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1.
J Clin Invest ; 129(6): 2463-2479, 2019 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-30912767

RESUMEN

Rationale Tumor infiltrating lymphocytes are widely associated with positive outcomes, yet carry key indicators of a systemic failed immune response against unresolved cancer. Cancer immunotherapies can reverse their tolerance phenotypes, while preserving tumor-reactivity and neoantigen-specificity shared with circulating immune cells. Objectives We performed comprehensive transcriptomic analyses to identify gene signatures common to circulating and tumor infiltrating lymphocytes in the context of clear cell renal cell carcinoma. Modulated genes also associated with disease outcome were validated in other cancer types. Findings Using bioinformatics, we identified practical diagnostic markers and actionable targets of the failed immune response. On circulating lymphocytes, three genes, LEF1, FASLG, and MMP9, could efficiently stratify patients from healthy control donors. From their associations with resistance to cancer immunotherapies and microbial infections, we uncovered not only pan-cancer, but pan-pathology failed immune response profiles. A prominent lymphocytic matrix metallopeptidase cell migration pathway, is central to a panoply of diseases and tumor immunogenicity, correlates with multi-cancer recurrence, and identifies a feasible, non-invasive approach to pan-pathology diagnoses. Conclusions The non-invasive differently expressed genes we have identified warrant future investigation towards the development of their potential in precision diagnostics and precision pan-disease immunotherapeutics.

2.
Cytokine Growth Factor Rev ; 41: 75-87, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29550265

RESUMEN

Campylobacter jejuni is an important enteric pathogen that causes diarrheas of different degrees of severity and several extra-intestinal manifestations, including Guillain-Barre syndrome. The variability of disease outcomes is thought to be linked to the immune response induced by C. jejuni. The virulence factors of C. jejuni induce a pro-inflammatory response, that is initiated by the intestinal epithelial cells, propagated by innate immune cells and modulated by the cells of the adaptive immune response. This review focuses on cytokines, that are reported to orchestrate the induction and propagation of pro-inflammatory immune response, and also those that are involved in control and resolution of inflammation. We describe the functional roles of a number of cytokines in modulating anti-Campylobacter immune responses: 1. cytokines of innate immunity (TNF-α, IL-6, and IL-8) as initiators of inflammatory response, 2. cytokines of antigen-presenting cells (IL-1ß, IL-12, and IL-23) as promoters of pro-inflammatory response, 3. cytokines produced by T cells (IFN-γ, IL-17, IL-22) as activators of T cells, and 4. anti-inflammatory cytokines (IL-4 and IL-10) as inhibitors of pro-inflammatory responses. We highlight the roles of cytokines as potential therapeutic agents that are under investigation. In the end, we pose several questions that remain unanswered in our quest to understand Campylobacter immunity.


Asunto(s)
Inmunidad Adaptativa/inmunología , Infecciones por Campylobacter/inmunología , Campylobacter jejuni/inmunología , Citocinas/inmunología , Inmunidad Innata/inmunología , Animales , Síndrome de Guillain-Barré/inmunología , Humanos
3.
Eur J Immunol ; 44(6): 1633-43, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24700244

RESUMEN

CCR4 and CXCR3 are expressed on several T-cell subsets in inflamed tissues, yet their role in tissue-specific recruitment is unclear. We examined the contributions of CCR4 and CXCR3 to T-cell recruitment into inflamed joints in collagen-induced arthritis, antigen-draining lymph nodes (LNs) and dermal inflammatory sites (poly I:C, LPS, concanavalin A, and delayed type hypersensitivity), using labeled activated T cells from CXCR3(-/-), CCR4(-/-), and WT mice. Both CXCR3 and CCR4 deficiency reduced the development of arthritis, but did not affect Th1-cell recruitment to the inflamed joints. Accumulation in inflamed LNs was highly CXCR3 dependent. In contrast, CCR4-deficient Th1 cells had an increased accumulation in these LNs. Migration to all four dermal inflammatory sites by activated Th1 and T cytotoxic cells and memory CD4(+) T cells was partially CXCR3-dependent, but Treg-cell migration was independent of CXCR3. The subset of cells expressing CCR4 has skin-migrating properties, but CCR4 itself is not required for the migration. Thus, migration into these inflamed tissues is CCR4-independent, and partially dependent on CXCR3, except for Treg cells, which require neither receptor. CCR4 may therefore affect retention of T cells in different tissues rather than trafficking out of the blood.


Asunto(s)
Artritis Experimental/inmunología , Movimiento Celular/inmunología , Dermatitis/inmunología , Articulaciones/inmunología , Ganglios Linfáticos/inmunología , Receptores CCR4/inmunología , Receptores CXCR3/inmunología , Linfocitos T/inmunología , Animales , Artritis Experimental/genética , Artritis Experimental/patología , Dermatitis/genética , Dermatitis/patología , Articulaciones/patología , Ganglios Linfáticos/patología , Ratones , Ratones Noqueados , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Receptores CCR4/genética , Receptores CXCR3/genética , Piel/inmunología , Piel/patología , Linfocitos T/patología
4.
J Basic Clin Physiol Pharmacol ; 24(1): 27-33, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23382309

RESUMEN

BACKGROUND: Changes in leukocyte-endothelial and microvascular perfusion are hallmark events in inflammation. Thus, protection of the intestinal microcirculation represents a pivotal therapeutic target in systemic inflammation and sepsis. The endocannabinoid system (ECS) modulates a number of critical homeostatic functions and has been associated with anti-inflammatory responses. Our study aimed to examine intestinal leukocyte adhesion and capillary perfusion following selective inhibition of the endocannabinoid degradation enzyme, fatty acid amide hydrolase (FAAH), in experimental sepsis (endotoxemia). METHODS: Five groups of rats were used: controls, endotoxemia [lipopolysaccharide (LPS)], FAAH inhibitor URB597 (0.3 mg/kg)+LPS, URB597 (0.6 mg/kg)+LPS, and URB597 (0.6 mg/kg)+cannabinoid 2 receptor (CB2R) antagonist (AM630)+LPS. After 2 h, intravital microscopy was performed to quantify intestinal leukocyte recruitment and functional capillary density (FCD), as well as macrohemodynamic monitoring and histological examinations. RESULTS: LPS induced a significant increase in leukocyte adhesion in collecting and postcapillary submucosal venules and a decrease in intestinal FCD. URB597 pretreatment prevented the LPS-induced increase in leukocyte adhesion in intestinal venules and a decrease in intestinal FCD. The administration of the CB2R inhibitor, AM630, with URB597 reversed the protective effects of URB597 on the LPS-induced increase in leukocyte adhesion in intestinal venules, but not URB597's effect on the intestinal FCD. CONCLUSIONS: FAAH inhibition prevents the LPS-induced increase in leukocyte adhesion and improves the capillary perfusion of the gut. This might be mediated in part by CB2R activation. Our study encourages further investigation into the therapeutic potential of drugs targeting the ECS in sepsis.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Endocannabinoides/metabolismo , Endotoxemia/fisiopatología , Leucocitos/metabolismo , Amidohidrolasas/metabolismo , Animales , Benzamidas/farmacología , Antagonistas de Receptores de Cannabinoides/farmacología , Capilares/metabolismo , Carbamatos/farmacología , Adhesión Celular , Modelos Animales de Enfermedad , Indoles/farmacología , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Leucocitos/efectos de los fármacos , Lipopolisacáridos/toxicidad , Masculino , Ratas , Ratas Endogámicas Lew , Receptor Cannabinoide CB2/efectos de los fármacos , Receptor Cannabinoide CB2/metabolismo
5.
Gut Pathog ; 4(1): 23, 2012 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-23244595

RESUMEN

BACKGROUND: Cytokine production and histopathological changes occur in the lungs of mice after intranasal inoculation with Campylobacter jejuni, but the levels of cytokines in different organs to which C. jejuni disseminates have not been studied. FINDINGS: Adult BALB/c mice were intranasally inoculated with C. jejuni 81-176 (test) or phosphate-buffered saline (control) (n=16 per group). The levels of cytokines in the organs (spleen, liver, and small and large intestines) to which C. jejuni disseminated were measured by ELISA. Two cytokine patterns were observed. First, increased proinflammatory cytokines, TNF-α, IL-1, and IL-2, were followed by anti-inflammatory cytokines, IL-4 and IL-10 in the spleen and large intestine. Second, in the liver and small intestine, there was a predominant production of anti-inflammatory cytokines, IL-4 and IL-10, with some increase in IL-2 levels. In the spleen and intestines, the levels of pro- and anti-inflammatory cytokines were concurrently increased. CONCLUSION: Dissemination of C. jejuni is associated with the production of different cytokine profiles in different tissues, with the proinflammatory response appearing in the spleen and large intestine at an earlier time point than in the liver and small intestine. The organs produce different cytokine profiles in response to C. jejuni dissemination. These preliminary findings should be confirmed with a study involving a larger group of animals.

6.
J Immunol ; 189(1): 337-46, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22664869

RESUMEN

CCR4 on T cells is suggested to mediate skin homing in mice. Our objective was to determine the interaction of CCR4, E-selectin ligand (ESL), and α(4)ß(1) on memory and activated T cells in recruitment to dermal inflammation. mAbs to rat CCR4 were developed. CCR4 was on 5-21% of memory CD4 cells, and 20% were also ESL(+). Anti-TCR-activated CD4 and CD8 cells were 40-55% CCR4(+), and ∼75% of both CCR4(+) and CCR4(-) cells were ESL(+). CCR4(+) memory CD4 cells migrated 4- to 7-fold more to dermal inflammation induced by IFN-γ, TNF, TLR agonists, and delayed-type hypersensitivity than CCR4(-) cells. CCR4(+) activated CD4 cells migrated only 5-50% more than CCR4(-) cells to these sites. E-selectin blockade inhibited ∼60% of CCR4(+) activated CD4 cell migration but was less effective on memory cells where α(4)ß(1) was more important. Anti-α(4)ß(1) also inhibited CCR4(-) activated CD4 cells more than CCR4(+) cells. Anti-E-selectin reduced activated CD8 more than CD4 cell migration. These findings modify our understanding of CCR4, ESL, α(4)ß(1), and dermal tropism. There is no strict relationship between CCR4 and ESL for skin homing of CD4 cells, because the activation state and inflammatory stimulus are critical determinants. Dermal homing memory CD4 cells express CCR4 and depend more on α(4)ß(1) than ESL. Activated CD4 cells do not require CCR4, but CCR4(+) cells are more dependent on ESL than on α(4)ß(1), and CCR4(-) cells preferentially use α(4)ß(1). The differentiation from activated to memory CD4 cells increases the dependence on CCR4 for skin homing and decreases the requirement for ESL.


Asunto(s)
Movimiento Celular/inmunología , Selectina E/fisiología , Memoria Inmunológica , Integrina alfa4beta1/fisiología , Activación de Linfocitos/inmunología , Receptores CCR4/fisiología , Piel/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Células CHO , Inhibición de Migración Celular/inmunología , Cricetinae , Cricetulus , Modelos Animales de Enfermedad , Selectina E/biosíntesis , Selectina E/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Integrina alfa4beta1/antagonistas & inhibidores , Masculino , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/fisiología , Ratas , Ratas Endogámicas Lew , Receptores CCR4/biosíntesis , Receptores CCR4/deficiencia , Receptores de Factores de Crecimiento de Fibroblastos/biosíntesis , Sialoglicoproteínas/biosíntesis , Piel/patología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología
7.
J Med Microbiol ; 57(Pt 2): 210-7, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18201988

RESUMEN

Campylobacter jejuni is a major cause of diarrhoea in humans. However, the pathogenesis of C. jejuni diarrhoea is poorly understood due to the lack of a good animal model of infection. Many animals have been tried with limited success, but a mouse lung model of infection has been found to be satisfactory previously; however, the lung pathology of this model has not been studied. For the purpose of characterizing the histopathological and ultrastructural lesions in the lung of the mouse pulmonary model of C. jejuni infection, C. jejuni strain 81-176 or sterile PBS was intranasally inoculated into BALB/c mice. The infection resulted in a mild illness only, and in an initial predominance of polymorphonuclear cells, followed by the accumulation of macrophages and later the prominence of epithelioid cells. Focal peribronchial pneumonia appeared on day 3, granuloma-like reaction on day 4 and bronchopneumonia on day 5 post-infection. These features developed until day 5 post-infection, but were less consistent afterwards when histopathology was monitored up to 9 days post-infection. Intracellular structures resembling bacteria were observed on days 3 and 5 post-infection, but not on day 7 post-infection. On days 3 and 5 post-infection, degenerative changes were also observed by transmission electron microscopy. The histological changes were not associated with acid-fast bacteria or any fungal elements. The infection was systemic as C. jejuni was isolated from blood and all organ homogenates (lung, spleen, liver, and small and large intestines) at 24 h post-infection. Thereafter, the organism was recovered from the intestine only, thus indicating its predilection for this location. This characterization of pathology should contribute to a better understanding of the animal model and pathogenesis of C. jejuni infection.


Asunto(s)
Bronconeumonía/microbiología , Bronconeumonía/patología , Infecciones por Campylobacter/microbiología , Infecciones por Campylobacter/patología , Campylobacter jejuni/crecimiento & desarrollo , Pulmón/microbiología , Pulmón/ultraestructura , Animales , Sangre/microbiología , Citosol/microbiología , Modelos Animales de Enfermedad , Granuloma/patología , Intestinos/microbiología , Hígado/microbiología , Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica de Transmisión , Neutrófilos/inmunología , Bazo/microbiología , Factores de Tiempo
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