Over-expression of programmed death-ligand 1 and programmed death-1 on antigen-presenting cells as a predictor of organ dysfunction and mortality during early sepsis: a prospective cohort study / 世界急诊医学杂志（英文）

@#BACKGROUND: This study aimed to explore the changes of programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) expression on antigen-presenting cells (APCs) and evaluate their association with organ failure and mortality during early sepsis. METHODS: In total, 40 healthy controls and 198 patients with sepsis were included in this study. Peripheral blood was collected within the first 24 h after the diagnosis of sepsis. The expression of PD-L1 and PD-1 was determined on APCs, such as B cells, monocytes, and dendritic cells (DCs), by flow cytometry. Cytokines in plasma, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-6, IL-10, and IL-17A were determined by Luminex assay. RESULTS: PD-1 expression decreased significantly on B cells, monocytes, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs) as the severity of sepsis increased. PD-1 expression was also markedly decreased in non-survivors compared with survivors. In contrast, PD-L1 expression was markedly higher on mDCs, pDCs, and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors. The PD-L1 expression on APCs (monocytes and DCs) was weakly related to organ dysfunction and inflammation. The area under the receiver operating characteristic curve (AUC) of the PD-1 percentage of monocytes (monocyte PD-1%)+APACHE II model (0.823) and monocyte PD-1%+SOFA model (0.816) had higher prognostic value than other parameters alone. Monocyte PD-1% was an independent risk factor for 28-day mortality. CONCLUSION: The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs. PD-L1 in monocytes and DCs was weakly correlated with inflammation and organ dysfunction during early sepsis. The combination of SOFA or APACHE II scores with monocyte PD-1% could improve the prediction ability for mortality.

Structural Integrity and Cellular Viability of Cryopreserved Allograft Heart Valves in Right Ventricular Outflow Tract Reconstruction: Correlation of Histopathological Changes with Donor Characteristics and Preservation Times

Abstract Introduction: Cryopreserved allograft heart valves (CAHV) show longer event-free survival compared to other types of protheses. However, all patients develop early and/or late allograft failure. Negative predictors are clinical, and there is a lack of evidence whether they correspond with the microscopic structure of CAHV. We assessed histopathological signs of structural degeneration, degree of cellular preservation, and presence of antigen-presenting cells (APC) in CAHV and correlated the changes with donor clinical characteristics, cryopreservation times, and CAHV types and diameters. Methods: Fifty-seven CAHV (48 pulmonary, nine aortic) used for transplantation between November/2017 and May/2019 were included. Donor variables were age, gender, blood group, height, weight, and body surface area (BSA). Types and diameters of CAHV, cold ischemia time, period from decontamination to cryopreservation, and cryopreservation time were recorded. During surgery, arterial wall (n=56) and valvar cusp (n=20) samples were obtained from the CAHV and subjected to microscopy. Microscopic structure was assessed using basic staining methods and immunohistochemistry (IHC). Results: Most of the samples showed signs of degeneration, usually of mild degree, and markedly reduced cellular preservation, more pronounced in aortic CAHV, correlating with arterial APC counts in both basic staining and IHC. There was also a correlation between the degree of degeneration of arterial samples and age, height, weight, and BSA of the donors. These findings were independent of preservation times. Conclusion: CAHV show markedly reduced cellular preservation negatively correlating with the numbers of APC. More preserved CAHV may be therefore prone to stronger immune rejection.

Avances en la inmunopatogenia de la hepatitis autoinmune / Advances in the immunopathogenesis of autoimmune hepatitis

RESUMEN Introducción: en la hepatitis autoinmune los mecanismos inmunopatogénicos no están totalmente esclarecidos, múltiples son las investigaciones en este campo, con vistas a enriquecer los conocimientos y ampliar las opciones terapéuticas. Objetivo: sintetizar los conocimientos más recientes acerca de la inmunopatogenia de esta enfermedad. Material y Método: se efectúa una búsqueda exhaustiva de la bibliografía disponible en SciELO, ScienceDirect, Google Académico y PubMed, incluyendo artículos de revisión, estudios experimentales, clínicos, de cohorte y metaanálisis. Desarrollo: se explican los principales mecanismos de tolerancia central y periférica, así como el papel de las subpoblaciones linfoides, las citocinas y el microambiente en la patogenia de la enfermedad. Conclusiones: los avances en el conocimiento de la inmunopatogenia de la hepatitis autoinmune permiten una mejor comprensión de esta enfermedad y son el referente para el diseño de estrategias futuras de tratamiento.

ABSTRACT Introduction: Immunopathogenic mechanisms are not fully clarified in autoimmune hepatitis; there are many investigations in this field with a view to enriching knowledge and expanding therapeutic options. Objective: To synthesize the most recent knowledge about the immunopathogenesis of this disease. Material and Methods: An exhaustive search of the bibliography available in SciELO, ScienceDirect, Google Scholar and PubMed was carried out, including review articles, experimental, clinical, cohort and meta-analysis studies. Development: The main mechanisms of central and peripheral tolerance are explained, as well as the role of lymphoid subpopulations, cytokines and the microenvironment in the pathogenesis of the disease. Conclusions: Advances in the knowledge of the immunopathogenesis of autoimmune hepatitis allow a better understanding of this disease and are the referents in the design of future treatment strategies.

Research progress on immune mechanism of dry eye / 国际眼科杂志(Guoji Yanke Zazhi)

The dry eye is a common ocular surface disease caused by multiple factors with multiple pathogenesis. With the increasing morbidity of dry eye in our country year by year, dry eye has gradually attracted people's attention. The pathogenesis of dry eye is more complicated whose critical influencing factors include inflammation, corneal and conjunctival epithelial cell changes, tear film composition changes, corneal nerve changes, and meibomian gland dysfunction and so on. The tear film hypertonicity leads to the hypertonicity of the ocular surface epithelial cells, stimulating the cascade of inflammation, which is the most critical part among the pathogenesis of dry eye. A variety of inflammatory mediators and immune cells are involved in this process, and more and more people have reached a consensus that the dry eye is an antigen-specific autoimmune inflammatory disease and they are closely correlated with each. In clinical treatment, various anti-inflammatory drugs and drugs promoting tear secretion mark the rapid development of drug therapy for dry eye to some extent, but dry eye treatment is not only to improve symptoms, but to carry out treatment according to specific etiology. Recently, researches on the immune mechanism of dry eye have been increasing. This article reviewed on the immune progress of dry eye to realize the clinical significance and systematically understand the role of which in the occurrence and development of dry eye.

The generation of PD-L1 and PD-L2 in cancer cells: From nuclear chromatin reorganization to extracellular presentation

The immune checkpoint blockade (ICB) targeting on PD-1/PD-L1 has shown remarkable promise in treating cancers. However, the low response rate and frequently observed severe side effects limit its broad benefits. It is partially due to less understanding of the biological regulation of PD-L1. Here, we systematically and comprehensively summarized the regulation of PD-L1 from nuclear chromatin reorganization to extracellular presentation. In PD-L1 and PD-L2 highly expressed cancer cells, a new TAD (topologically associating domain) (chr9: 5,400,000-5,600,000) around CD274 and CD273 was discovered, which includes a reported super-enhancer to drive synchronous transcription of PD-L1 and PD-L2. The re-shaped TAD allows transcription factors such as STAT3 and IRF1 recruit to PD-L1 locus in order to guide the expression of PD-L1. After transcription, the PD-L1 is tightly regulated by miRNAs and RNA-binding proteins via the long 3'UTR. At translational level, PD-L1 protein and its membrane presentation are tightly regulated by post-translational modification such as glycosylation and ubiquitination. In addition, PD-L1 can be secreted via exosome to systematically inhibit immune response. Therefore, fully dissecting the regulation of PD-L1/PD-L2 and thoroughly detecting PD-L1/PD-L2 as well as their regulatory networks will bring more insights in ICB and ICB-based combinational therapy.

Bioresponsive immune-booster-based prodrug nanogel for cancer immunotherapy

The combination of chemotherapy and immunotherapy motivates a potent immune system by triggering immunogenic cell death (ICD), showing great potential in inhibiting tumor growth and improving the immunosuppressive tumor microenvironment (ITM). However, the therapeutic effectiveness has been restricted by inferior drug bioavailability. Herein, we reported a universal bioresponsive doxorubicin (DOX)-based nanogel to achieve tumor-specific co-delivery of drugs. DOX-based mannose nanogels (DM NGs) was designed and choosed as an example to elucidate the mechanism of combined chemo-immunotherapy. As expected, the DM NGs exhibited prominent micellar stability, selective drug release and prolonged survival time, benefited from the enhanced tumor permeability and prolonged blood circulation. We discovered that the DOX delivered by DM NGs could induce powerful anti-tumor immune response facilitated by promoting ICD. Meanwhile, the released mannose from DM NGs was proved as a powerful and synergetic treatment for breast cancer in vitro and in vivo, via damaging the glucose metabolism in glycolysis and the tricarboxylic acid cycle. Overall, the regulation of tumor microenvironment with DOX-based nanogel is expected to be an effectual candidate strategy to overcome the current limitations of ICD-based immunotherapy, offering a paradigm for the exploitation of immunomodulatory nanomedicines.

Mecanismos de evasión tumoral a la respuesta inmune / Mechanisms of tumor evasion to the immune response

El desarrollo del cáncer se determina por la capacidad proliferativa de las células tumorales y por presentar facultades invasoras y de metastatizar a tejidos distantes. La compleja relación de la patología con el sistema inmunitario facilita la evolución de la enfermedad, por lo que mediante esta bidireccionalidad, la célula cancerígena tiene la capacidad de escapar de la regulación del huésped, evadiendo la respuesta inmune antitumoral, mediante mecanismos intrínsecos y extrínsecos. El objetivo de este manuscrito es describir a cabalidad y de una forma actualizada dichos mecanismos, con la finalidad de generar un impacto tangible y mayor conocimiento en la comunidad médico-científica sobre la génesis de posibles nuevos diagnósticos y tratamientos específicos que busquen disminuir las estadísticas de tan letal enfermedad. Para la realización de este trabajo, se hizo uso de las plataformas y bases de datos de PubMed, Google Académico, Scielo y Elsevier, durante un período de dos meses, así como de libros especializados en inmunología e inmunopatología, y artículos publicados en los últimos cinco años. Esta revisión narrativa permite incentivar la investigación de rutas de comunicación intercelulares que puedan cumplir en un futuro, quizás no muy lejano, con este propósito

Cancer's development is determined by the proliferative capacity of tumor cells and by presenting invasive abilities and to metastasize to distant tissues. The complex relationship of this pathology with the immune system facilitates its natural evolution; thus, this bidirectionality allows cancer cells to escape from the host's regulation, evading antitumoral immune responses, through intrinsic and extrinsic mechanisms. The aim of this manuscript is to describe exhaustively, and in the most updated way possible, said mechanisms, with the objective of generating a tangible impact and more awareness the medical-scientific community, regarding the genesis of possible new and more specific diagnostic and treatment options that diminish this lethal disease's statistics. The information used to write this article was obtained from medical digital archives, including PubMed, Google Scholar, Scielo, and Elsevier, as well as specialized books in immunology and immunopathology, and articles published in the last five years. This narrative review encourages the investigation of intercellular communication routes that may be fulfilled, in the non-too distant future, for this purpose

Uptake and trafficking of different sized PLGA nanoparticles by dendritic cells in imiquimod-induced psoriasis-like mice model

Psoriasis is an autoimmune inflammatory disease, where dendritic cells (DCs) play an important role in its pathogenesis. In our previous work, we have demonstrated that topical delivery of curcumin-loaded poly (lactic-

The biology, function, and applications of exosomes in cancer

Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial-mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.

Microneedle-based devices for point-of-care infectious disease diagnostics

Recent infectious disease outbreaks, such as COVID-19 and Ebola, have highlighted the need for rapid and accurate diagnosis to initiate treatment and curb transmission. Successful diagnostic strategies critically depend on the efficiency of biological sampling and timely analysis. However, current diagnostic techniques are invasive/intrusive and present a severe bottleneck by requiring specialist equipment and trained personnel. Moreover, centralised test facilities are poorly accessible and the requirement to travel may increase disease transmission. Self-administrable, point-of-care (PoC) microneedle diagnostic devices could provide a viable solution to these problems. These miniature needle arrays can detect biomarkers in/from the skin in a minimally invasive manner to provide (near-) real-time diagnosis. Few microneedle devices have been developed specifically for infectious disease diagnosis, though similar technologies are well established in other fields and generally adaptable for infectious disease diagnosis. These include microneedles for biofluid extraction, microneedle sensors and analyte-capturing microneedles, or combinations thereof. Analyte sampling/detection from both blood and dermal interstitial fluid is possible. These technologies are in their early stages of development for infectious disease diagnostics, and there is a vast scope for further development. In this review, we discuss the utility and future outlook of these microneedle technologies in infectious disease diagnosis.

Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy: opportunities, challenges, and future development

Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy (PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are discussed. Moreover, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia utilization. Finally, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.

Role and mechanism of action of intrahepatic intrinsic antigen-presenting cells in regulating anti-hepatitis B virus immune response / 临床肝胆病杂志

The liver has a unique immune microenvironment, and the intrinsic antigen-presenting cells in the liver interact with each other and form a network to accurately regulate the homeostasis between liver immune tolerance and immune response. During hepatitis B virus (HBV) infection, on the one hand, the intrahepatic intrinsic antigen-presenting cells induce immune tolerance to help the virus escape immune clearance and thus result in persistent infection; on the other hand, the maturation and activation of the intrahepatic intrinsic antigen-presenting cells can also mediate effective anti-HBV immune response to achieve virus clearance. This article elaborates on the research advances in the role and mechanism of action of intrahepatic intrinsic antigen-presenting cells in regulating immune response against HBV infection.

Protective role of berberine on ulcerative colitis through modulating enteric glial cells-intestinal epithelial cells-immune cells interactions

Ulcerative colitis (UC) manifests as an etiologically complicated and relapsing gastrointestinal disease. The enteric nervous system (ENS) plays a pivotal role in rectifying and orchestrating the inflammatory responses in gut tract. Berberine, an isoquinoline alkaloid, is known as its anti-inflammatory and therapeutic effects in experimental colitis. However, little research focused on its regulatory function on ENS. Therefore, we set out to explore the pathological role of neurogenic inflammation in UC and the modulating effects of berberine on neuro-immune interactions. Functional defects of enteric glial cells (EGCs), with decreased glial fibrillary acidic protein (GFAP) and increased substance P expression, were observed in DSS-induced murine UC. Administration of berberine can obviously ameliorate the disease severity and restore the mucosal barrier homeostasis of UC, closely accompanying by maintaining the residence of EGCs and attenuating inflammatory infiltrations and immune cells overactivation. , berberine showed direct protective effects on monoculture of EGCs, bone marrow-derived dendritic cells (BMDCs), T cells, and intestinal epithelial cells (IECs) in the simulated inflammatory conditions. Furthermore, berberine could modulate gut EGCs-IECs-immune cell interactions in the co-culture systems. In summary, our study indicated the EGCs-IECs-immune cell interactions might function as a crucial paradigm in mucosal inflammation and provided an infusive mechanism of berberine in regulating enteric neurogenic inflammation.

Red blood cell membrane-camouflaged nanoparticles: a novel drug delivery system for antitumor application

Erythrocytes (red blood cells, RBCs) are the most abundant circulating cells in the blood and have been widely used in drug delivery systems (DDS) because of their features of biocompatibility, biodegradability, and long circulating half-life. Accordingly, a "camouflage" comprised of erythrocyte membranes renders nanoparticles as a platform that combines the advantages of native erythrocyte membranes with those of nanomaterials. Following injection into the blood of animal models, the coated nanoparticles imitate RBCs and interact with the surroundings to achieve long-term circulation. In this review, the biomimetic platform of erythrocyte membrane-coated nano-cores is described with regard to various aspects, with particular focus placed on the coating mechanism, preparation methods, verification methods, and the latest anti-tumor applications. Finally, further functional modifications of the erythrocyte membranes and attempts to fuse the surface properties of multiple cell membranes are discussed, providing a foundation to stimulate extensive research into multifunctional nano-biomimetic systems.

Human Immunity Against Campylobacter Infection

Campylobacter is a worldwide foodborne pathogen, associated with human gastroenteritis. The efficient translocation of Campylobacter and its ability to secrete toxins into host cells are the 2 key features of Campylobacter pathophysiology which trigger inflammation in intestinal cells and contribute to the development of gastrointestinal symptoms, particularly diarrhoea, in humans. The purpose of conducting this literature review is to summarise the current understanding of: i) the human immune responses involved in the elimination of Campylobacter infection and ii) the resistance potential in Campylobacter against these immune responses. This review has highlighted that the intestinal epithelial cells are the preliminary cells which sense Campylobacter cells by means of their cell-surface and cytosolic receptors, activate various receptors-dependent signalling pathways, and recruit the innate immune cells to the site of inflammation. The innate immune system, adaptive immune system, and networking between these systems play a crucial role in bacterial clearance. Different cellular constituents of Campylobacter, mainly cell membrane lipooligosaccharides, capsule, and toxins, provide protection to Campylobacter against the human immune system mediated killing. This review has also identified gaps in knowledge, which are related to the activation of following during Campylobacter infection: i) cathelicidins, bactericidal permeability-increasing proteins, chemokines, and inflammasomes in intestinal epithelial cells; ii) siglec-7 receptors in dendritic cell; iii) acute phase proteins in serum; and iv) T-cell subsets in lymphoid nodules. This review evaluates the existing literature to improve the understanding of human immunity against Campylobacter infection and identify some of the knowledge gaps for future research.

Preparation of PLGA wrinkled microparticles for bovine serum albumin immobilization / 国际生物医学工程杂志

Objective To develop a method for the synthesis of poly [lactic-co-(glycolic acid)] (PLGA) wrinkled microparticles,and to investigate their immobilization on model protein,i.e.bovine serum albumin (BSA),so as to provide a scientific basis for the preparation of artificial antigen-presenting cells (aAPCs).PLGA wrinkled microparticles were prepared by double emulsion-solvent evaporation method combined with porogen NH4HCO3.The effects of PLGA relative molecular mass,porogen mass concentration and double emulsion stirring speed on the morphology of PLGA micro particles were investigated.The PLGA wrinkled particles were incubated with different concentrations of FITC-conjugated BSA (FITC-BSA).The levels of BGA loaded with PLGA wrinkled particles were detected by laser scanning confocal microscopy,flow cytometry and diquinoline formic acid.The effect of the loading process on the BSA structure was analyzed by circular dichroism spectrometer.Results The molecular weight of 5 000 was the optimized parameters for PLGA wrinkled microparticles preparation.The morphology of PLGA wrinkled particles could be maintained when the mass concentration of porogen NH4HCO3 was less than 10 g/L.When the mixing speed of multiple emulsion increased from 400 r/min to 3 600 r/min,the average particle size of PLGA wrinkled particles decreased from 35 μm to 9 μm,which meets the size requirement of artificial aAPCs.The fluorescence intensity of PLGA wrinkled particles was directly proportional to the concentration of BSA,and the BSA structure was not affected by the adsorption of BSA by the PLGA wrinkled particles.Conclusion The relative molecular mass of PLGA has an important influence on the morphology of the particles.PLGA with a relative molecular mass of 5 000 can be used to prepare particles with a wrinkled topology,which can load proteinaceous macromolecules and maintain protein activity.This result has potential applications in artificial aAPCs.

Fundamental role of dendritic cells in inducing Th2 responses

A mysterious puzzle in immunology is how the immune system decides what types of immune response to initiate against various stimuli. Although much is known about control of T helper 1 (Th1) and Th17 responses, the mechanisms that initiate Th2 responses remain obscure. Antigen-presenting cells, particularly dendritic cells (DCs), are mandatory for the induction of a Th cell response. Numerous studies have documented the organizing role of DCs in this process. The present review summarizes the fundamental roles of DCs in inducing Th2 responses.

Dendritic Cell Dysfunction in Patients with End-stage Renal Disease

End-stage renal disease (ESRD) with immune disorder involves complex interactions between the innate and adaptive immune responses. ESRD is associated with various alterations in immune function such as a reduction in polymorphonuclear leukocyte bactericidal activity, a suppression of lymphocyte proliferative response to stimuli, and a malfunction of cell-mediated immunity at the molecular level. ESRD also increases patients' propensity for infections and malignancies as well as causing a diminished response to vaccination. Several factors influence the immunodeficiency in patients with ESRD, including uremic toxins, malnutrition, chronic inflammation, and the therapeutic dialysis modality. The alteration of T-cell function in ESRD has been considered to be a major factor underlying the impaired adaptive cellular immunity in these patients. However, cumulative evidence has suggested that the immune defect in ESRD can be caused by an Ag-presenting dendritic cell (DC) dysfunction in addition to a T-cell defect. It has been reported that ESRD has a deleterious effect on DCs both in terms of their number and function, although the precise mechanism by which DC function becomes altered in these patients is unclear. In this review, we discuss the effects of ESRD on the number and function of DCs and propose a possible molecular mechanism for DC dysfunction. We also address therapeutic approaches to improve immune function by optimally activating DCs in patients with ESRD.

Immunodetection of myeloid and plasmacytoid dendritic cells in mammary carcinomas of female dogs / Imunodetecção de células dendríticas mieloides e plasmocitoides nos carcinomas mamários em cadelas

Dendritic cells have attracted great interest from researchers as they may be used as targets of tumor immune evasion mechanisms. The main objective of this study was to evaluate the relationship between the dendritic cells (DCs) subpopulation in simple type mammary carcinomas in female dogs. Two groups of samples were used: the control group consisted of 18 samples of mammary tissue without changes and the tumor group with 26 simple type mammary carcinomas. In these groups, we evaluated the immunodetection of immature and mature myeloid DCs, plasmacytoid DCs and MHC-II. In mammary tumor, mature myeloid DCs predominated in the peritumoral region, while immature myeloid DCs and plasmacytoid DCs were evident in the intratumoral region. Immunostaining of MHC-II was visualized in mammary acini (control group), in tumor cells and inflammatory infiltration associated with tumors. The comparison between the control and tumor groups showed a statistically significant difference between immature myeloid DCs, mature myeloid DCs and plasmacytoid DCs. The immunodetection of MHC-II was not significant when comparing the groups. The predominance of immature DCs in the tumor group is possibly related to an inefficient immune response, promoting the development and survival of tumor cells. The presence of plasmacytoid DCs in the same group suggests a worse prognosis for female dogs with mammary tumors. Therefore, the ability of differentiation of canine dendritic cells could be influenced by neoplastic cells and by the tumor microenvironment...

As células dendríticas têm despertado grande interesse dos pesquisadores, pois podem ser alvo dos mecanismos de evasão imune do tumor. O objetivo principal deste estudo foi avaliar a relação entre as subpopulações de células dendríticas (DCs) nos carcinomas mamários do tipo simples em cadelas. Dois grupos de amostras foram utilizados, o grupo controle composto por 18 amostras de tecido mamário sem alterações e o grupo tumor com 26 carcinomas mamários do tipo simples. Nestes grupos foram avaliadas a imunodetecção de DCs mieloides imaturas e maduras, DCs plasmocitoides e de MHC-II. Nas mamas com tumor, as DCs mieloides maduras predominaram na região peritumoral, enquanto que as DCs mieloides imaturas e as DCs plasmocitoides foram evidentes na região intratumoral. A imunomarcação do MHC-II foi visualizada nos ácinos mamários (grupo controle), nas células tumorais e no infiltrado inflamatório associado aos tumores. Na comparação entre os grupos controle e tumor houve diferença estatística significativa entre as DCs mieloides imaturas, DCs mieloides maduras e DCs plasmocitoides. A imunodetecção de MHC-II não foi significativa na comparação entre os grupos. A predominância de DCs imaturas no grupo tumor, possivelmente, está relacionada com uma resposta imune ineficiente, favorecendo o desenvolvimento e a sobrevivência das células tumorais. A presença das DCs plasmocitoides no mesmo grupo sugere um prognóstico pior para cadelas com tumores de mama. Portanto, a capacidade de diferenciação das células dendríticas caninas poderia ser influenciada pelas células neoplásicas e pelo microambiente tumoral...

Inhibitory effects of mesenchymal stem cells on antigen-specific T cells and antigen presenting cells in experimental autoimmune uveitis / 中华实验眼科杂志

Background Our previous studies found that mesenchymal stem cells (MSCs) can ameliorate experimental autoimmune uveitis (EAU) and reduce tissue impairment.Its mechanism is still pending.Objective This study was performed to investigate the effects of MSCs on T cell subsets and antigen presenting cells (APCs) in EAU rats.Methods MSCs were isolated from bone marrow of six male Wistar rats and cultured by plastic adherence method.Twelve female Lewis rats were assigned randomly into MSCs group and PBS group.EAU rat model was induced by immunization with 200 μl emulsion containing 30 μg interphotoreceptor retinoid-binding protein (IRBP) 1177-1191 polypeptide fragment R16 and complete Freund adjuvant (CFA).The eye manifestations of the rats were observed and scored under the slit lamp microscope after modeling.The R16-immunized rats were treated intravenously with 5×106/ml MSCs for 3 consecutive days from day 9 to 11 after modeling in the MSCs group,and the equivalent volume of PBS was used with the same way in the PBS group.Fifteen days after modeling,the spleens and draining lymph nodes were collected to evaluate the proportion of interferon-γ (IFN-γ) positive CD4+ T cells,interleukin-17 (IL-17)positive CD4+ T cells and forkhead helix transcription factor p3 (Foxp3) positive CD4+ T cells by flow cytometry.The T cells and APCs from the different groups were cocultured and divided into PBS cocultured group,MSCs cocultured group, PBS-MSCs cross-cultured group and MSCs-PBS cross-cultured group under the stimulation of R16 at the concentration of 0.3,1.0 or 10.0 μg/ml, and the proliferation indexes of the T cells in different groups were assayed by 5-bromodeoxyuridine (BrdU) Elisa kit.The use of experimental animals complied with the regulations on the management of experimental animals promulgated by the national science and technology commission.Results The ocular surface inflammatory scores of 11,12,13 and 14 days after modeling in the MSCs group were significantly lower than that in the PBS group (t=3.825,5.100,4.250,3.400, all at P＜0.05).Compared with the PBS group, the proportions of IFN-γ positive CD4+ T cells in spleen and draining lymph notes were considerably decreased in the MSCs group (t =5.651,4.376, both at P＜0.05) , so were the IL-17+ CD4+ T cells (t =3.300,4.925, both at P＜0.05).However,the proportions of Foxp3 + CD4+ T cells in spleen and draining lymph notes were statistically raised in the MSCs group compared with the PBS group (t =-5.172,-2.825,both at P＜0.05).The proliferation index of T cells increased with the rise of R16 dose in the PBS cocultured group, and the proliferation indexes were all declined in the MSCs cocultured group compared with the PBS cocultured group under the stimulation of 0.3,1.0 and 10.0 μg/ml of R16 (P =0.027,0.000,0.000).In addition, significant reduces of proliferation indexes of T cells were seen in the PBS-MSCs cross-cultured group and MSCs-PBS cross-cultured group in comparison with the PBS cocultured group when stimulated by 1.0 μg/ml and 10.0 μg/ml R16 (1.0 μg/ml R16 : P =0.001,0.000;10.0 μg/ml R16:P=0.000,0.000).Conclusions MSCs can ameliorate EAU by inhibiting the functions of antigen-specific T cells and APCs and up-regulating T regulatory cells in EAU rats.