RESUMEN
BACKGROUND: Hyperbaric oxygen therapy (HBOT) delivers 100% oxygen in a pressurized chamber, increasing tissue oxygen levels and regulating inflammatory pathways. Mounting evidence suggests that HBOT may be effective for inflammatory bowel disease. Our systematic review and meta-analysis aimed to quantify the efficacy and safety of HBOT in fistulizing Crohn's disease (CD). METHODS: A systematic review was conducted using the EMBASE, Web of Science, Pubmed, and Cochrane Library databases according to the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" criteria. Study bias was assessed using the Cochrane Handbook guidelines. RESULTS: Sixteen studies with 164 patients were included in the analysis. For all fistula subtypes, the pooled overall clinical response was 87% (95% CI: 0.70-0.95, I2 = 0) and the pooled clinical remission was 59% (95% CI: 0.35-0.80, I2 = 0). The overall clinical response was 89%, 84%, and 29% for perianal, enterocutaneous, and rectovaginal fistulas, respectively. On meta-regression, hours in the chamber and the number of HBOT sessions were not found to correlate with clinical response. The pooled number of adverse events was low at 51.7 per 10,000 HBOT sessions for all fistula types (95% CI: 16.8-159.3, I2 = 0). The risk of bias was observed across all studies. CONCLUSION: HBOT is a safe and potentially effective treatment option for fistulizing CD. Randomized control trials are needed to substantiate the benefit of HBOT in fistulizing CD.
Asunto(s)
Enfermedad de Crohn , Oxigenoterapia Hiperbárica , Femenino , Humanos , Enfermedad de Crohn/terapia , Fístula/terapia , Oxigenoterapia Hiperbárica/efectos adversos , Oxígeno/uso terapéutico , Resultado del TratamientoRESUMEN
Helminthic infections modulate host immunity and may protect their hosts from developing immunological diseases like inflammatory bowel disease. Induction of regulatory T cells (Tregs) may be an important part of this protective process. Heligmosomoides polygyrus bakeri infection also promotes the production of the regulatory cytokines TGF-ß and IL-10 in the gut. In the intestines, TGF-ß helps induce regulatory T cells. This study used Foxp3/IL-10 double reporter mice to investigate the effect of TGF-ß on the differentiation of colon and mesenteric lymph node-derived murine Foxp3- IL-10- CD4+ T cells into their regulatory phenotypes. Foxp3- IL-10- CD4+ T cells from H. polygyrus bakeri-infected mice, as opposed to T cells from uninfected animals, cultured in vitro with TGF-ß and anti-CD3/CD28 mAb differentiated into Foxp3+ and/or IL-10+ T cells. The IL-10-producing T cells nearly all displayed CD25. Smad7 is a natural inhibitor of TGF-ß signaling. In contrast to gut T cells from uninfected mice, Foxp3- IL10- CD4+ T cells from H. polygyrus bakeri-infected mice displayed reduced Smad7 expression and responded to TGF-ß with Smad2/3 phosphorylation. The TGF-ß-induced Tregs that express IL-10 blocked colitis when transferred into the Rag/CD25- CD4+ T cell transfer model of inflammatory bowel disease. TGF-ß had a greatly diminished capacity to induce Tregs in H. polygyrus bakeri-infected transgenic mice with constitutively high T cell-specific Smad7 expression. Thus, infection with H. polygyrus bakeri causes down-modulation in Smad7 expression in intestinal CD4+ T cells, which allows the TGF-ß produced in response to the infection to induce the Tregs that prevent colitis.
Asunto(s)
Colitis/inmunología , Interleucina-10/inmunología , Nematospiroides dubius/inmunología , Proteína smad7/inmunología , Infecciones por Strongylida/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Animales , Colitis/patología , Colitis/prevención & control , Interleucina-10/genética , Ratones , Ratones Transgénicos , Proteína smad7/genética , Infecciones por Strongylida/genética , Infecciones por Strongylida/patología , Linfocitos T Reguladores/patología , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Helminthic infections modulate host immunity and may protect people in less-developed countries from developing immunological diseases. In a murine colitis model, the helminth Heligmosomoides polygyrus bakeri prevents colitis via induction of regulatory dendritic cells (DCs). The mechanism driving the development of these regulatory DCs is unexplored. There is decreased expression of the intracellular signaling pathway spleen tyrosine kinase (Syk) in intestinal DCs from H. polygyrus bakeri-infected mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk(-/-) mice were powerful inhibitors of murine colitis, suggesting that loss of Syk was sufficient to convert these cells into their regulatory phenotype. DCs sense gut flora and damaged epithelium via expression of C-type lectin receptors, many of which signal through the Syk signaling pathway. It was observed that gut DCs express mRNA encoding for C-type lectin (CLEC) 7A, CLEC9A, CLEC12A, and CLEC4N. H. polygyrus bakeri infection downmodulated CLEC mRNA expression in these cells. Focusing on CLEC7A, which encodes for the dectin-1 receptor, flow analysis showed that H. polygyrus bakeri decreases dectin-1 expression on the intestinal DC subsets that drive Th1/Th17 development. DCs become unresponsive to the dectin-1 agonist curdlan and fail to phosphorylate Syk after agonist stimulation. Soluble worm products can block CLEC7A and Syk mRNA expression in gut DCs from uninfected mice after a brief in vitro exposure. Thus, downmodulation of Syk expression and phosphorylation in intestinal DCs could be important mechanisms through which helminths induce regulatory DCs that limit colitis.
Asunto(s)
Colitis/prevención & control , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Intestinos/citología , Transducción de Señal , Quinasa Syk/metabolismo , Animales , Colitis/inmunología , Colitis/parasitología , Modelos Animales de Enfermedad , Intestinos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nematospiroides dubius/inmunología , ARN Mensajero/genética , ARN Mensajero/inmunología , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitología , Quinasa Syk/deficiencia , Quinasa Syk/genéticaRESUMEN
Helminthic infection has become rare in highly industrialized nations. Concurrent with the decline in helminthic infection has been an increase in the prevalence of inflammatory disease. Removal of helminths from our environment and their powerful effects on host immunity may have contributed to this increase. Several helminth species can abrogate disease in murine models of inflammatory bowel disease, type 1 diabetes, multiple sclerosis, and other conditions. Helminths evoke immune regulatory pathways often involving dendritic cells, regulatory T cells, and macrophages that help to control disease. Cytokines, such as IL-4, IL-10, and TGF-ß, have a role. Notable is the helminthic modulatory effect on innate immunity, which impedes development of aberrant adaptive immunity. Investigators are identifying key helminth-derived immune modulatory molecules that may have therapeutic usefulness in the control of inflammatory disease.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Células Dendríticas/inmunología , Helmintiasis/inmunología , Helmintos/inmunología , Macrófagos/inmunología , Linfocitos T Reguladores/inmunología , Animales , Citocinas/inmunología , Humanos , Inmunidad Innata , RatonesRESUMEN
Helminthic infections protect mice from colitis in murine models of inflammatory bowel disease and also may protect people. Helminths like Heligmosomoides polygyrus bakeri can induce regulatory T cells (Treg). Experiments explored whether H. polygyrus bakeri infection could protect mice from colitis through activation of colonic Treg and examined mechanisms of action. We showed that H. polygyrus bakeri infection increased the number of T cells expressing Foxp3 in the colon. More importantly, Foxp3(+)/IL-10(-) and Foxp3(+)/IL-10(+) T cell subsets isolated from the colon of H. polygyrus bakeri-infected mice prevented colitis when adoptively transferred into a murine model of inflammatory bowel disease, whereas Treg from uninfected mice could not provide protection. Only the transferred colonic Foxp3(+)/IL-10(-) T cells from H. polygyrus bakeri-infected mice readily accumulated in the colon and mesenteric lymph nodes of recipient mice, and they reconstituted the Foxp3(+)/IL-10(-) and Foxp3(+)/IL-10(+) T cell subsets. However, transferred Foxp3(+)/IL-10(+) T cells disappeared. IL-10 expression by Foxp3(+) T cells was necessary for colitis prevention. Thus, H. polygyrus bakeri infection activates colonic Foxp3(+) T cells, making them highly regulatory. The Foxp3(+) T cells that fail to express IL-10 may be critical for populating the colon with the Foxp3(+)/IL-10(+) T cells, which are required to control colitis.
Asunto(s)
Colitis/prevención & control , Colon/inmunología , Parasitosis Intestinales/inmunología , Nematospiroides dubius/inmunología , Infecciones por Strongylida/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Terapia con Helmintos , Animales , Colitis/inmunología , Colitis/parasitología , Colon/parasitología , Citocinas/biosíntesis , Citocinas/metabolismo , Proteínas de Unión al ADN/deficiencia , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/análisis , Factores de Transcripción Forkhead/deficiencia , Genes Reporteros , Supervivencia de Injerto , Helmintiasis Animal/inmunología , Inmunoterapia Adoptiva , Enfermedades Inflamatorias del Intestino/terapia , Interleucina-10/análisis , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Mesenterio , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Organismos Libres de Patógenos Específicos , Bazo/inmunología , Bazo/patología , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/trasplante , Linfocitos T Reguladores/química , Linfocitos T Reguladores/trasplanteRESUMEN
Cells can innately recognize generic products of viruses, bacteria, fungi, or injured tissue by engagement of pattern recognition receptors. Innate immune cells rapidly respond to this engagement to control commensals, thwart pathogens, and/or prompt repair. Insufficient or excessive activation of the innate immune response results in disease. This review focuses on pattern recognition receptors and cells of the innate immune system that are important for intestinal function. Our improving knowledge pertaining to this important aspect of our immune response is opening potential important new therapeutic opportunities for the treatment of disease.
Asunto(s)
Enfermedades Gastrointestinales/inmunología , Enfermedades Gastrointestinales/patología , Inmunidad Innata , Citocinas/metabolismo , Humanos , Leucocitos/inmunología , Receptores de Reconocimiento de Patrones/metabolismoRESUMEN
Immunological diseases such as inflammatory bowel disease (IBD) are infrequent in less developed countries, possibly because helminths provide protection by modulating host immunity. In IBD murine models, the helminth Heligmosomoides polygyrus bakeri prevents colitis. It was determined whether H. polygyrus bakeri mediated IBD protection by altering dendritic cell (DC) function. We used a Rag IBD model where animals were reconstituted with IL10â»/â» T cells, making them susceptible to IBD and with OVA Ag-responsive OT2 T cells, allowing study of a gut antigenic response. Intestinal DC from H. polygyrus bakeri-infected Rag mice added to lamina propria mononuclear cells (LPMC) isolated from colitic animals blocked OVA IFN-γ/IL-17 responses in vitro through direct contact with the inflammatory LPMC. DC from uninfected Rag mice displayed no regulatory activity. Transfer of DC from H. polygyrus bakeri-infected mice into Rag mice reconstituted with IL10â»/â» T cells protected animals from IBD, and LPMC from these mice lost OVA responsiveness. After DC transfer, OT2 T cells populated the intestines normally. However, the OT2 T cells were rendered Ag nonresponsive through regulatory action of LPMC non-T cells. The process of regulation appeared to be regulatory T cell independent. Thus, H. polygyrus bakeri modulates intestinal DC function, rendering them tolerogenic. This appears to be an important mechanism through which H. polygyrus bakeri suppresses colitis. IFN-γ and IL-17 are colitogenic. The capacity of these DC to block a gut Ag-specific IFN-γ/IL-17 T cell response also is significant.
Asunto(s)
Colitis/inmunología , Células Dendríticas/inmunología , Tolerancia Inmunológica , Enfermedades Inflamatorias del Intestino/inmunología , Infecciones por Strongylida/inmunología , Subgrupos de Linfocitos T/inmunología , Traslado Adoptivo , Animales , Células Cultivadas , Colitis/parasitología , Colitis/prevención & control , Células Dendríticas/parasitología , Células Dendríticas/patología , Modelos Animales de Enfermedad , Enterocolitis/inmunología , Enterocolitis/parasitología , Enterocolitis/prevención & control , Epítopos de Linfocito T/inmunología , Enfermedades Inflamatorias del Intestino/parasitología , Enfermedades Inflamatorias del Intestino/prevención & control , Interleucina-10/administración & dosificación , Interleucina-10/deficiencia , Interleucina-10/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Nematospiroides dubius/inmunología , Infecciones por Strongylida/patología , Infecciones por Strongylida/prevención & control , Subgrupos de Linfocitos T/parasitología , Subgrupos de Linfocitos T/patologíaRESUMEN
Although inhibitory Fc gamma receptors have been demonstrated to promote mucosal tolerance, the role of activating Fc gamma receptors in modulating T helper type (Th)2-dependent inflammatory responses characteristic of asthma and allergies remains unclear. Here, we demonstrate that signaling via activating Fc gamma receptors in conjunction with Toll-like receptor 4 stimulation modulated cytokine production from bone marrow-derived dendritic cells (DCs) and augmented their ability to promote Th2 responses. Ligation of the low affinity receptor Fc gamma RIII was specifically required for the enhanced Th2 responses, as Fc gamma RIII(-/-) DCs failed to augment Th2-mediated airway inflammation in vivo or induce Th2 differentiation in vitro. Further, Fc gamma RIII(-/-) mice had impaired Th2 cytokine production and exhibited reduced airway inflammation, whereas no defect was found in Fc gamma RI(-/-) mice. The augmentation of Th2 immunity was regulated by interleukin 10 production from the DCs but was distinct and independent of the well-established role of Fc gamma RIII in augmenting antigen presentation. Thus, our studies reveal a novel and specific role for Fc gamma RIII signaling in the regulation of Th cell responses and suggest that in addition to immunoglobulin (Ig)E, antigen-specific IgG also contributes to the pathogenesis of Th2-mediated diseases such as asthma and allergies.
Asunto(s)
Regulación de la Expresión Génica , Receptores de IgG/metabolismo , Células Th2/metabolismo , Animales , Presentación de Antígeno , Asma/metabolismo , Células Dendríticas/metabolismo , Femenino , Hipersensibilidad/metabolismo , Inflamación , Interleucina-10/metabolismo , Ratones , Ratones Endogámicos BALB C , Transducción de Señal , Receptor Toll-Like 4/metabolismoAsunto(s)
Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/terapia , Enfermedades Inflamatorias del Intestino/terapia , Terapia con Helmintos , Animales , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/inmunología , Ensayos Clínicos como Asunto , Colitis Ulcerosa/complicaciones , Colitis Ulcerosa/inmunología , Colitis Ulcerosa/terapia , Enfermedad de Crohn/complicaciones , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/terapia , Células Dendríticas/inmunología , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/inmunología , Macrófagos/inmunología , Ratones , Esclerosis Múltiple/terapia , Linfocitos T Reguladores/inmunología , Terapia con Helmintos/efectos adversos , Tricuriasis/complicaciones , Trichuris/fisiologíaRESUMEN
Substance P (SP) is a proinflammatory mediator implicated in inflammatory bowel disease (IBD) and other inflammatory states. SP acts by stimulating the neurokinin-1 receptor (NK-1R) on T lymphocytes and other cell types, and regulates these cells in a complex interplay with multiple cytokines. The mechanisms of interaction among these inflammatory mediators are not yet fully understood. Here, we demonstrate that function of the NK-1R, a member of the G protein-coupled receptor (GPCR) superfamily, is modulated by TGF-beta. The latter acts not on a GPCR but via serine-threonine kinase-class receptors. By flow confocal image analysis, we demonstrate that TGF-beta delays SP-induced NK-1R internalization on mucosal T cells isolated from a mouse model of IBD and on granuloma T cells in murine schistosomiasis. Furthermore, luciferase reporter-gene assays revealed that NK-1R stimulation activates the nuclear factor of activated T cell- and activator protein-1-dependent signaling pathways, which are known triggers of effector T-cell cytokine production. TGF-beta markedly increases SP-induced activation of these signaling cascades, suggesting that delayed NK-1R internalization results in enhanced signaling. Providing a link to amplified immune function, SP and TGF-beta, when applied in combination, trigger a strong release of the proinflammatory cytokines IFN-gamma and IL17 from intestinal inflammatory T cells, whereas either agonist alone shows no effect. These observations establish precedent that members of two distinct receptor superfamilies can interact via a previously unrecognized mechanism, and reveal a paradigm of GPCR transregulation that is relevant to IBD and possibly other disease processes.
Asunto(s)
Endocitosis , Receptores de Neuroquinina-1/inmunología , Linfocitos T/inmunología , Factor de Crecimiento Transformador beta/fisiología , Animales , Línea Celular , Citometría de Flujo , Humanos , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-10/genética , Interleucina-10/fisiología , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Receptores de Neuroquinina-1/metabolismo , Transducción de Señal , Sustancia PRESUMEN
Persistent airway inflammation, mucus production, and airway hyperreactivity are the major contributors to the frequency and severity of asthma. Why lung inflammation persists in asthmatics remains unclear. It has been proposed that Fas-mediated apoptosis of inflammatory cells is a fundamental mechanism involved in the resolution of eosinophilic airway inflammation. Because infiltrating eosinophils are highly sensitive to Fas-mediated apoptosis, it has been presumed that direct ligation of Fas on eosinophils is involved. Here, we utilize adoptive transfers of T cells to demonstrate that the delayed resolution of eosinophilia in Fas-deficient mice is a downstream effect of Fas deficiency on T cells, not eosinophils. Interestingly, the mice that received Fas-deficient T cells, but not the controls, developed a persistent phase of inflammation that failed to resolve even 6 wk after the last challenge. This persistent phase correlated with decreased interferon (IFN)gamma production by Fas-deficient T cells and could be reproduced with adoptive transfer of IFNgamma-deficient T cells. These data demonstrate that Fas deficiency on T cells is sufficient for the development of long-term allergic airway disease in mice and implies that deregulation of death receptors such as Fas on human T cells could be an important factor in the development and/or chronic nature of asthma.
Asunto(s)
Asma/inmunología , Eosinófilos/inmunología , Linfocitos T/inmunología , Receptor fas/inmunología , Traslado Adoptivo , Animales , Asma/genética , Asma/patología , Asma/terapia , Enfermedad Crónica , Modelos Animales de Enfermedad , Eosinofilia/genética , Eosinofilia/inmunología , Eosinofilia/patología , Eosinofilia/terapia , Eosinófilos/patología , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Inflamación/terapia , Interferón gamma/inmunología , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Noqueados , Linfocitos T/patología , Linfocitos T/trasplante , Factores de Tiempo , Receptor fas/genéticaRESUMEN
PURPOSE OF REVIEW: There is something about living in an industrialized country that dramatically increases the risk of acquiring inflammatory bowel disease (IBD). Loss of routine exposure to parasitic worms (helminths), due to modern highly hygienic life styles, likely contributes to this risk. This article reviews current understanding on how helminths influence intestinal inflammation and mucosal immune responses. RECENT FINDINGS: IBD emerges in populations as regions develop socioeconomically and lose exposure to previously ubiquitous helminthic infections. Helminthic infections provided strong selective pressure for the dissemination of gene variants, many of which predispose to development of IBD. In animal models of IBD, helminth colonization suppresses intestinal inflammation through multiple mechanisms including induction of innate and adaptive regulatory circuits. Trials using helminths like hookworm (Necator americanus) or porcine whipworm (Trichuris suis) show that they are safe and may be effective therapies for the control of the aberrant intestinal inflammation seen in Crohn's disease and ulcerative colitis. SUMMARY: Evidence is accumulating that highly hygienic living conditions create risk for developing immune-mediated disease such as IBD. To live in their host, helminths have developed the ability to activate cells of innate and adaptive immunity that suppress inflammation. Therapeutic trials using helminths are in progress.
Asunto(s)
Helmintiasis/inmunología , Inflamación/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Mucosa Intestinal/inmunología , Animales , Modelos Animales de Enfermedad , Helmintiasis/epidemiología , Helmintos/inmunología , Humanos , Hipótesis de la Higiene , Inmunidad Mucosa , Inflamación/parasitología , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/terapia , Mucosa Intestinal/parasitología , Factores Socioeconómicos , Terapia con HelmintosRESUMEN
Less developed countries have a low incidence of immunological diseases like inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections in their populations. In the Rag IL-10(-/-) T cell transfer model of colitis, Heligmosomoides polygyrus, an intestinal helminth, prevents and reverses intestinal inflammation. This model of colitis was used to explore the importance of innate immunity in H. polygyrus protection from IBD. Rag mice briefly exposed to H. polygyrus before reconstitution with IL-10(-/-) colitogenic T cells are protected from colitis. Exposure to H. polygyrus before introduction of IL-10(-/-) and OT2 T cells reduced the capacity of the intestinal mucosa to make IFN-gamma and IL-17 after either anti-CD3 mAb or OVA stimulation. This depressed cytokine response was evident even in the absence of colitis, suggesting that the downmodulation in proinflammatory cytokine secretion was not just secondary to improvement in intestinal inflammation. Following H. polygyrus infection, dendritic cells (DCs) from the lamina propria of Rag mice displayed decreased expression of CD80 and CD86, and heightened expression of plasmacytoid dendritic cell Ag-1 and CD40. They were also less responsive to lamina proprias, producing less IL-12p40 and IL-10. Also diminished was their capacity to present OVA to OT2 T cells. These experiments infer that H. polygyrus does not require direct interactions with T or B cells to render animals resistant to colitis. DCs have an important role in driving both murine and human IBD. Data suggest that phenotypic alternations in mucosal DC function are part of the regulatory process.
Asunto(s)
Colitis/inmunología , Colitis/prevención & control , Inmunidad Innata , Nematospiroides dubius/inmunología , Infecciones por Strongylida/inmunología , Animales , Células Cultivadas , Colitis/parasitología , Células Dendríticas/inmunología , Células Dendríticas/parasitología , Modelos Animales de Enfermedad , Inmunidad Innata/genética , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/parasitología , Enfermedades Inflamatorias del Intestino/prevención & control , Interleucina-10/deficiencia , Interleucina-10/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Membrana Mucosa/inmunología , Membrana Mucosa/parasitología , Membrana Mucosa/patología , Ovalbúmina/inmunología , Infecciones por Strongylida/genética , Infecciones por Strongylida/parasitología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/parasitología , Subgrupos de Linfocitos T/trasplanteRESUMEN
Diagnosis of eosinophilic esophagitis (EoE) and determination of response to therapy is based on histological assessment of the esophagus, which requires upper endoscopy. In children, in whom a dietary approach is commonly used, multiple endoscopies are needed, because foods are eliminated and then gradually reintroduced. Ideally, noninvasive methods could supplement or replace upper endoscopy to facilitate management. Fractionated exhaled nitric oxide (FeNO) has been proposed as a useful measure for monitoring disease activity in studies of patients with eosinophil-predominant asthma and in other atopic disorders. Thus, we evaluated whether FeNO levels could be a useful biomarker to assess the response to therapy in EoE patients. This study was designed to determine whether there is a change in FeNO levels during treatment with topical corticosteroids and whether changes correlated with clinical response. This was a prospective, multicenter study that enrolled nonasthmatic patients with established EoE. FeNO levels and symptom scores were measured at baseline, biweekly during 6-week swallowed fluticasone treatment, and 4 weeks posttreatment. Twelve patients completed the trial. We found a statistically significant difference between median pre- and posttreatment FeNO levels [20.3 ppb (16.0 -29.0 ppb) vs 17.6 ppb (11.7 -27.3 ppb), [corrected] p=0.009]. However, neither the pretreatment FeNO level, a change of FeNO level after 2 weeks of treatment, nor the FeNO level at the end of treatment confidently predicted a clinical or histological response. Although our findings suggest nitric oxide possibly has a physiological role in EoE, our observations do not support a role of FeNo determination for management of EoE.
Asunto(s)
Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/metabolismo , Óxido Nítrico/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores/química , Biomarcadores/metabolismo , Niño , Esofagitis Eosinofílica/diagnóstico , Espiración , Femenino , Humanos , Masculino , Persona de Mediana Edad , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/química , Proyectos Piloto , Estudios Prospectivos , Adulto JovenRESUMEN
Our previous studies revealed that, in a murine model of asthma, mice that received Fas-deficient T cells developed a prolonged phase of airway inflammation, mucus production, and airway hyperreactivity that failed to resolve even 6 weeks after the last challenge. To investigate how Fas-Fas ligand (FasL) interaction occurs between T cells and other cells in vivo, Gld mice with abnormalities of the FasL signaling pathway were used. The reconstituted mice were made by transferring T cells from B6 or Gld mice to Rag(-/-) or FasL-deficient Rag(-/-) mice. We found that Rag(-/-) mice that received B6 T cells resolved the airway inflammation, whereas FasL-deficient Rag(-/-) mice that received Gld T cells developed a prolonged airway inflammation at Day 28, with decreased IFN-gamma production. Both FasL-deficient Rag(-/-) mice that received B6 T cells and Rag(-/-) mice that received Gld T cells also had completely resolved their airway inflammation by Day 28 after challenge. Interestingly, FasL-deficient Rag(-/-) mice that received Gld T cells eventually resolved airway inflammation at Day 42, with a similar level of IFN-gamma production to that of control group. These results demonstrate that FasL expression on either T cells only or non-T cells only was sufficient for the eventual resolution of airway inflammation, and the prolonged airway inflammation in FasL-deficient Rag(-/-) mice that received Gld T cells was correlated with decreased IFN-gamma production by Gld T cells.
Asunto(s)
Asma/prevención & control , Modelos Animales de Enfermedad , Proteína Ligando Fas/fisiología , Sistema Respiratorio/metabolismo , Linfocitos T/metabolismo , Traslado Adoptivo , Animales , Asma/inmunología , Asma/metabolismo , Células Cultivadas , Citocinas/metabolismo , Citometría de Flujo , Proteínas de Homeodominio/fisiología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Noqueados , Linfocitos T/trasplanteRESUMEN
Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-beta, that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell (LPMC) Th1 cytokine generation in an IL-10-dependent manner in WT mice. Helminths also stimulate mucosal TGF-beta release. As TGF-beta exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-beta signaling in helminthic modulation of intestinal immunity. T cell TGF-beta signaling is interrupted in TGF-beta receptor II dominant negative (TGF-betaRII DN) mice by T-cell-specific over-expression of a TGF-betaRII DN. We studied LPMC responses in WT and TGF-betaRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-beta signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-beta-signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-betaRII DN mice. Thus, T cell TGF-beta signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal IFN-gamma generation and H. polygyrus-mediated suppression of chronic colitis.
Asunto(s)
Citocinas/metabolismo , Nematospiroides dubius/fisiología , Transducción de Señal/fisiología , Infecciones por Strongylida/metabolismo , Linfocitos T/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Animales , Células Cultivadas , Colitis/inmunología , Colitis/metabolismo , Colitis/parasitología , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Interacciones Huésped-Parásitos , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Parasitosis Intestinales/inmunología , Parasitosis Intestinales/metabolismo , Parasitosis Intestinales/parasitología , Intestino Delgado/citología , Intestino Delgado/metabolismo , Intestino Delgado/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Transducción de Señal/genética , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitología , Linfocitos T/citología , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Helminth exposure appears to protect hosts from inappropriate inflammatory responses, such as those causing inflammatory bowel disease. A recently identified, strongly proinflammatory limb of the immune response is characterized by T cell IL-17 production. Many autoimmune type inflammatory diseases are associated with IL-17 release. Because helminths protect from these diseases, we examined IL-17 production in helminth-colonized mice. We colonized mice with Heligmosomoides polygyrus, an intestinal helminth, and analyzed IL-17 production by lamina propria mononuclear cells (LPMC) and mesenteric lymph node (MLN) cells. Colonization with H. polygyrus reduces IL-17A mRNA by MLN cells and inhibits IL-17 production by cultured LPMC and MLN cells. Helminth exposure augments IL-4 and IL-10 production. Blocking both IL-4 and IL-10, but not IL-10 alone, restores IL-17 production in vitro. Colonization of colitic IL-10-deficient mice with H. polygyrus suppresses LPMC IL-17 production and improves colitis. Ab-mediated blockade of IL-17 improves colitis in IL-10-deficient mice. Thus, helminth-associated inhibition of IL-17 production is most likely an important mechanism mediating protection from inappropriate intestinal inflammation.
Asunto(s)
Tolerancia Inmunológica , Interleucina-17/antagonistas & inhibidores , Interleucina-17/biosíntesis , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Nematospiroides dubius/crecimiento & desarrollo , Nematospiroides dubius/inmunología , Animales , Células Cultivadas , Colitis/inmunología , Colitis/metabolismo , Colitis/parasitología , Interleucina-17/metabolismo , Interleucina-4/fisiología , Mucosa Intestinal/metabolismo , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/parasitología , Mesenterio , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/parasitologíaRESUMEN
The T cell costimulatory molecule ICOS regulates Th2 effector function in allergic airway disease. Recently, several studies with ICOS(-/-) mice have also demonstrated a role for ICOS in Th2 differentiation. To determine the effects of ICOS on the early immune response, we investigated augmenting ICOS costimulation in a Th2-mediated immune response to Schistosoma mansoni Ags. We found that augmenting ICOS costimulation with B7RP-1-Fc increased the accumulation of T and B cells in the draining lymph nodes postimmunization. Interestingly, the increased numbers were due in part to increased migration of undivided Ag-specific TCR transgenic T cells and surprisingly B cells, as well as non-TCR transgenic T cells. B7RP-1-Fc also increased the levels of the chemokines CCL21 and CXCL13 in the draining lymph node, suggesting ICOS costimulation contributes to migration by direct or indirect effects on dendritic cells, stromal cells and high endothelial venules. Further, the effects of B7RP-1-Fc were not dependent on immunization. Our data support a model in which ICOS costimulation augments the pool of lymphocytes in the draining lymph nodes, leading to an increase in the frequency of potentially reactive T and B cells.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/inmunología , Antígeno B7-1/inmunología , Citocinas/metabolismo , Ganglios Linfáticos/inmunología , Linfocitos/inmunología , Schistosoma mansoni/inmunología , Células Th2/inmunología , Animales , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos B/inmunología , Antígeno B7-1/metabolismo , Movimiento Celular , Citocinas/inmunología , Femenino , Ligando Coestimulador de Linfocitos T Inducibles , Proteína Coestimuladora de Linfocitos T Inducibles , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Linfocitos/citología , Linfocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Linfocitos T/inmunologíaRESUMEN
Previous work has shown ICOS can function independently of CD28, but whether either molecule can compensate for the other in vivo is not known. Since ICOS is a potent inducer of Th2 cytokines and linked to allergy and elevated serum IgE in humans, we hypothesized that augmenting ICOS costimulation in murine allergic airway disease may overcome CD28 deficiency. While ICOS was expressed on T cells from CD28(-/-) mice, Th2-mediated airway inflammation was not induced in CD28(-/-) mice by increased ICOS costimulation. Further, we determined if augmenting CD28 costimulation could compensate for ICOS deficiency. ICOS(-/-) mice had a defect in airway eosinophilia that was not overcome by augmenting CD28 costimulation. CD28 costimulation also did not fully compensate for ICOS for antibody responses, germinal center formation or the development of follicular B helper T cells. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos CD28/inmunología , Enfermedades Pulmonares/inmunología , Células Th2/inmunología , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Histocitoquímica , Inmunidad Celular/inmunología , Inmunoglobulina E/sangre , Proteína Coestimuladora de Linfocitos T Inducibles , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Organismos Libres de Patógenos EspecíficosRESUMEN
There is an epidemic of immune-mediated disease in highly-developed industrialized countries. Such diseases, like inflammatory bowel disease, multiple sclerosis and asthma increase in prevalence as populations adopt modern hygienic practices. These practices prevent exposure to parasitic worms (helminths). Epidemiologic studies suggest that people who carry helminths have less immune-mediated disease. Mice colonized with helminths are protected from disease in models of colitis, encephalitis, Type 1 diabetes and asthma. Clinical trials show that exposure to helminths reduce disease activity in patients with ulcerative colitis or Crohn's disease. This chapter reviews some of the work showing that colonization with helminths alters immune responses, against dysregulated inflammation. These helminth-host immune interactions have potentially important implications for the treatment of immune-mediated diseases.