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1.
Immunity ; 41(6): 960-72, 2014 Dec 18.
Artículo en Inglés | MEDLINE | ID: mdl-25526309

RESUMEN

Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell-autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently. In vitro migration assays showed that active GzmB was released from migrating cytotoxic lymphocytes and enabled chemokine-driven movement through basement membranes. Finally, proteomic analysis demonstrated that GzmB cleaved basement membrane constituents. Our results highlight an important role for GzmB in expediting cytotoxic lymphocyte diapedesis via basement membrane remodeling.


Asunto(s)
Virus de la Ectromelia/inmunología , Ectromelia Infecciosa/inmunología , Granzimas/metabolismo , Células Asesinas Naturales/fisiología , Linfocitos T Citotóxicos/fisiología , Animales , Membrana Basal/metabolismo , Movimiento Celular/genética , Células Cultivadas , Quimiocinas/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Granzimas/genética , Células Asesinas Naturales/virología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteolisis , Linfocitos T Citotóxicos/virología , Migración Transendotelial y Transepitelial/genética
2.
Int J Mol Sci ; 23(19)2022 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-36232524

RESUMEN

Methamphetamine (METH) is a highly addictive drug abused by millions of users worldwide, thus becoming a global health concern with limited management options. The inefficiency of existing treatment methods has driven research into understanding the mechanisms underlying METH-induced disorders and finding effective treatments. This study aims to understand the complex interactions of the gastrointestinal-immune-nervous systems following an acute METH dose administration as one of the potential underlying molecular mechanisms concentrating on the impact of METH abuse on gut permeability. Findings showed a decreased expression of tight junction proteins ZO-1 and EpCAm in intestinal tissue and the presence of FABP-1 in sera of METH treated mice suggests intestinal wall disruption. The increased presence of CD45+ immune cells in the intestinal wall further confirms gut wall inflammation/disruption. In the brain, the expression of inflammatory markers Ccl2, Cxcl1, IL-1ß, TMEM119, and the presence of albumin were higher in METH mice compared to shams, suggesting METH-induced blood-brain barrier disruption. In the spleen, cellular and gene changes are also noted. In addition, mice treated with an acute dose of METH showed anxious behavior in dark and light, open field, and elevated maze tests compared to sham controls. The findings on METH-induced inflammation and anxiety may provide opportunities to develop effective treatments for METH addiction in the future.


Asunto(s)
Trastornos Relacionados con Anfetaminas , Estimulantes del Sistema Nervioso Central , Metanfetamina , Albúminas/metabolismo , Trastornos Relacionados con Anfetaminas/metabolismo , Animales , Ansiedad , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Molécula de Adhesión Celular Epitelial/metabolismo , Inflamación/metabolismo , Metanfetamina/metabolismo , Metanfetamina/toxicidad , Ratones
3.
Molecules ; 26(6)2021 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-33809496

RESUMEN

BACKGROUND: Carnosine is a dipeptide molecule (ß-alanyl-l-histidine) with anti-inflammatory, antioxidant, anti-glycation, and chelating properties. It is used in exercise physiology as a food supplement to increase performance; however, in vitro evidence suggests that carnosine may exhibit anti-cancer properties. METHODS: In this study, we investigated the effect of carnosine on breast, ovarian, colon, and leukemic cancer cell proliferation. We further examined U937 promonocytic, human myeloid leukemia cell phenotype, gene expression, and cytokine secretion to determine if these are linked to carnosine's anti-proliferative properties. RESULTS: Carnosine (1) inhibits breast, ovarian, colon, and leukemic cancer cell proliferation; (2) upregulates expression of pro-inflammatory molecules; (3) modulates cytokine secretion; and (4) alters U937 differentiation and phenotype. CONCLUSION: These effects may have implications for a role for carnosine in anti-cancer therapy.


Asunto(s)
Antineoplásicos/farmacología , Carnosina/farmacología , Dipéptidos/farmacología , Neoplasias/tratamiento farmacológico , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocinas/genética , Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Neoplasias/genética , Células U937
4.
Biol Chem ; 400(12): 1603-1616, 2019 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-31091192

RESUMEN

In human α1-antitrypsin deficiency, homozygous carriers of the Z (E324K) mutation in the gene SERPINA1 have insufficient circulating α1-antitrypsin and are predisposed to emphysema. Misfolding and accumulation of the mutant protein in hepatocytes also causes endoplasmic reticulum stress and underpins long-term liver damage. Here, we describe transgenic zebrafish (Danio rerio) expressing the wildtype or the Z mutant form of human α1-antitrypsin in hepatocytes. As observed in afflicted humans, and in rodent models, about 80% less α1-antitrypsin is evident in the circulation of zebrafish expressing the Z mutant. Although these zebrafish also show signs of liver stress, they do not accumulate α1-antitrypsin in hepatocytes. This new zebrafish model will provide useful insights into understanding and treatment of α1-antitrypsin deficiency.


Asunto(s)
Hepatocitos/metabolismo , Modelos Animales , Deficiencia de alfa 1-Antitripsina/metabolismo , alfa 1-Antitripsina/metabolismo , Animales , Células CHO , Línea Celular , Cricetulus , Humanos , Mutación , Pez Cebra , alfa 1-Antitripsina/genética , Deficiencia de alfa 1-Antitripsina/genética
5.
Int J Mol Sci ; 20(15)2019 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-31374832

RESUMEN

Chronic inflammation can lead to tumour initiation and progression. Vitamin B complex has the ability to regulate the immune response and, therefore, inflammation but many of the mechanistic and molecular processes involved in this regulation are still not fully understood. This study sought to determine some of these processes by studying the effects of vitamin B2 (riboflavin) B6 (pyridoxine) and B9 (folic acid) on un-differentiated pro-monocytic lymphoma cells in regard to their ability to alter the proliferation, migration, apoptosis, cytokines and expression levels of programmed death ligand 1. We show that vitamin B2, B6 and B9, on pro-monocytic lymphoma cells exerted an anti-tumorigenic effect. This data could form the basis for future studies in using vitamin B supplementation to reduce cancer cell growth in vivo.


Asunto(s)
Anticarcinógenos/farmacología , Ácido Fólico/farmacología , Linfoma/tratamiento farmacológico , Riboflavina/farmacología , Vitamina B 6/farmacología , Adulto , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Humanos , Linfoma/patología , Masculino
6.
Immunol Cell Biol ; 95(10): 884-894, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28722018

RESUMEN

Intracellular serpins are proposed to inactivate proteases released from lysosome-related organelles into the host cell interior, preventing cell death. Serpinb9 opposes the immune cytotoxic protease, granzyme B, and in a number of settings protects cells against granzyme B-mediated cell death. Using a knockout mouse line engineered to express green fluorescent protein under the serpbinb9 promoter, we demonstrate that serpinb9 is vital for host survival during Ectromelia virus infection by maintaining both mature natural killer NK) cells, and activated CD8+ T cells. Serpinb9 expression parallels granzyme B expression within both populations during infection. Maturing serpinb9-null NK cells exhibit higher levels of granzyme B-mediated apoptosis during infection; hence there are fewer mature NK cells, and these cells also have lower cytotoxic potential. Thus the serpinb9-granzyme B axis is important for homeostasis of both major cytotoxic effector cell populations.


Asunto(s)
Granzimas/antagonistas & inhibidores , Células Asesinas Naturales/inmunología , Proteínas de la Membrana/farmacología , Infecciones por Poxviridae/inmunología , Poxviridae/inmunología , Serpinas/farmacología , Animales , Muerte Celular , Supervivencia Celular , Homeostasis , Humanos , Espacio Intracelular , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
7.
Pharmacol Res ; 120: 60-67, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28302577

RESUMEN

Methamphetamine (METH) is a powerful central nervous system stimulant which elevates mood, alertness, energy levels and concentration in the short-term. However, chronic use and/or at higher doses METH use often results in psychosis, depression, delusions and violent behavior. METH was formerly used to treat conditions such as obesity and attention deficit hyperactivity disorder, but now is primarily used recreationally. Its addictive nature has led to METH abuse becoming a global problem. At a cellular level, METH exerts a myriad of effects on the central and peripheral nervous systems, immune system and the gastrointestinal system. Here we present how these effects might be linked and their potential contribution to the pathogenesis of neuropsychiatric disorders. In the long term, this pathway could be targeted therapeutically to protect people from the ill effects of METH use. This model of METH use may also provide insight into how gut, nervous and immune systems might break down in other conditions that may also benefit from therapeutic intervention.


Asunto(s)
Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Tracto Gastrointestinal/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Metanfetamina/farmacología , Animales , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/efectos adversos , Deluciones/inducido químicamente , Depresión/inducido químicamente , Humanos , Metanfetamina/administración & dosificación , Metanfetamina/efectos adversos , Psicosis Inducidas por Sustancias/etiología
8.
Int J Mol Sci ; 18(6)2017 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-28594344

RESUMEN

Encephalitogenic T cells are heavily implicated in the pathogenesis of multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system. Their stimulation is triggered by the formation of a trimolecular complex between the human leukocyte antigen (HLA), an immunodominant myelin basic protein (MBP) epitope, and the T cell receptor (TCR). We detail herein our studies directed towards the rational design and synthesis of non-peptide mimetic molecules, based on the immunodominant MBP83-96 epitope that is recognized by the TCR in complex with HLA. We focused our attention on the inhibition of the trimolecular complex formation and consequently the inhibition of proliferation of activated T cells. A structure-based pharmacophore model was generated, in view of the interactions between the TCR and the HLA-MBP83-96 complex. As a result, new candidate molecules were designed based on lead compounds obtained through the ZINC database. Moreover, semi-empirical and density functional theory methods were applied for the prediction of the binding energy between the proposed non-peptide mimetics and the TCR. We synthesized six molecules that were further evaluated in vitro as TCR antagonists. Analogues 15 and 16 were able to inhibit to some extent the stimulation of T cells by the immunodominant MBP83-99 peptide from immunized mice. Inhibition was followed to a lesser degree by analogues 17 and 18 and then by analogue 19. These studies show that lead compounds 15 and 16 may be used for immunotherapy against MS.


Asunto(s)
Mimetismo Biológico , Diseño de Fármacos , Mapeo Epitopo , Epítopos de Linfocito T/química , Proteína Básica de Mielina/química , Fragmentos de Péptidos/química , Receptores de Antígenos de Linfocitos T/química , Secuencia de Aminoácidos , Animales , Técnicas de Química Sintética , Simulación por Computador , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/metabolismo , Femenino , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Ratones , Modelos Moleculares , Proteína Básica de Mielina/inmunología , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/farmacología , Unión Proteica , Conformación Proteica , Receptores de Antígenos de Linfocitos T/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/metabolismo
9.
Acta Biochim Biophys Sin (Shanghai) ; 48(4): 334-41, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26893144

RESUMEN

Colorectal cancer (CRC) is a major health problem worldwide. It is often diagnosed late due to its asymptomatic nature. As with all cancers, an immune reaction is involved; however, in CRC, it is unknown if this immune response is favorable or unfavorable for disease progression. In this study, the immune response in mesenteric lymph nodes (MLNs) and Peyer's patches was investigated during development of CRC in an orthotopic mouse model. CRC was induced by injecting CT26 cells into the cecum wall of BALB/c mice. Flow cytometry was used to analyze leukocyte populations involved in tumor immunity in MLNs and Peyer's patches. Cryostat sections for immunohistochemistry were prepared from the caecum and colon from CRC-induced and sham-operated animals. Cytokines produced by mouse CT26 cell line were measuredin vitroandin vivo Significant increases in the number of CD8(+)/TCR(+)and CD49b(+)/TCR(-)(natural killer) cells were found in MLNs and Peyer's patches in the CRC group. In addition, γδT cells were present in the lamina propria of the colon tissues from sham-operated mice, but absent in the colon tissues from mice with CRC. Immunohistochemical analysis of tumorous tissues showed eosinophil, CD69(+)T cell, and CD11b(+)cell infiltration. Bothin vitroandin vivoCT26 tumor cells were interleukin (IL)-6 positive. In addition, tumor-infiltrating CD45(+)cells were also IL-6 positive. In summary, the kinetics of the immune response to CRC and the key effector lymphocytes that are implicated in tumor immunity are demonstrated. Furthermore, IL-6 is a key cytokine present within the tumor microenvironment.


Asunto(s)
Neoplasias Colorrectales/patología , Interleucina-6/metabolismo , Leucocitos/citología , Microambiente Tumoral , Animales , Línea Celular Tumoral , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/metabolismo , Citocinas/metabolismo , Xenoinjertos , Humanos , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ganglios Linfáticos Agregados/inmunología , Ganglios Linfáticos Agregados/patología
10.
Am J Pathol ; 183(1): 49-59, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23669344

RESUMEN

A homozygous mutation of SERPINB6, a gene encoding an intracellular protease inhibitor, has recently been associated with post-lingual, autosomal-recessive, nonsyndromic hearing loss in humans (DFNB91). Herein, we describe the physiological changes underlying SERPINB6 deficiency by analyzing mutant mice in which the orthologous gene is replaced by enhanced green fluorescent protein. SERPINB6A is present in the neurosensory epithelium, lateral wall, and spiral limbus of the cochlea, with highest levels in the inner and outer hair cells of the organ of Corti, cells lining the inner sulcus, and supporting cells distributed along the epithelial gap junction layer to the outer sulcus. Measurements of hearing thresholds in these mice demonstrated age-related hearing loss in all homozygous-null, but not heterozygous, mice. Hearing impairment was first detected at 3 weeks of age, affecting only high frequencies before spreading to other frequencies as the mice aged. The defect is associated with progressive cellular degeneration within the cochlea. This begins with the hair cells, then involves the primary auditory neurons, and, finally, the fibrocytes in the lateral wall. These findings establish these mutant mice as a suitable model system to elucidate how SERPINB6 deficiency causes deafness in humans.


Asunto(s)
Pérdida Auditiva Sensorineural/metabolismo , Serpinas/deficiencia , Factores de Edad , Animales , Biomarcadores/metabolismo , Cóclea/metabolismo , Cóclea/patología , Pérdida Auditiva Sensorineural/patología , Ratones , Ratones Noqueados , Órgano Espiral/metabolismo , Órgano Espiral/patología , Serpinas/metabolismo
11.
Inflamm Bowel Dis ; 28(8): 1229-1243, 2022 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-35380670

RESUMEN

BACKGROUND: The autonomic nervous system (ANS) is thought to play a critical role in the anti-inflammatory reflex pathway in acute colitis via its interaction with the spleen and colon. Inflammation in the intestine is associated with a blunting of vagal signaling and increased sympathetic activity. As a corollary, methods to restore sympatho-vagal balance are being investigated as therapeutic strategies for the treatment of intestinal inflammation. Nevertheless, it is indefinite whether these autonomic signaling adaptations in colitis are detrimental or beneficial to controlling intestinal inflammation. In this study, models of moderate and severe chronic colitis are utilized to resolve the correlations between sympatho-vagal signaling and the severity of intestinal inflammation. METHODS: Spleens and colons were collected from Winnie (moderate colitis), Winnie-Prolapse (severe colitis), and control C57BL/6 mice. Changes to the size and histomorphology of spleens were evaluated. Flow cytometry was used to determine the expression of adrenergic and cholinergic signaling proteins in splenic B and T lymphocytes. The inflammatory profile of the spleen and colon was determined using a RT-PCR gene array. Blood pressure, heart rate, splanchnic sympathetic nerve and vagus nerve activity were recorded. RESULTS: Spleens and colons from Winnie and Winnie-Prolapse mice exhibited gross abnormalities by histopathology. Genes associated with a pro-inflammatory response were upregulated in the colons from Winnie and further augmented in colons from Winnie-Prolapse mice. Conversely, many pro-inflammatory markers were downregulated in the spleens from Winnie-Prolapse mice. Heightened activity of the splanchnic nerve was observed in Winnie but not Winnie-Prolapse mice. Conversely, vagal nerve activity was greater in Winnie-Prolapse mice compared with Winnie mice. Splenic lymphocytes expressing α1 and ß2 adrenoreceptors were reduced, but those expressing α7 nAChR and producing acetylcholine were increased in Winnie and Winnie-Prolapse mice. CONCLUSIONS: Sympathetic activity may correlate with an adaptive mechanism to reduce the severity of chronic colitis. The Winnie and Winnie-Prolapse mouse models of moderate and severe chronic colitis are well suited to examine the pathophysiology of progressive chronic intestinal inflammation.


In this study we use mouse models of moderate and severe colitis to resolve the relationship between autonomic and neuroimmune signaling with inflammation. Increased expression of cholinergic markers on immune cells correlated with an anti-inflammatory profile in the spleen, consistent with activation of the splenic cholinergic anti-inflammatory pathway in mice with spontaneous chronic colitis. However, enhanced sympathetic signaling occurred in mice with a less severe phenotype of colitis, which could represent an adaptive mechanism to mitigate the progression of intestinal inflammation.


Asunto(s)
Colitis , Animales , Colitis/patología , Modelos Animales de Enfermedad , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Prolapso , Nervio Vago
12.
PLoS One ; 16(3): e0247492, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33690618

RESUMEN

Plant polyphenols have an array of health benefits primarily thought to be related to their high content of anti-oxidants. These are commonly undervalued and knowledge of their biological properties have grown exponentially in the last decade. Polyphenol-rich sugarcane extract (PRSE), a natural extract from sugar cane, is marketed as high in anti-oxidants and polyphenols, but its anti-cancer activity has not been reported previously. We show that, PRSE exerts anti-cancer properties on a range of cancer cells including human (LIM2045) and mouse (MC38, CT26) colon cancer cells lines; human lung cancer (A549), human ovarian cancer (SKOV-3), pro-monocytic human leukemia (U937) and to mouse melanoma (B16) cell lines; whereas no effects were noted on human breast (ZR-75-1) and human colon (HT29) cancer cell lines, as well as to human normal colon epithelial cell line (T4056). Anti-proliferative effects were shown to be mediated via alteration in cytokines, VEGF-1 and NF-κB expression.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Extractos Vegetales/farmacología , Polifenoles/farmacología , Saccharum/química , Células A549 , Animales , Antiinflamatorios/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Citocinas/metabolismo , Células HT29 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , FN-kappa B/metabolismo , Células U937
13.
Biomed Res Int ; 2019: 4650695, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30906773

RESUMEN

PURPOSE: Oxaliplatin is a platinum-based chemotherapeutic agent demonstrating significant antitumor efficacy. Unlike conventional anticancer agents which are immunosuppressive, oxaliplatin has the capacity to stimulate immunological effects in response to the presentation of damage associated molecular patterns (DAMPs) elicited upon cell death. However, the effects of oxaliplatin treatment on systemic immune responses remain largely unknown. Aims of this study were to investigate the effects of oxaliplatin treatment on the proportions of (1) splenic T cells, B cells, macrophages, pro-/anti-inflammatory cytokines, gene expression of splenic cytokines, chemokines, and mediators; (2) double-positive and single-positive CD4+ and CD8+ T thymocytes; (3) bone-marrow hematopoietic stem and progenitor cells. METHODS: Male BALB/c mice received intraperitoneal injections of oxaliplatin (3mg/kg/d) or sterile water tri-weekly for 2 weeks. Leukocyte populations within the spleen, thymus, and bone-marrow were assessed using flow cytometry. RT-PCR was performed to characterise changes in splenic inflammation-associated genes. RESULTS: Oxaliplatin treatment reduced spleen size and cellularity (CD45+ cells), increased the proportion of CD4+, CD8+, and Treg cells, and elevated TNF-α expression. Oxaliplatin was selectively cytotoxic to B cells but had no effect on splenic macrophages. Oxaliplatin treatment altered the gene expression of several cytokines, chemokines, and cell mediators. Oxaliplatin did not deplete double-positive thymocytes but increased the single-positive CD8+ subset. There was also an increase in activated (CD69+) CD8+ T cells. Bone-marrow hematopoietic progenitor pool was demonstrably normal following oxaliplatin treatment when compared to the vehicle-treated cohort. CONCLUSION: Oxaliplatin does not cause systemic immunosuppression and, instead, has the capacity to induce beneficial antitumor immune responses.


Asunto(s)
Tolerancia Inmunológica/efectos de los fármacos , Inmunidad Celular/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Oxaliplatino/administración & dosificación , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD8-positivos/efectos de los fármacos , Quimiocinas/genética , Quimiocinas/inmunología , Citocinas/genética , Citocinas/inmunología , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/inmunología , Humanos , Inmunidad Celular/inmunología , Masculino , Ratones Endogámicos BALB C , Neoplasias/inmunología , Oxaliplatino/inmunología , Bazo/efectos de los fármacos , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Timocitos/efectos de los fármacos , Timocitos/inmunología
14.
Front Immunol ; 9: 3109, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30740111

RESUMEN

There is great interest in developing efficient therapeutic cancer vaccines, as this type of therapy allows targeted killing of tumor cells as well as long-lasting immune protection. High levels of tumor-infiltrating CD8+ T cells are associated with better prognosis in many cancers, and it is expected that new generation vaccines will induce effective production of these cells. Epigenetic mechanisms can promote changes in host immune responses, as well as mediate immune evasion by cancer cells. Here, we focus on epigenetic modifications involved in both vaccine-adjuvant-generated T cell immunity and cancer immune escape mechanisms. We propose that vaccine-adjuvant systems may be utilized to induce beneficial epigenetic modifications and discuss how epigenetic interventions could improve vaccine-based therapies. Additionally, we speculate on how, given the unique nature of individual epigenetic landscapes, epigenetic mapping of cancer progression and specific subsequent immune responses, could be harnessed to tailor therapeutic vaccines to each patient.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/uso terapéutico , Epigénesis Genética/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Neoplasias/terapia , Adyuvantes Inmunológicos/administración & dosificación , Vacunas contra el Cáncer/farmacología , Metilación de ADN/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Código de Histonas , Humanos , MicroARNs/inmunología , MicroARNs/metabolismo , Neoplasias/genética , Neoplasias/inmunología , ARN Largo no Codificante/inmunología , ARN Largo no Codificante/metabolismo , Escape del Tumor/genética , Escape del Tumor/inmunología
15.
PLoS One ; 13(6): e0198359, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29894476

RESUMEN

Oxaliplatin is a platinum-based chemotherapeutic used for cancer treatment. Its use associates with peripheral neuropathies and chronic gastrointestinal side-effects. Oxaliplatin induces immunogenic cell death by provoking the presentation of damage associated molecular patterns. The damage associated molecular patterns high-mobility group box 1 (HMGB1) protein exerts pro-inflammatory cytokine-like activity and binds to toll-like receptors (namely TLR4). Gastrointestinal microbiota may influence chemotherapeutic efficacy and contribute to local and systemic inflammation. We studied effects of oxaliplatin treatment on 1) TLR4 and high-mobility group box 1 expression within the colon; 2) gastrointestinal microbiota composition; 3) inflammation within the colon; 4) changes in Peyer's patches and mesenteric lymph nodes immune populations in mice. TLR4+ cells displayed pseudopodia-like extensions characteristic of antigen sampling co-localised with high-mobility group box 1 -overexpressing cells in the colonic lamina propria from oxaliplatin-treated animals. Oxaliplatin treatment caused significant reduction in Parabacteroides and Prevotella1, but increase in Prevotella2 and Odoribacter bacteria at the genus level. Downregulation of pro-inflammatory cytokines and chemokines in colon samples, a reduction in macrophages and dendritic cells in mesenteric lymph nodes were found after oxaliplatin treatment. In conclusion, oxaliplatin treatment caused morphological changes in TLR4+ cells, increase in gram-negative microbiota and enhanced HMGB1 expression associated with immunosuppression in the colon.


Asunto(s)
Bacterias/clasificación , Colon/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Proteína HMGB1/metabolismo , Oxaliplatino/efectos adversos , Ganglios Linfáticos Agregados/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Bacterias/efectos de los fármacos , Bacterias/genética , Colon/efectos de los fármacos , Colon/microbiología , ADN Bacteriano/genética , ADN Ribosómico/genética , Regulación de la Expresión Génica/efectos de los fármacos , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos Comunes de Leucocito/metabolismo , Masculino , Ratones , Ganglios Linfáticos Agregados/efectos de los fármacos , Ganglios Linfáticos Agregados/microbiología , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN
16.
Maturitas ; 96: 58-71, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28041597

RESUMEN

Increasing evidence indicates that there are various interactions between the nervous system and the immune system, and that the immune system plays an important role in the pathogenesis of depression. Pro-inflammatory cytokines (such as IL-1, IL-6, TNF-α) have been implicated in the neurobiological manifestations of depression. The immune/cytokine network has a powerful influence on the brain. In addition, deficiency in B vitamins has been linked to depression. Hence, greater knowledge of how immune cells change in the presence of vitamin B derivatives could improve understanding of how immune changes may correlate with depression, all of which are discussed herein.


Asunto(s)
Citocinas/inmunología , Depresión/inmunología , Sistema Inmunológico , Complejo Vitamínico B/inmunología , Deficiencia de Vitamina B/complicaciones , Humanos , Interleucina-1/inmunología , Interleucina-6/inmunología , Factor de Necrosis Tumoral alfa/inmunología
17.
Inflamm Bowel Dis ; 22(11): 2694-2703, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27753693

RESUMEN

Cancer development is often associated with chronic inflammation. To date, research into inflammation-induced cancer has largely focused on chemokines, cytokines, and their downstream targets. These inflammatory mediators may promote tumor growth, invasion, metastasis, and facilitate angiogenesis. However, the exact mechanisms by which inflammation promotes neoplasia remain unclear. Inflammatory bowel disease (IBD) is characterized by recurrent, idiopathic intestinal inflammation, the complications of which are potentially fatal. IBD incidence in Australia is 24.2 per 100,000 and its peak onset is in people aged 15 to 24 years. Symptoms include abdominal pain, cramps, bloody stool, and persistent diarrhoea or constipation and so seriously compromise quality of life. However, due to its unknown etiology, current treatment strategies combat the symptoms rather than the disease and are limited by inefficacy, toxicity, and adverse side-effects. IBD is also associated with an increased risk of colorectal cancer, for which treatment options are similarly limited. In recent years, there has been much interest in the therapeutic potential of mesenchymal stem cells (MSCs). However, whether MSCs suppress or promote tumor development is still contentious within the literature. Many studies indicate that MSCs exert anti-tumor effects and suppress tumor growth, whereas other studies report pro-tumor effects. Studies using MSCs as treatment for IBD have shown promising results in both animal models and human trials. However, as MSC treatment is still novel, the long-term risks remain unknown. This review aims to summarize the current literature on MSC treatment of inflammation-induced cancer, with a focus on colorectal cancer resulting from IBD.


Asunto(s)
Neoplasias Colorrectales/terapia , Enfermedades Inflamatorias del Intestino/complicaciones , Trasplante de Células Madre Mesenquimatosas/métodos , Adolescente , Australia , Neoplasias Colorrectales/etiología , Femenino , Humanos , Masculino , Resultado del Tratamiento , Adulto Joven
18.
Nat Med ; 22(11): 1277-1284, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27694934

RESUMEN

Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities. Using high-throughput 16S rRNA gene amplicon sequencing and bioinformatics analyses, we provide evidence demonstrating that the source of the bacteria forming the microbial community in the lungs of post-stroke mice was indeed the host small intestine. Additionally, stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. This study identifies a novel pathway in which stroke promotes the translocation and dissemination of selective strains of bacteria that originated from the host gut microbiota.


Asunto(s)
Infecciones Bacterianas/inmunología , Traslocación Bacteriana/inmunología , Microbioma Gastrointestinal/genética , Infecciones por Bacterias Grampositivas/inmunología , Intestino Delgado/metabolismo , ARN Ribosómico 16S/genética , Accidente Cerebrovascular/inmunología , Antagonistas Adrenérgicos beta/farmacología , Anciano , Anciano de 80 o más Años , Animales , Bacteriemia/inmunología , Bacteriemia/metabolismo , Bacteriemia/microbiología , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/microbiología , Cultivo de Sangre , Biología Computacional , Modelos Animales de Enfermedad , Enterococcus faecalis , Femenino , Células Caliciformes/citología , Células Caliciformes/metabolismo , Infecciones por Bacterias Grampositivas/metabolismo , Infecciones por Bacterias Grampositivas/microbiología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Infarto de la Arteria Cerebral Media/inmunología , Intestino Delgado/citología , Intestino Delgado/efectos de los fármacos , Intestino Delgado/microbiología , Masculino , Ratones , Microbiota/genética , Persona de Mediana Edad , Permeabilidad/efectos de los fármacos , Neumonía Bacteriana/inmunología , Neumonía Bacteriana/metabolismo , Neumonía Bacteriana/microbiología , Receptores Adrenérgicos beta/metabolismo , Análisis de Secuencia de ARN , Organismos Libres de Patógenos Específicos , Infecciones Urinarias/inmunología , Infecciones Urinarias/metabolismo , Infecciones Urinarias/microbiología , Proteína de la Zonula Occludens-1/metabolismo
19.
Nat Commun ; 5: 3164, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24445777

RESUMEN

Maspin (SERPINB5) is accepted as an important tumour suppressor lost in many cancers. Consistent with a critical role in development or differentiation maspin knockout mice die during early embryogenesis, yet clinical data conflict on the prognostic utility of maspin expression. Here to reconcile these findings we made conditional knockout mice. Surprisingly, maspin knockout embryos develop into overtly normal animals. Contrary to original reports, maspin re-expression does not inhibit tumour growth or metastasis in vivo, or influence cell migration, invasion or survival in vitro. Bioinformatic analyses reveal that maspin is not commonly under-expressed in cancer, and that perturbation of genes near maspin may in fact explain poor survival in certain patient cohorts with low maspin expression.


Asunto(s)
Desarrollo Embrionario/fisiología , Neoplasias/fisiopatología , Serpinas/fisiología , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Noqueados
20.
Immunol Cell Biol ; 87(3): 249-54, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19079360

RESUMEN

Granzyme B (GrB) plays a well-established intracellular role in cytotoxic lymphocyte (CL)-mediated killing of abnormal cells; however, emerging evidence suggests that it participates in extracellular matrix remodeling and target cell destruction through anoikis. As these processes require the release of GrB from the CL into the extracellular environment, we examined the secretion of GrB from natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). We found that a proportion of GrB is constitutively secreted by both CTLs and NK cells in the absence of target cell engagement. In NK cells, the protease is primarily released in an active form through secretory granules. By contrast, T lymphocytes primarily secrete inactive GrB zymogen, bypassing the granules. The release of GrB through two routes from unconjugated CLs suggests that it functions outside the cell and may contribute to pathology in cases of immune dysregulation, such as familial hemophagocytic lymphohistiocytosis (FHL). Our findings also predict the existence of an extracellular activator of GrB.


Asunto(s)
Precursores Enzimáticos/metabolismo , Granzimas/metabolismo , Células Asesinas Naturales/inmunología , Linfocitos T Citotóxicos/inmunología , Línea Celular , Humanos , Células Asesinas Naturales/enzimología , Vesículas Secretoras/enzimología , Linfocitos T Citotóxicos/enzimología
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