RESUMEN
1. This study determined the effects of (E)-3-(2-(4-(3-(2,4-dimethoxyphenyl)acryloyl)phenoxy)ethoxy)-5,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-4H-chromen-4-one (EDACO) on the differentiation of Gaoyou duck embryonic osteoclasts cultured in vitro. 2. Bone marrow mononuclear cells (BM-MNC) were collected from 23-d-old Gaoyou duck embryos and induced by macrophage colony-stimulating factor and receptor activator of nuclear factor κB ligand in the presence of EDACO at different concentrations (i.e. 10, 20, 40, 80 and 160 µM). Tartrate-resistant acid phosphatase (TRAP) staining and resorption ability determination were conducted. 3. Results suggested that EDACO suppressed the shaping of positive multinucleated cells and the number of TRAP-positive cells in the 20, 40, 80 and 160 µM EDACO groups was significantly decreased (P < 0.05 or P < 0.01). Besides, the absorption activity of differentiated duck embryonic osteoclasts was significantly inhibited (P < 0.05) in both 80 and 160 µM EDACO groups. 4. Overall, EDACO can inhibit the differentiation of BM-MNC into mature osteoclasts in duck embryos.1.
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Diferenciación Celular/efectos de los fármacos , Patos/embriología , Embrión no Mamífero/efectos de los fármacos , Flavonoides/metabolismo , Osteoclastos/fisiología , Animales , Células Cultivadas , Embrión no Mamífero/embriologíaRESUMEN
OBJECTIVE: The aim of this study was to examine the efficacy and safety of second-line immunotherapy and targeted treatment in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: From January 2000 to January 2023, ProQuest, PubMed, Web of Science, Scopus, Embase, and the Cochrane Library databases were searched for randomized controlled trials (RCTs) using immunotherapy or targeted therapy as second-line therapy for mid-to-advanced stages of HCC. Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) are all examples of measures of success. RESULTS: This analysis included twenty Randomized Clinical Trials (RCTs) from phases II and III. Collective data revealed better OS with immunotherapy (HR = 0.79; 95% CI: 0.67, 0.93 vs. 0.85; 95% CI: 0.78, 0.92), while the targeted therapy played a more effective role in PFS (0.67; 95% CI: 0.56, 0.81). Also, the second-line immunotherapy had a lower odds ratio of AEs of grades 3-5 than the targeted therapy did (OR = 1.75; 95% CI = 0.89, 3.46). CONCLUSIONS: Overall, it appears that targeted medication and immunotherapy as a second-line treatment strategy have generally improved substantially, as well as progression-free survival for patients with mid-to-advanced HCC. Although it is difficult to judge their efficiency, the occurrences of AEs were greater in targeted therapy compared to immunotherapy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/etiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Inmunoterapia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/etiologíaRESUMEN
LIGHT was recently described as a member of the tumor necrosis factor (TNF) 'superfamily'. We have isolated a mouse homolog of human LIGHT and investigated its immunoregulatory functions in vitro and in vivo. LIGHT has potent, CD28-independent co-stimulatory activity leading to T-cell growth and secretion of gamma interferon and granulocyte-macrophage colony-stimulating factor. Gene transfer of LIGHT induced an antigen-specific cytolytic T-cell response and therapeutic immunity against established mouse P815 tumor. In contrast, blockade of LIGHT by administration of soluble receptor or antibody led to decreased cell-mediated immunity and ameliorated graft-versus-host disease. Our studies identify a previously unknown T-cell co-stimulatory pathway as a potential therapeutic target.
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Enfermedad Injerto contra Huésped/inmunología , Proteínas de la Membrana/inmunología , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Secuencia de Aminoácidos , Animales , Antígenos CD18/inmunología , Línea Celular , Clonación Molecular , Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Humanos , Inmunidad Celular , Interferón gamma/biosíntesis , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones , Modelos Biológicos , Datos de Secuencia Molecular , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Transfección , Células Tumorales Cultivadas , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Serotype M1 group A Streptococcus strains cause epidemic waves of human infections long thought to be mono- or pauciclonal. The gene encoding an extracellular group A Streptococcus protein (streptococcal inhibitor of complement) that inhibits human complement was sequenced in 1,132 M1 strains recovered from population-based surveillance of infections in Canada, Finland and the United States. Epidemic waves are composed of strains expressing a remarkably heterogeneous array of variants of streptococcal inhibitor of complement that arise very rapidly by natural selection on mucosal surfaces. Thus, our results enhance the understanding of pathogen population dynamics in epidemic waves and infectious disease reemergence.
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Antígenos Bacterianos , Proteínas de la Membrana Bacteriana Externa , Proteínas Bacterianas/genética , Proteínas Inactivadoras de Complemento/genética , Brotes de Enfermedades , Infecciones Estreptocócicas/epidemiología , Streptococcus pyogenes/genética , Animales , Variación Antigénica/genética , Canadá , Proteínas Portadoras/genética , Cromosomas Bacterianos/genética , Ensayo de Actividad Hemolítica de Complemento , Finlandia , Ratones , Membrana Mucosa/microbiología , Faringitis/microbiología , Filogenia , Streptococcus pyogenes/inmunología , Streptococcus pyogenes/aislamiento & purificación , Estados UnidosRESUMEN
Lymphotoxin (LT)alpha is expressed by activated T cells, especially CD4(+) T helper type 1 cells, and by activated B and natural killer cells, but the functions of this molecule in vivo are incompletely defined. We have previously shown that follicular dendritic cell (FDC) clusters and germinal centers (GCs) are absent from the peripheral lymphoid tissues of LTalpha-deficient (LTalpha-/-) mice. LTalpha-/- mice produce high levels of antigen-specific immunoglobulin (Ig)M, but very low levels of IgG after immunization with sheep red blood cells. We show here that LTalpha-expressing B cells are essential for the recovery of primary, secondary, and memory humoral immune responses in LTalpha-/- mice. It is not necessary for T cells to express LTalpha to support these immune functions. Importantly, LTalpha-expressing B cells alone are essential and sufficient for the formation of FDC clusters. Once these clusters are formed by LTalpha-expressing B cells, then LTalpha-deficient T cells can interact with B cells to generate GCs and productive class-switched antibody responses. Thus, B cells themselves provide an essential signal that induces and maintains the lymphoid microenvironment essential for GC formation and class-switched Ig responses.
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Linfocitos B/fisiología , Células Dendríticas/metabolismo , Proteínas de Homeodominio , Linfotoxina-alfa/fisiología , Animales , Células de la Médula Ósea/inmunología , Linfocitos T CD4-Positivos/metabolismo , Quimera/genética , Proteínas de Unión al ADN/genética , Células Dendríticas/citología , Centro Germinal/metabolismo , Inmunidad/inmunología , Inmunohistoquímica , Linfotoxina-alfa/genética , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T/genética , Transducción de Señal/fisiología , Bazo/citología , Trasplante Isogénico/inmunologíaRESUMEN
LTalpha-deficient (LTalpha-/-) mice show altered splenic microarchitecture. This includes loss of normal B cell-T cell compartmentalization, of follicular dendritic cell (FDC) clusters, and of ability to form germinal centers (GC). LTalpha-/- mice immunized with sheep red blood cells (SRBC) produced high levels of antigen-specific IgM but no IgG in either primary or secondary responses, demonstrating failure of Ig class switching. This inability to switch to IgG could have been due to the altered splenic microarchitecture in these mice. Alternatively, it could have been due directly to a requirement for LTalpha expression by lymphocytes cooperating in the antibody response. To investigate this, we performed reciprocal spleen cell transfers. When irradiated LTalpha-/- mice were reconstituted with wild-type splenocytes and immunized immediately with SRBC, splenic microarchitecture remained disturbed and there was no IgG response. In contrast, when irradiated wild-type animals received splenocytes from LTalpha-/- mice, follicle structure and a strong IgG response were retained. These data indicate that LTalpha-deficient B cells and T cells have no intrinsic defect in ability to generate an IgG response. Rather, the altered microenvironment characteristic of LTalpha-/- mice appears to result in impaired ability to switch to a productive IgG response. To investigate whether prolonged expression of LTalpha could alter the structure and function of spleen follicles, reciprocal bone marrow (BM) transplantation was performed. Six weeks after reconstitution of LTalpha-/- mice with wild-type BM, spleen follicle structure was partially restored, with return of FDC clusters and GC. B cell/T cell compartmentalization remained abnormal and white pulp zones were small. This was accompanied by restoration of IgG response to SRBC. Reconstitution of wild-type mice with LTalpha-/- BM resulted in loss of FDC clusters and GC, and loss of the IgG response, although compartmentalized B cell and T cell zones were largely retained. Thus, defective IgG production is not absolutely associated with abnormal B cell and T cell compartmentalization. Rather, expression of LTalpha supports the maturation of spleen follicle structure, including the development and maintenance of FDC clusters, which supports Ig class switching and an effective IgG response.
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Inmunoglobulina G/biosíntesis , Linfotoxina-alfa/fisiología , Bazo/ultraestructura , Animales , Trasplante de Médula Ósea , Células Dendríticas/ultraestructura , Eritrocitos/inmunología , Centro Germinal/ultraestructura , Inmunoglobulina M/biosíntesis , Ratones , Ratones Endogámicos C57BLRESUMEN
Although several cytokines, including tumor necrosis factor (TNF), can promote the growth of dendritic cells (DCs) in vitro, the cytokines that naturally regulate DC development and function in vivo have not been well defined. Here, we report that membrane lymphotoxin (LT), instead of TNF, regulates the migration of DCs in the spleen. LTalpha(-/-) mice, lacking membrane LTalpha/beta and LTalpha(3), show markedly reduced numbers of DCs in the spleen. Unlike wild-type mice and TNF(-/-) mice that have densely clustered DCs in the T cell zone and around the marginal zone, splenic DCs in LTalpha(-/-) mice are randomly distributed. The reduced number of DCs in lymphoid tissues of LTalpha(-/-) mice is associated with an increased number of DCs in nonlymphoid tissues. The number of splenic DCs in LTalpha(-/-) mice is restored when additional LT-expressing cells are provided. Blocking membrane LTalpha/beta in wild-type mice markedly diminishes the accumulation of DCs in lymphoid tissues. These data suggest that membrane LT is an essential ligand for the presence of DCs in the spleen. Mice deficient in TNF receptor, which is the receptor for both soluble LTalpha(3) and TNF-alpha(3) trimers, have normal numbers of DCs. However, LTbetaR(-/-) mice show reduced numbers of DCs, similar to the mice lacking membrane LT alpha/beta. Taken together, these results support the notion that the signaling via LTbetaR by membrane LTalpha/beta is required for the presence of DCs in lymphoid tissues.
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Células Dendríticas/inmunología , Células Dendríticas/fisiología , Tejido Linfoide/citología , Tejido Linfoide/inmunología , Linfotoxina-alfa/fisiología , Animales , Células de la Médula Ósea/inmunología , Recuento de Células , Movimiento Celular/inmunología , Movimiento Celular/fisiología , Femenino , Prueba de Cultivo Mixto de Linfocitos , Receptor beta de Linfotoxina , Linfotoxina-alfa/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Fenotipo , Receptores del Factor de Necrosis Tumoral/deficiencia , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/fisiología , Transducción de Señal , Solubilidad , Bazo/citología , Bazo/inmunología , Factor de Necrosis Tumoral alfa/deficiencia , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Lymph nodes (LNs) are important sentinal organs, populated by circulating lymphocytes and antigen-bearing cells exiting the tissue beds. Although cellular and humoral immune responses are induced in LNs by antigenic challenge, it is not known if LNs are essential for acquired immunity. We examined immune responses in mice that lack LNs due to genetic deletion of lymphotoxin ligands or in utero blockade of membrane lymphotoxin. We report that LNs are absolutely required for generating contact hypersensitivity, a T cell-dependent cellular immune response induced by epicutaneous hapten. We show that the homing of epidermal Langerhans cells in response to hapten application is specifically directed to LNs, providing a cellular basis for this unique LN function. In contrast, the spleen cannot mediate contact hypersensitivity because antigen-bearing epidermal Langerhans cells do not access splenic white pulp. Finally, we formally demonstrate that LNs provide a unique environment essential for generating this acquired immune response by reversing the LN defect in lymphotoxin-alpha(-/)- mice, thereby restoring the capacity for contact hypersensitivity.
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Dermatitis por Contacto/etiología , Ganglios Linfáticos/fisiología , Linfotoxina-alfa/fisiología , Animales , Movimiento Celular , Células Dendríticas/fisiología , Femenino , Células de Langerhans/fisiología , Linfotoxina beta , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3HRESUMEN
One striking feature of spontaneous autoimmune diabetes is the prototypic formation of lymphoid follicular structures within the pancreas. Lymphotoxin (LT) has been shown to play an important role in the formation of lymphoid follicles in the spleen. To explore the potential role of LT-mediated microenvironment in the pathogenesis of insulin-dependent diabetes mellitus (IDDM), an LTbeta receptor-immunoglobulin fusion protein (LTbetaR-Ig) was administered to nonobese diabetic mice. Early treatment with LTbetaR-Ig prevented insulitis and IDDM, suggesting that LT plays a critical role in the insulitis development. LTbetaR-Ig treatment at a late stage of the disease also dramatically reversed insulitis and prevented diabetes. Moreover, LTbetaR-Ig treatment prevented the development of IDDM by diabetogenic T cells in an adoptive transfer model. Thus, LTbetaR-Ig can disassemble the well established lymphoid microenvironment in the islets, which is required for the development and progression of IDDM.
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Diabetes Mellitus Tipo 1/prevención & control , Islotes Pancreáticos/patología , Receptores del Factor de Necrosis Tumoral/fisiología , Animales , Moléculas de Adhesión Celular , Femenino , Inmunoglobulinas/fisiología , Receptor beta de Linfotoxina , Proteínas de la Membrana/fisiología , Ratones , Ratones Endogámicos NOD , Mucoproteínas/fisiología , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
In mice deficient in either lymphotoxin alpha (LT-alpha) or type I tumor necrosis factor receptor (TNFR-I), organized clusters of follicular dendritic cells (FDC) and germinal centers (GC) are absent from the spleen. We investigated the role of LT-alpha and TNFR-I in the establishment of spleen FDC and GC structure by using reciprocal bone marrow (BM) transfer. When LT-alpha-deficient mice were reconstituted with wild-type BM, FDC organization and the ability to form GC were restored, indicating that the LT-alpha-expressing cells required to establish organized FDC are derived from BM. The role of LT-alpha in establishing organized FDC structure was further investigated by the transfer of complement receptor 1 and 2 (CR1/2)-deficient BM cells into LT-alpha-deficient mice. Organized FDC were identified with both the FDC-M1 and anti-CR1 monoclonal antibodies in these BM-chimeric mice, indicating that these cells were derived from the LT-alpha-deficient recipient. Thus, expression of LT-alpha in the BM-derived cells, but not in the non-BM-derived cells, is required for the maturation of FDC from non-BM precursor cells. In contrast, when TNFR-I-deficient mice were reconstituted with wild-type BM, they showed no detectable FDC clusters or GC formation. This indicates that TNFR-I expression on non-BM-derived cellular components is necessary for the establishment of these lymphoid structures. TNFR-I-deficient BM was able to restore FDC organization and GC formation in LT-alpha-deficient mice, indicating that formation of these structures does not require TNFR-I expression on BM-derived cells. The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-alpha-expressing BM-derived cells and by TNFR-I-expressing non-BM-derived cells.
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Células de la Médula Ósea/citología , Células Dendríticas/citología , Linfotoxina-alfa/fisiología , Receptores del Factor de Necrosis Tumoral/fisiología , Animales , Trasplante de Médula Ósea , Centro Germinal/citología , Técnicas para Inmunoenzimas , Ratones , Ratones Noqueados , Ratones Transgénicos , Bazo/citologíaRESUMEN
One major objective of tumor immunologists is to prevent cancer development in individuals at high risk. (TG.AC x C57BL/6)F1 mice serve as a model for testing the feasibility of this objective. The mice carry in the germline a mutant ras oncogene that has an arginine at codon 12 instead of glycine present in the wild-type, and after physical (wounding) or chemical promotion, these mice have a high probability for developing papillomas that progress to cancer. Furthermore, F1 mice immunized with Arg(12) mutant ras peptide in complete Freund's adjuvant (CFA) develop T cells within 10 d that proliferate in vitro on stimulation with the Arg(12) mutant ras peptide. Within 14 d, these mice have delayed-type hypersensitivity to the peptide. Immunization with CFA alone or with a different Arg(12) mutant ras peptide in CFA induced neither response. To determine the effect of immunization on development of tumors, mice immunized 3 wk earlier were painted on the back with phorbol 12-myristate 13-acetate every 3 d for 8 wk. The time of appearance and the number of papillomas were about the same in immunized and control mice, but the tumors grew faster and became much larger in the mice immunized with the Arg(12) mutant ras peptide. Thus, the immunization failed to protect against growth of papillomas. The peptide-induced CD4(+) T cells preferentially recognized the peptide but not the native mutant ras protein. On the other hand, mice immunized with Arg(12) mutant ras peptide and bearing papillomas had serum antibodies that did bind native mutant ras protein. Together, these studies indicate that active immunization of cancer-prone individuals may result in immune responses that fail to eradicate mutant oncogene-expressing tumor cells, but rather induce a remarkable enhancement of tumor growth.
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Arginina/inmunología , Glicina/inmunología , Proteína Oncogénica p21(ras)/inmunología , Papiloma/inmunología , Mutación Puntual , Animales , Anticuerpos Antineoplásicos/inmunología , Arginina/genética , Vacunas contra el Cáncer/inmunología , Femenino , Glicina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Oncogénica p21(ras)/genética , Papiloma/fisiopatología , Péptidos/inmunología , VacunaciónRESUMEN
Objective: To investigate the expression of gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3) on cleft palate in C57BL/6J mice induced by 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). Methods: Sixty C57BL/6J pregnant mice on gestation day (GD) 10.5 were divided into two groups: one group was administered through gastric tubes one dose of 28 µg/kg TCDD (experimental group) and the other group was administered through gastric tubes one dose of 5.6 ml/kg corn oil (control group). Embryos were removed by cesarean section from pregnant mice during the palatal formation stage (GD 13.5-17.5) and the palatal tissue studied in morphological and histological observation. The relative mRNA and protein expression of GABRB3 was measured by real-time quantitative PCR and Western blotting. Localization of GABRB3 protein was measured by immunohistochemistry or immunofluorescence. Results: The incidence of cleft palate at GD17.5 was 100% in experimental group and there was no cleft palate occurred in the control group (0); elevation of palatine processes in experimental group was completed on GD15.5 which was clearly delayed by a day compared with that in control group. On GD14.5-GD17.5, the mRNA expression (0.561±0.073, 0.728±0.104, 0.782±0.137, 0.686±0.145) and protein expression (0.288±0.013, 0.404±0.017, 0.399±0.012, 0.307±0.010) in the experimental group were significantly lower than the control group mRNA expression (0.818±0.088, 0.865±0.086, 1.021±0.054, 1.163±0.179) and protein expression (0.481±0.017, 0.456±0.009, 0.474±0.016, 0.529±0.015)(P<0.05). Immunohistochemistry and immunofluorescence showed that GABRB3 was mainly expressed in the mesenchymal cells and medial edge epithelium. Conclusions: TCDD delayed palatal shelf elevation and eventually led to cleft palate may be associated with a decrease in GABRB3. GABRB3 may play an important role in the elevation and fusion phases of the palate development.
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Fisura del Paladar , Dibenzodioxinas Policloradas , Receptores de GABA-A , Animales , Cesárea , Fisura del Paladar/inducido químicamente , Fisura del Paladar/metabolismo , Femenino , Ratones , Ratones Endogámicos C57BL , Hueso Paladar , Dibenzodioxinas Policloradas/toxicidad , Embarazo , Receptores de GABA-A/metabolismo , Ácido gamma-AminobutíricoRESUMEN
OBJECTIVE: Osteosarcoma is a malignant bone tumor with high incidence. The prognosis of osteosarcoma is very poor when it is diagnosed with metastasis. Numerous studies have demonstrated that aberrant expressions of microRNAs are involved in cancer initiation and development. However, the potential role of miR-214 in osteosarcoma remains largely unrevealed. The current study investigated the relationship between the miR-214 and TNF receptor-associated factor 3 (TRAF3) in osteosarcoma tissues and cell lines. We also aimed to evaluate the potential roles of miR-214 on the occurrence and metastasis in osteosarcoma and verify its effect on the regulation of TRAF3. PATIENTS AND METHODS: The miR-214 expression and TRAF3 expression in osteosarcoma tissue samples and cell line were measured using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Followed by transfection assays, transwell assay was conducted to detect the migration and invasion abilities of osteosarcoma cells. Subsequently, Western blotting and luciferase reporter assay were performed in osteosarcoma cells to confirm the target of miR-214. RESULTS: The results showed that miR-214 expression levels were significantly increased not only in osteosarcoma tissues but also in osteosarcoma cell lines as compared with adjacent normal tissues and matched cell lines, respectively. On the contrary, the TRAF3 expression levels in osteosarcoma tissues and cell lines were frequently decreased compared to the control group. Moreover, TRAF3 was identified as a direct target of miR-214 and the inverse relationship between them was also observed in osteosarcoma tissues. Additionally, we found that miR-214 restoration could significantly promote osteosarcoma cell invasion and migration via targeting TRAF3. CONCLUSIONS: MicroRNA-214 functioned as an oncogene in osteosarcoma via targeting TRAF3, which may provide new insights into osteosarcoma prevention and treatment.
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Neoplasias Óseas/metabolismo , MicroARNs/biosíntesis , Oncogenes/fisiología , Osteosarcoma/metabolismo , Factor 3 Asociado a Receptor de TNF/biosíntesis , Anciano , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Femenino , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Osteosarcoma/genética , Osteosarcoma/patología , Factor 3 Asociado a Receptor de TNF/genéticaRESUMEN
Costimulatory molecules on antigen-presenting cells (APCs) play an important role in T cell activation and expansion. However, little is known about the surface molecules involved in direct T-T cell interaction required for their activation and expansion. LIGHT, a newly discovered TNF superfamily member (TNFSF14), is expressed on activated T cells and immature dendritic cells. Here we demonstrate that blockade of LIGHT activity can reduce anti-CD3-mediated proliferation of purified T cells, suggesting that T cell-T cell interaction is essential for this proliferation. To test the in vivo activity of T cell-derived LIGHT in immune homeostasis and function, transgenic (Tg) mice expressing LIGHT in the T cell lineage were generated. LIGHT Tg mice have a significantly enlarged T cell compartment and a hyperactivated peripheral T cell population. LIGHT Tg mice spontaneously develop severe autoimmune disease manifested by splenomegaly, lymphadenopathy, glomerulonephritis, elevated autoantibodies, and severe infiltration of various peripheral tissues. Furthermore, the blockade of LIGHT activity ameliorates the severity of T cell-mediated diseases. Collectively, these findings establish a crucial role for this T cell-derived costimulatory ligand in T cell activation and expansion; moreover, the dysregulation of T cell-derived LIGHT leads to altered T cell homeostasis and autoimmune disease.
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Enfermedades Autoinmunes/etiología , Proteínas de la Membrana/fisiología , Linfocitos T/fisiología , Factor de Necrosis Tumoral alfa/fisiología , Animales , Linaje de la Célula , Citocinas/biosíntesis , Homeostasis , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis TumoralRESUMEN
The gene AML1/PEBP2 alphaB encodes the alpha subunit of transcription factor PEBP2/CBF and is essential for the establishment of fetal liver hematopoiesis. Rearrangements of AML1 are frequently associated with several types of human leukemia. Three types of AML1 cDNA isoforms have been described to date; they have been designated AML1a, AML1b, and AML1c. All of these isoforms encode the conserved-Runt domain, which harbors the DNA binding and heterodimerization activities. We have identified a new isoform of the AML1 transcript, termed AML1 deltaN, in which exon 1 is directly connected to exon 4 by alternative splicing. The AML1 deltaN transcript was detected in various hematopoietic cell lines of lymphoid to myeloid cell origin, as revealed by RNase protection and reverse transcriptase PCR analyses. The protein product of AML1 deltaN lacks the N-terminal region of AML1, including half of the Runt domain, and neither binds to DNA nor heterodimerizes with the beta subunit. However, AML1 deltaN was found to interfere with the transactivation activity of PEBP2, and the molecular region responsible for this activity was identified. Stable expression of AML1 deltaN in 32Dcl3 myeloid cells blocked granulocytic differentiation in response to granulocyte colony-stimulating factor. These results suggest that AML1 deltaN acts as a modulator of AML1 function and serves as a useful tool to dissect the functional domains in the C-terminal region of AML1.
Asunto(s)
Granulocitos/citología , Hematopoyesis , Factores de Transcripción/genética , Activación Transcripcional , Secuencia de Aminoácidos , Secuencia de Bases , Diferenciación Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Proteínas de Unión al ADN/genética , Dimerización , Proteínas de Drosophila , Factor Estimulante de Colonias de Granulocitos/farmacología , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-ets , ARN Mensajero/genética , Eliminación de Secuencia , Relación Estructura-Actividad , Factores de Transcripción/metabolismo , Células Tumorales CultivadasRESUMEN
Objective: To know the drug resistance of Acinetobacter baumannii (AB) in wound of children with traffic injury and its relationship with antibiotic use. Methods: Wound exudate of 226 children with traffic injury admitted to our unit from January 2010 to December 2015 were collected. API bacteria identification panels and fully automatic microbiological identification system were used to identify pathogens. Kirby-Bauer paper disk diffusion method was used to detect the drug resistance of pathogens to 18 antibiotics including amoxycillin/clavulanic acid, piperacillin/tazobactam, and imipenem. The detection situation of pathogen of children's wounds and drug resistance of detected AB to 18 antibiotics in each year were collected. Forty-six AB positive children (2 children excluded) were divided into imipenem-resistant group (IR, n=19) and non imipenem-resistant group (NIR, n=25) according to whether AB was 100% resistant to imipenem. Drug resistance of AB in wounds of children to 18 antibiotics in two groups was compared. The antibiotic use of AB positive children was collected, and the antibiotic use intensity of children in two groups was compared. Data were processed with Fisher's exact test, independent sample t test, and corrected t test. Results: (1) The detection rates of pathogen in wounds of children in 2010-2015 were 95.6% (43/45), 89.8% (53/59), 81.3% (148/182), 81.1% (107/132), 81.6% (120/147), and 77.5% (62/80), respectively, showing a trend of decreasing year by year. A total of 665 strains and 75 pathogens were detected, and the top 5 pathogens with detection rate from high to low were AB, Pseudomonas aeruginosa, Enterobacter cloacae, Staphylococcus epidermidis, and Escherichia coli, respectively. (2) Drug resistance rates of AB to amoxycillin/clavulanic acid, cefazolin, aztreonam, and piperacillin were all 100%, while AB was 100% sensitive to polymyxin, and the total drug resistance rates of AB to the other 13 antibiotics were all above 50%. The drug resistance rate of AB in wounds of children to piperacillin was higher than that to piperacillin/tazobactam in 2010-2015. (3) Except for imipenem, amoxycillin/clavulanic acid, cefazolin, aztreonam, piperacillin, and polymyxin, the drug resistance rates of AB in wounds of children in group IR to the other 12 antibiotics were higher than those in group NIR (with P values below 0.01). Besides, AB strains in wounds of children in group IR were completely resistant to at least 3 kinds of antibiotics including carbapenems, aminoglycosides, and quinolones, so that they were multidrug-resistant AB. (4) A total of 32 antibiotics were used in 46 AB positive children, and the 10-top-used antibiotics with use intensity from high to low were cefoperazone/sulbactam, piperacillin/tazobactam, cefazolin, imipenem, ceftizoxime, amoxycillin/clavulanate, ceftazidime, cefepime, amoxycillin/sulbactam, and cefmetazole, respectively. (5) Twenty-one antibiotics were not included in the comparison because of their small amount of usage. For the other 11 antibiotics, only the use intensity of metronidazole of children in two groups was statistically different (t=-3.104, P<0.05). There was no statistically significant difference in total antibiotic use of children in two groups (t=0.368, P>0.05). Conclusions: AB is one of the main pathogens in wounds of children with traffic injury, with high drug resistant rate. The high intensity of antibiotic use may lead to its drug resistance. In this study, the top-used antibiotics were in accord with AB resistant drugs, indicating a lack of normative use of antibiotics.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Antibacterianos/farmacología , Quemaduras/complicaciones , Quemaduras/microbiología , Farmacorresistencia Bacteriana , Infección de Heridas/microbiología , Acinetobacter baumannii/aislamiento & purificación , Antibacterianos/uso terapéutico , Quemaduras/tratamiento farmacológico , Niño , Infección Hospitalaria/microbiología , Humanos , Pruebas de Sensibilidad Microbiana , Ácido Penicilánico/análogos & derivados , Piperacilina , Combinación Piperacilina y Tazobactam , Infección de Heridas/tratamiento farmacológicoRESUMEN
In advanced cancer, current conventional therapies or immunotherapies cannot eradicate all tumor cells for most patients. Integration of these two treatments for synergistic effects could eradicate more tumor cells and increase the overall survival rates. However, since how conventional treatments impact on immune system remains unclear, proper integration is still a challenge. Intensive chemo/radiotherapy may impair ongoing immune responses, while lower intensity of therapy might not kill enough tumor cells, both leading to tumor relapse. Current understanding of mechanisms of resistance to conventional and targeted cancer therapies has focused on cell intrinsic pathways that trigger DNA damage/repair or signaling pathways related to cell growth. Recent reports show that host T cells properly primed against tumor-specific antigens after conventional treatment, which can integrate with direct cytotoxic effects induced by radiation or chemotherapy to profoundly control tumors. Following cytotoxic anticancer treatment, tumor-derived DAMPs (damage-associated molecular patterns) can be sensed by innate cells, which drives type I interferon production for cross-priming of CD8+ T cells. Some types and protocols of chemotherapy or radiation can increase tumor-infiltrating lymphocytes that overcome resistance to immunotherapy. As such, a deeper understanding of the immune mechanisms of conventional and targeted cancer therapies will lead toward novel combinatorial anticancer strategies with improved clinical benefit.
Asunto(s)
Inmunoterapia/métodos , Neoplasias/terapia , Animales , Anticuerpos/inmunología , Terapia Combinada , Humanos , Terapia Molecular Dirigida , Neoplasias/inmunología , Neoplasias/patologíaAsunto(s)
Tejido Linfoide/inmunología , Proteínas Nucleares , Proteínas de Unión al ARN , Factores de Transcripción/genética , Animales , Modelos Animales de Enfermedad , Rechazo de Injerto/inmunología , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Receptor beta de Linfotoxina , Linfotoxina-alfa/genética , Ratones , Ratones Noqueados , Ratones Mutantes , Mutación , Receptores del Factor de Necrosis Tumoral/deficiencia , Receptores del Factor de Necrosis Tumoral/genética , Trasplante HomólogoRESUMEN
Using an immunogenic nonmetastatic murine mammary adenocarcinoma (D1-DMBA-3) induced in BALB/c mice by dimethylbenzanthracene, we have previously shown that splenocytes from tumor bearers have depressed lymphocyte responses to mitogens and antigens, including tumor-associated antigens. In addition, they display decreased natural killer and T-cell cytotoxic activities. Macrophages from tumor-bearing mice appear to be responsible for the suppression of T- and B-cell responses to concanavalin A, lipopolysaccharide, and tumor-associated antigens observed in tumor bearers. The appearance of these macrophages in the spleen tightly parallels the progressive growth of the tumor and the concomitant immunosuppression. Simultaneously high levels of macrophage progenitors were observed in blood, bone marrow, lung, and liver. A significant increase of colony-stimulating activity of the granulocyte-macrophage lineage was detected in the sera from tumor-bearing mice. Higher levels of this colony-stimulating activity (CSA) were detected in tumor cystic fluid as compared with the levels in serum. A tumor cell line established in vitro from the D1-DMBA-3 in vivo tumor produces high levels of a factor with CSA in culture supernatant fluids. Partial purification of the CSA from the tumor cell line supernatants was achieved using CentriCell ultrafiltration and SephacrylS-300 chromatography. These studies revealed that the molecular weight of the colony-stimulating-like factor is 32,000 to 35,000. The morphology of the colonies obtained in cultures using this factor is similar to that of the colonies that develop in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) but not with macrophage colony-stimulating factor (M-CSF). CSA from tumor cell supernatants was neutralized by antiserum to GM-CSF but not with anti-M-CSF or anti-granulocyte colony-stimulating factor (G-CSF). Macrophages from bone marrow or peritoneal exudates from normal mice cultured with tumor supernatant for 2 to 3 days strongly inhibit normal splenocyte responses to concanavalin A and lipopolysaccharide. The data suggest that the tumor releases a GM-CSF that alters the hemopoietic system and induces or expands macrophages, which exert a suppressive function on the immune system of tumor-bearing mice.
Asunto(s)
Factores Estimulantes de Colonias/fisiología , Sustancias de Crecimiento/fisiología , Macrófagos/inmunología , Neoplasias Mamarias Experimentales/inmunología , Animales , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Tolerancia Inmunológica , Factor Estimulante de Colonias de Macrófagos , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos BALB C , Peso Molecular , Proteínas Recombinantes/farmacología , Linfocitos T Reguladores/fisiologíaRESUMEN
It is imperative to research the treatment strategy for infections caused by multi-drug resistant (MDR) bacteria, as there are increasing reports showing that more and more patients are decimated by the infections of MDR bacteria and the development of antimicrobial drugs is in downturn. Current researches mainly focus on the following three aspects: developing new antimicrobial agents with the aid of basic scientific achievements in finding new antibacterial targets, achieving antimicrobial purpose by specific lysis of host bacteria with phages of high specificity, and killing bacteria potently by destroying its cytomembrane using broad-spectrum antimicrobial peptides.