream flow cytometry reveals that CD11b+ and CD11c+ cells, but neither NK nor T cells, directly respond to CBLB502 as determined by NFκB nuclear translocation. Our findings demonstrate that CBLB502 stimulates a robust antitumor response by directly activating TLR5-expressing accessory immune cells, which in turn activate cytotoxic lymphocytes.

Tracheal stenosis after intubation and/or tracheostomy

IntroductionThe tracheal iatrogenic stenosis remains a frequent, sometimes severe tracheal resection, anastomosis is the treatment of choice. However, the endoscopic treatment is used as an alternative therapy. Materials and methodsWe report a retrospective study for a period of 8years. Results174 patients had an iatrogenic tracheal stenosis of intubation (55.17%) and/or tracheotomy (44.82%).The appearance and extent of stenosis were assessed by bronchoscopy, we noted a tracheal malacia (15%), a circumferential stenosis (58%), a little tight stenosis (12%) and diaphragm (5%).Some patients have benefited from several therapeutic procedures, 90 patients were operated on early interventions with 53 and 37 after surgery, an improvement of the patient’s clinical status have been postponed earlier, after failure of endoscopic methods. 293 interventional bronchoscopies were performed, 192 stenting, 45 Nd-YAG laser, 55 patients required a recalibration in the tube of the bronchoscope and one patient received cryotherapy, knowing that there are the patients who received combination therapy. We lamented death in the immediate postoperative sepsis, a recurrence of stenosis in 117 patients, and among the 192 implants placed we identified 37 migrations, 52 congestion, development of granulomatous lesions, an overhaul of the prosthesis is noted in 7.29%, three implants were embedded in the tracheal mucosa and there was only one spontaneous rejection. The long-term evolution was satisfactory in 92 patients. ConclusionNevertheless, the management of post intubation tracheal stenosis and/or post tracheostomy cannot be that requiring a multidisciplinary collaboration.

Exploiting the immune response to halt progression of ocular melanoma

AbstractPurpose The purpose of this study was to characterize the requirements for spontaneous rejection of tumors transplanted in the anterior chamber (a.c.) of splenectomized mice as a first step toward identifying how to harness the immune reponses to eliminate intaocular tumors.Methods Luciferase expressing E.G7‐OVA (Luc E.G7) tumors were injected in the a.c. of the eye of wildtype, CD8 depleted, perforin deficient, IFNγ deficient, IFNγ receptor 1 deficient (IFNγR1), or inducible nitric oxide synthase (NOS2) deficient mice that were splenectomized or left untreated prior to tumor challenge. In some experiments intraocular macrophages were depleted by subconjunctival administration of clodronate liposomes. Luc E.G7 tumor growth was measured by bioluminescent imaging using an IVIS imager. Tumor‐specific OT‐I CD8+ T cells were monitored in vivo by flow cytometry.Results Luc‐E.G7 tumors grew progressively in the a.c. of nonsplenectomized mice but were spontaneously rejected in splenectomized mice. Rejection of ocular tumors in splenectomized mice required CD8+ T cells, macrophages, IFNγ and IFNγR1 expression by host cells. Infiltration of ocular tumors by CD8+ T cells and their expression of IFNγ were equivalent in splenectomized and nonsplenectomized mice. Perforin expression and nitric oxide production were not required for rejection of intraocular tumors.Conclusion These data suggest a model of ocular tumor regression in splenectomized mice in which CD8+ T cells express IFNγ to induce nitric oxide‐independent tumoricidal activity within intratumoral macrophages. Therefore, restoring tumoricidal activity in intratumoral macrophages is critical for CD8+ T cell mediated elimination of ocular tumors

Targeting regulatory T cells

Cancers express tumor-associated antigens that should elicit immune response to antagonize the tumor growth, but spontaneous immune rejection of established cancer is rare, suggesting an immunosuppressive environment hindering host antitumor immunity. Among the specific and active tumor-mediated mechanisms, CD4(+)CD25(high) T regulatory cells (Treg) are important mediators of active immune evasion in cancer. In this review, we will discuss Treg subpopulations and the mechanisms of their suppressive functions. Treg depletion improves endogenous antitumor immunity and the efficacy of active immunotherapy in animal models for cancer, suggesting that inhibiting Treg function could also improve the limited successes of human cancer immunotherapy. We will also discuss specific strategies for devising effective cancer immunotherapy targeting Treg.

Adipose tissue-derived PAI-1: A molecular link for thrombo-inflammatory disease states?

Adipose tissue (particularly the visceral adipose tissue of the omentum) was long thought to be a passive, fat-storing cell clump; however, many years ago this view became out-dated. Numerous studies made us aware of the actual character of this contour-determining part of our body: Adipose tissue is considered to be a true organ capable of producing multiple types of hormones, proand anti-inflammatory mediators such as adipokines and other components that are relevant for metabolic control and vascular homeostasis. No wonder that fat tissue-derived factors are dynamically involved in obesity-associated diseases, play an important part in insulin resistance or metabolic syndrome, and are relevant control elements of the cardiovascular system (1). Adipokines constitute a heterogenous group of macromolecules and are divided into those produced by fat cells (such as leptin or adiponectin) and those released by non-fat cells, including several interleukins, tumour necrosis factor (TNF)-α as well as plasminogen activator inhibitor-1 (PAI-1) (2, 3). Moreover, the repertoire of adipokines, particularly when released under stimulatory/inflammatory conditions, may differ considerably between omental and subcutaneous fat tissue. Thus, adipose tissuederived factors may act in a paracrine fashion at the interface with other organs or tissues, as was proposed for the fat–bone relationship (4). Against this background, in this issue of Thrombosis and Haemostasis, Ekstrom et al. (5) provide experimental evidence in humans for a potential cross-talk between an acute inflammatory situation (such as open heart surgery in a small group of patients) and fat. This situation lead to a significant stimulation of PAI-1 gene expression in omental adipose tissue, accompanied by increased plasma levels of PAI-1 antigen over several hours during the post-operative period (5). Consequently, the authors propose that such inflammation-provoked elevated PAI-1 levels would diminish the t-PAmediated fibrinolytic potential in these patients, resulting in an increased risk of myocardial infarction. As the origin of chronically elevated PAI-1 levels in situations of spontaneous arterial thrombosis or early vein graft rejection is largely unknown, this first study in human subjects offers a promising approach to define mechanistic relations between adipose tissue and other disturbed organs with regard to the thrombo-inflammatory axis. Yet, one should be careful to over-interpret these findings (as already indicated by the authors), since several aspects may limit the conclusions of this small study. Further experimental work is required to clarify the following issues: (a) Although the elevation in PAI-1 antigen may also imply increased PAI-1 activity and enhanced inhibition of t-PA (with an increase in t-PA-PAI-1 complexes), these parameters were not determined, indicating that an impact on fibrinolysis may be assumed but was not experimentally demonstrated; (b) in addition to omental tissue being a major origin of the protease inhibitor, elevated plasma PAI-1 levels could be derived from activated platelets as well, which would fit with the known inflammatory role of platelets in different vascular diseases (6); (c) although quantitatively less pronounced when compared to omental fat tissue, epicardial adipose tissue may very well be responsive to acute inflammatory situations during open heart surgery, particularly due to its close proximity to the organ under operation. Here, further analysis to clarify mechanisms of a paracrine crosstalk provoked by adipokines may be worth considering. And finally, (d) the authors did not mention any PAI-1 targeting approaches that may add to an anti-inflammatory regimen with antagonists towards interleukins or TNF-α; here, PAI-1 inhibitors may very well be suitable to limit the risk of vascular diseases, including myocardial infarction, in the post-operative period and beyond (7). Together with their first study in human patients the authors provide some clues for a thrombo-inflammatory connection between open heart surgery and increased PAI-1 production in adipose tissue. These initial findings may stimulate further translational investigations as to the potential role of adipokines and their direct or indirect contribution in thrombosis and haemostasis.

Spontaneous rejection of intradermally transplanted non-engineered tumor cells by neutrophils and macrophages from syngeneic strains of mice

It is not surprising that tumors arising spontaneously are rarely rejected by T cells, because in general they lack molecules to elicit a primary T-cell response. In fact, cytokine-engineered tumors can induce granulocyte infiltration leading to tumor rejection. In the present study, we i.d. injected seven kinds of non-engineered tumor cells into syngeneic strains of mice. Three of them (i.e. B16, KLN205, and 3LL cells) continued to grow, whereas four of them (i.e. Meth A, I-10, CL-S1, and FM3A cells) were spontaneously rejected after transient growth or without growth. In contrast to the i.d. injection of B16 cells into C57BL/6 mice, which induces infiltration of TAMs into the tumors, the i.d. injection of Meth A cells into BALB/c mice induced the invasion of cytotoxic inflammatory cells, but not of TAMs, into or around the tumors leading to an IFN-γ-dependent rejection. On day 5, the cytotoxic activity against the tumor cells reached a peak; and the effector cells were found to be neutrophils and macrophages. The i.d. Meth A or I-10 cell-immunized, but not non-immunized, mice rejected i.p.- or i.m.-transplanted Meth A or I-10 cells without growth, respectively. The main effector cells were CTLs; and there was no cross-sensitization between these two kinds of tumor cells, suggesting specific rejection of tumor cells by CTLs from i.d. immunized mice. These results indicate that infiltration of cytotoxic myeloid cells (i.e. neutrophils and macrophages, but not TAMs) into or around tumors is essential for their IFN-γ-dependent spontaneous rejection.

Spontaneous Regression of Highly Immunogenic Molluscum contagiosum Virus (MCV)-Induced Skin Lesions Is Associated with Plasmacytoid Dendritic Cells and IFN-DC Infiltration

Molluscum contagiosum virus (MCV) infection induces self-limiting cutaneous lesions in an immunocompetent host that can undergo spontaneous regression preceded by local inflammation. On histology, a large majority of MCV-induced lesions are characterized by islands of hyperplastic epithelium containing infected keratinocytes and surrounded by scarce inflammatory infiltrate. However, spontaneous regression has been associated with the occurrence of a dense inflammatory reaction. By histology and immunohistochemistry, we identified MCV-induced lesions showing a dense inflammatory infiltrate associated with cell death in keratinocytes (inflammatory Molluscum contagiosum (I-MC)). In I-MC, hyperplastic keratinocytes were highly immunogenic as demonstrated by the expression of major histocompatibility complex class I and II molecules. Immune cell infiltration consisted of numerous cytotoxic T cells admixed with natural killer cells and plasmacytoid dendritic cells (PDCs). Accordingly, a type I IFN signature associated with PDC infiltration was demonstrated in both keratinocytes and inflammatory cells. Among the latter, a cell population resembling IFN-DC (CD123(+)CD11c(+)CD16(+)CD14(+)MxA(+)) was identified in proximity to islands of apoptotic keratinocytes. In vitro-generated IFN-DCs expressed a strong cytotoxic signature, as demonstrated by high levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL). This study establishes a previously unreported model to underpin the role of innate immune cells in viral immune surveillance.