RESUMEN
Helminth infections likely provide a protective influence against some immune-mediated and metabolic diseases because helminth infection dramatically decreased in developed countries shortly before the explosive rise in the prevalence of these diseases. The capacity of helminths to activate immune-regulatory circuits in their hosts and to modulate the composition of intestinal flora appears to be the mechanisms of protective action. Animal models of disease show that various helminth species prevent and/or block inflammation in various organs in a diverse range of diseases. Clinical trials have demonstrated that medicinal exposure to Trichuris suis or small numbers of Necator americanus is safe with minor, if any, reported adverse effects. This includes exposure of inflamed intestine to T. suis, asthmathic lung to N. americanus and in patients with atopy. Efficacy has been suggested in some small studies, but is absent in others. Factors that may have led to inconclusive results in some trials are discussed. To date, there have been no registered clinical trials using helminths to treat metabolic syndrome or its component conditions. However, the excellent safety profile of T. suis or N. americanus suggests that such studies should be possible.
Asunto(s)
Helmintiasis/inmunología , Inflamación/terapia , Terapia con Helmintos , Animales , Humanos , Necator americanus/inmunología , Trichuris/inmunologíaRESUMEN
BACKGROUND: Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). AIM: To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. METHODS: This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. RESULTS: Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. CONCLUSIONS: A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461.
Asunto(s)
Alérgenos/inmunología , Antígenos Helmínticos/inmunología , Enfermedad de Crohn/terapia , Óvulo/inmunología , Terapia con Helmintos/métodos , Trichuris/inmunología , Adulto , Animales , Enfermedad de Crohn/inmunología , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Crohn's disease is common in highly industrialised Western countries where helminths are rare and uncommon in less developed areas of the world where most people carry worms. Helminths diminish immune responsiveness in naturally colonised humans and reduce inflammation in experimental colitis. Thus exposure to helminths may help prevent or even ameliorate Crohn's disease. AIMS: The aim of the study was to determine the safety and possible efficacy of the intestinal helminth Trichuris suis in the treatment of patients with active Crohn's disease. PATIENTS: Twenty nine patients with active Crohn's disease, defined by a Crohn's disease activity index (CDAI) > or =220 were enrolled in this open label study. METHODS: All patients ingested 2500 live T suis ova every three weeks for 24 weeks, and disease activity was monitored by CDAI. Remission was defined as a decrease in CDAI to less than 150 while a response was defined as a decrease in CDAI of greater than 100. RESULTS: At week 24, 23 patients (79.3%) responded (decrease in CDAI >100 points or CDAI <150) and 21/29 (72.4%) remitted (CDAI <150). Mean CDAI of responders decreased 177.1 points below baseline. Analysis at week 12 yielded similar results. There were no adverse events. CONCLUSIONS: This new therapy may offer a unique, safe, and efficacious alternative for Crohn's disease management. These findings also support the premise that natural exposure to helminths such as T suis affords protection from immunological diseases like Crohn's disease.
Asunto(s)
Enfermedad de Crohn/terapia , Tricuriasis/parasitología , Trichuris/fisiología , Adolescente , Adulto , Anciano , Animales , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/parasitología , Femenino , Interacciones Huésped-Parásitos , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) regulate CD4+ T cell interferon-gamma (IFN-gamma) secretion in schistosome granulomas. The role of IL-12 was determined using C57BL/6 and CBA mice. C57BL/6 IL-4-/- granuloma cells were stimulated to produce IFN-gamma when cultured with IL-10 or TGF-beta neutralizing monoclonal antibody. In comparison, C57BL/6 wild-type (WT) control granuloma cells produced less IFN-gamma. IL-12, IL-18, and soluble egg antigen stimulated IFN-gamma release from C57BL/6 IL-4-/- and WT mice. IFN-gamma production in C57 IL-4-/- and WT granulomas was IL-12 dependent, because IL-12 blockade partly abrogated IFN-gamma secretion after stimulation. All granuloma cells released IL-12 (p70 and p40), and IL-12 production remained constant after anti-TGF-beta, anti-IL-10, recombinant IL-18, or antigen stimulation. C57 WT and IL-4-/- mouse granuloma cells expressed IL-12 receptor (IL-12R) beta1-subunit mRNA but little beta2 mRNA. TGF-beta or IL-10 blockade did not influence beta1 or beta2 mRNA expression. CBA mouse dispersed granuloma cells released no measurable IFN-gamma, produced IL-12 p70 and little p40, and expressed IL-12R beta2 and little beta1 mRNA. In T helper 2 (Th2) granulomas of C57BL/6 WT and IL-4-/- mice, cells produce IL-12 (for IFN-gamma production) and IL-10 and TGF-beta modulate IFN-gamma secretion via mechanisms independent of IL-12 and IL-12R mRNA regulation. We found substantial differences in control of granuloma IFN-gamma production and IL-12 circuitry in C57BL/6 and CBA mice.
Asunto(s)
Granuloma de Cuerpo Extraño/inmunología , Interferón gamma/biosíntesis , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Esquistosomiasis mansoni/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Células Cultivadas , Granuloma de Cuerpo Extraño/parasitología , Interleucina-12/farmacología , Hígado/citología , Hígado/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Óvulo/fisiología , Receptores de Interleucina/metabolismo , Receptores de Interleucina-12 , Proteínas Recombinantes/farmacología , Bazo/citología , Células Th2/inmunologíaRESUMEN
Substance P (SP) regulates interferon-gamma (IFN-gamma) production through interaction with the SP receptor NK1 (SPr) on T cells at sites of inflammation. Using murine schistosomiasis, we evaluated whether SPr expression was subject to immunoregulation. Splenocytes from schistosome-infected mice cultured for < or =18 h did not express SPr, as determined by quantitative polymerase chain reaction assay. However, exposure to schistosome egg antigen (SEA) for < or =4 h induced strong receptor expression. Experiments using splenocytes fractionated with antibody-coupled, paramagnetic beads showed that induction localized exclusively to T cells. Receptor protein expression was confirmed with Western blot. Interleukin 12 (IL-12) also induced strong T-cell SPr expression. Both SEA and IL-12 remained strong inducers of T-cell SPr in lymphocytes from the IL-12 (p40) and IFN-gamma R double-knockout mouse, which suggested that SEA did not require IL-12 to induce SPr and that both worked independently of IFN-gamma. Splenocytes from wild-type mice cultured with SEA and neutralizing anti-IL-12 monoclonal antibody (mAb) also showed SPr induction. However, anti-Ia mAb inhibited SEA induction of SPR: Thus, SPr is inducible on T cells. SEA induces SPr through interaction with T-cell receptor (TCR), independently of IL-12 and IFN-gamma. IL-12 induces SPr independently of TCR activation and IFN-gamma expression. SP and its receptor, which regulate IFN-gamma production, are probably part of the IL-12-Th1 circuit.
Asunto(s)
Antígenos Helmínticos/farmacología , Proteínas del Helminto/farmacología , Interleucina-12/farmacología , Receptores de Neuroquinina-1/metabolismo , Esquistosomiasis mansoni/metabolismo , Linfocitos T/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Granuloma/metabolismo , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , ARN Mensajero/metabolismo , Receptores de Neuroquinina-1/genética , Esquistosomiasis mansoni/patología , Bazo/metabolismo , Bazo/patología , Linfocitos T/metabolismoRESUMEN
Two polarized patterns (Th1 and Th2) of cytokines regulate inflammatory responses. Each cytokine pattern inhibits production of the opposing pattern. Lymphocytes from inflamed intestine due to Crohn's disease secrete a Th1 pattern of cytokines. Crohn's disease is most prevalent in highly industrialized countries with temperate climates. It occurs rarely in tropical third world countries with poor sanitation. We propose that exposure to an environmental agent predisposes individuals to Crohn's disease. Parasitic worms (helminths) are common in tropical climates and in populations subject to crowding and poor sanitation. Children are most subject to helminthic colonization. Many helminths live within or migrate through the human gut where they interact with the mucosal immune system. The host mounts a mucosal response that includes Th2 cytokine production limiting helminthic colonization. Helminths and their eggs probably are the most potent stimulators of mucosal Th2 responses. The Th2 response provoked by parasitic worms can modulate immune reactions to unrelated parasitic, bacterial, and viral infections. Many people in developed countries now live in increasingly hygienic environments, avoiding exposure to helminths. Perhaps failure to acquire these parasites and experience mucosal Th2 conditioning predisposes to Crohn's disease, which is an overly active Th1 inflammation.
Asunto(s)
Enfermedad de Crohn/etiología , Helmintiasis/inmunología , Helmintos/inmunología , Linfocitos T/inmunología , Animales , Enfermedad de Crohn/inmunología , Ambiente , Predisposición Genética a la Enfermedad , Humanos , Enfermedades Inflamatorias del Intestino/genéticaRESUMEN
In murine schistosomiasis, granuloma T cells express VPAC2 mRNA, whereas there is none in splenocytes. This suggests that T cell VPAC2 mRNA is inducible. To address this issue, splenocytes from schistosome-infected mice were incubated with anti-CD3 to induce VPAC2 mRNA, which only appeared when cell cultures also contained anti-IL-4 mAb. Granuloma cells expressed VPAC2 mRNA. This natural expression decreased substantially when cells were cultured 3 days in vitro. However, granuloma cells cultured with anti-IL-4 mAb strongly expressed VPAC2 mRNA. IL-4 KO mice were examined to further address the importance of IL-4 in VPAC2 regulation. Splenocytes and dispersed granuloma cells from IL-4 KO animals had substantially more VPAC2 mRNA than those in wild-type controls. VPAC2 mRNA content decreased when cells were cultured with rIL-4. VPAC2 mRNA localized to CD4+ T cells. Th1 cell lines expressed VPAC2 mRNA much stronger than Th2 cells. Anti-IL-4 mAb increased VPAC2 mRNA expression in Th2 cells cultured in vitro. However, rIL-4 could not suppress VPAC2 mRNA expression in Th1 cells. Thus, VPAC2 is an inducible CD4+ T cell receptor, and IL-4 down-modulates VPAC2 mRNA expression in Th2 cells.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Interleucina-4/fisiología , ARN Mensajero/genética , Receptores de Péptido Intestinal Vasoactivo/genética , Esquistosomiasis/genética , Linfocitos T/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Línea Celular , Femenino , Regulación de la Expresión Génica/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Receptores de Péptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo II del Péptido Intestinal Vasoactivo , Células TH1/metabolismo , Células Th2/metabolismoRESUMEN
Macrophages secrete the immunoregulatory peptide somatostatin (SOM) that inhibits IFN-gamma release by splenocytes and granuloma cells of schistosome-infected mice. In this report we demonstrate that granuloma cells express mRNA for the SOM receptor SSTR2 but not the other four SSTR subtypes. Blocking SSTR2 activity with anti-SSTR2 antiserum prevents SOM inhibition of T cell IFN-gamma production. This demonstrates that SOM regulates T cell function via SSTR2. Two isoforms of SSTR2 exist due to alternative RNA splicing. We developed sensitive and specific competitive PCR assays to quantify total SSTR2, SSTR2A and SSTR2B mRNA levels. The SSTR2A isoform accounts for 99% of inflammatory cell SSTR2 mRNA and does not appear to be regulated at the transcripitonal level. B cells and macrophage cell lines also express SSTR2 mRNA which raises the possibility that SOM influences T cell IFN-gamma release by regulating accessory cell function. We show that SOM acts directly on T cells to inhibit TCR-stimulated IFN-gamma release. Thus, SOM may directly regulate T cell IFN-gamma release at inflammatory sites.
Asunto(s)
Inflamación/inmunología , Inflamación/metabolismo , Interferón gamma/metabolismo , Receptores de Somatostatina/metabolismo , Linfocitos T/inmunología , Animales , Anticuerpos , Linfocitos B/metabolismo , Secuencia de Bases , Línea Celular , Citocinas/farmacología , Cartilla de ADN/genética , Femenino , Expresión Génica , Técnicas In Vitro , Inflamación/genética , Mediadores de Inflamación/farmacología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos CBA , Octreótido/farmacología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Somatostatina/clasificación , Receptores de Somatostatina/genética , Somatostatina/farmacologíaRESUMEN
Immune cells within the granulomas of murine schistosomiasis mansoni make the neuropeptide substance P (SP) and express neurokine 1 receptor, which is the specific receptor for substance P (SPr). It was determined if mice with deletion of the SPr (SPr-/-) would develop a normal granulomatous response to schistosome ova during the course of natural infection. Mean liver granuloma size was smaller in SPr-/- mice compared with that of wild-type control animals. Although flow analysis revealed little difference in the cellular composition of the granulomas, both splenocytes and granuloma cells from SPr-/- mice produced much less IFN-gamma and IgG2a and less IgE. The expression of Th2 cytokines (IL-4/IL-5) and IgG1 was comparable to the wild-type control. The mouse with targeted disruption of its SPr had the nonmammalian gene encoding the enzyme beta-galactosidase inserted in exon 1 of the SPr gene. There was beta-galactosidase activity in many mononuclear cells scattered throughout the schistosome granulomas of SPr-/- mice. Also, a granuloma T cell line derived from this transgenic mouse produced beta-galactosidase. These results provide further evidence that in murine schistosomiasis SPr is displayed commonly on granuloma inflammatory cells and is important for granuloma development and expression of IFN-gamma circuitry in this natural infection.
Asunto(s)
Granuloma/etiología , Receptores de Neuroquinina-1/metabolismo , Esquistosomiasis mansoni/inmunología , Animales , Linfocitos B/inmunología , Citocinas/análisis , Genes Reporteros , Granuloma/inmunología , Granuloma/patología , Inmunoglobulina E/biosíntesis , Inmunoglobulina G/biosíntesis , Isotipos de Inmunoglobulinas/biosíntesis , Interferón gamma/biosíntesis , Hígado/inmunología , Hígado/parasitología , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , ARN Mensajero/aislamiento & purificación , Receptores de Neuroquinina-1/genética , Células Th2/inmunologíaRESUMEN
Substance P (SP) and somatostatin (SOM) are made at mucosal surfaces and sites of inflammation. There is a SP/SOM immunoregulatory circuit that modulates the IFN-gamma response in murine schistosomiasis. SP enhances, while SOM decreases, IFN-gamma secretion. Various inflammatory mediators induce macrophages to make SOM, but no known factor limits this expression. It was discovered that SP regulates SOM synthesis. Splenocytes from normal, uninfected mice cultured with LPS, IFN-gamma, or IL-10 for 4 h strongly expressed SOM mRNA, but failed to do so in the presence of SP. The inhibition with 10(-9) M SP was > 85% shown by quantitative PCR. Also, splenocyte SOM content decreased from 1048 +/- 275 to < 10 pg/4 x 10(8) cells following SP exposure. Immunohistochemistry identified SOM solely within splenic macrophages following cytokine stimulation. Mice infected with Schistosoma mansoni form granulomas in the liver and intestines resulting from deposition of parasite eggs in these organs. The granulomas contain macrophages that make SOM constitutively. SP at 10(-8) M decreased SOM mRNA expression > 90% in dispersed granuloma cells cultured for 4 h or longer. Specific SP receptor antagonists blocked SP suppression of SOM expression in splenocytes and dispersed granuloma cells, showing that an authentic SP receptor mediated the regulation. Additional studies revealed that IL-4 antagonized the SP effect in the spleen. It is concluded that in granulomas and splenocytes from mice with schistosomiasis and in splenocytes from uninfected animals that 1) SP inhibits macrophage SOM induction and ongoing expression at the mRNA and protein levels acting through the SP receptor, and 2) IL-4 can antagonizes this SP effect.
Asunto(s)
Mediadores de Inflamación/fisiología , Somatostatina/biosíntesis , Sustancia P/fisiología , Animales , Linfocitos B/fisiología , Femenino , Granuloma/inmunología , Granuloma/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Interleucina-4/fisiología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Precursores de Proteínas/antagonistas & inhibidores , Precursores de Proteínas/biosíntesis , Precursores de Proteínas/genética , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , Receptores de Neuroquinina-1/fisiología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/metabolismo , Somatostatina/antagonistas & inhibidores , Somatostatina/genética , Bazo/citología , Bazo/metabolismo , Sustancia P/antagonistas & inhibidores , Linfocitos T/fisiologíaRESUMEN
Schistosome granulomas from normal or IL-4-deficient C57BL/6 mice make little IFN-gamma and show no Th1 polarization. This could signify that these granulomas have few cells capable of IFN-gamma synthesis or that such cells are under tight control. Granulomas can make IL-10 and TGF-beta, which can regulate IFN-gamma synthesis. Using FACS analysis and ELISA, we explored the origin and regulation of IFN-gamma in schistosome granulomas from both IL-4(-/-) and IL-4(+/+) mice. FACS analysis of intracytoplasmic IFN-gamma staining showed that some granuloma Thy1.2+ T cells (CD8+ and CD4+) express IFN-gamma. Granulomas had NK1.1+ cells, but they appeared to produce little or no IFN-gamma. Purified granuloma Thy1.2+ cells made IFN-gamma in vitro, whereas isolated NK1.1+ lymphocytes secreted little even with rIL-12 stimulation. Culture of granuloma cells with blocking anti-IL-10 or anti-TGF-beta mAb or with rIL-12 substantially increased T cell IFN-gamma synthesis, particularly in the IL-4(-/-) animals. Cultured granuloma cells depleted of Thy1.2+ lymphocytes by Ab and C released no IFN-gamma. It is concluded that granuloma IFN-gamma comes from T cells, not NK cells. Also, this T cell-derived IFN-gamma is subject to IL-10 and TGF-beta regulation, which is particularly evident in IL-4(-/-) mice. Thus, the Th2 granuloma of schistosomiasis has large numbers of activated Th1 or Th0 lymphocytes that are under tight restraint.
Asunto(s)
Granuloma/inmunología , Interferón gamma/biosíntesis , Interleucina-4/fisiología , Esquistosomiasis/inmunología , Animales , Femenino , Interleucina-10/fisiología , Interleucina-4/deficiencia , Células Asesinas Naturales/metabolismo , Ratones , Ratones Endogámicos C57BL , Linfocitos T/fisiología , Factor de Crecimiento Transformador beta/fisiologíaRESUMEN
Somatostatin (SOM) is a 14-amino acid cyclic peptide that regulates granulomatous inflammation. SOM inhibits the release of IFN-gamma from murine granuloma T cells that express SOM receptors. SOM is synthesized as preprosomatostatin (ppSOM), a precursor peptide that is cleaved to release active SOM. In this paper, we demonstrate that granuloma cells express mRNA for this important immunoregulator, and that inflammatory mediators rapidly induce ppSOM mRNA in the splenocytes of uninfected, normal (NL) mice. We developed a sensitive, quantitative PCR assay that measures ppSOM mRNA down to 100 transcripts per microg of total RNA. Dispersed granuloma cells expressed authentic ppSOM mRNA as determined by RT-PCR and cDNA sequencing. The PCR assay readily detected ppSOM mRNA in splenocytes isolated from schistosome-infected mice, but not in splenocytes from NL mice. Splenic ppSOM mRNA expression correlated with the onset of parasite egg deposition and granuloma formation. A 4-h in vitro stimulation with LPS, rIL-10, rIFN-gamma, rTNF-alpha, prostaglandin E2, or dibutyryl cAMP induced ppSOM mRNA in NL splenocytes that otherwise lacked this transcript. Splenocytes from severe combined immunodeficient or recombination activating gene 1-deficient mice expressed ppSOM after exposure to rIL-10, suggesting that neither T nor B cells are necessary for ppSOM mRNA induction. A survey of cell lines demonstrated expression of ppSOM mRNA by P388D1 and J774A.1 macrophage-like cells. These data suggest that SOM, which is probably derived from macrophages, is an inducible component of the innate immune system that regulates T cell IFN-gamma production.
Asunto(s)
Citocinas/farmacología , Mediadores de Inflamación/farmacología , Inflamación/genética , Inflamación/fisiopatología , Precursores de Proteínas/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Somatostatina/genética , Animales , Secuencia de Bases , Línea Celular , Citocinas/fisiología , Cartilla de ADN/genética , Femenino , Expresión Génica/efectos de los fármacos , Granuloma/genética , Granuloma/inmunología , Granuloma/patología , Mediadores de Inflamación/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Precursores de Proteínas/fisiología , Schistosoma mansoni/patogenicidad , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/patología , Somatostatina/fisiologíaRESUMEN
We describe a case of eosinophilic esophagitis in a 38-year-old man with aspirin-sensitivity asthma which presented as noncardiac chest pain. Manometric measurements demonstrated tertiary contractions. Biopsies showed a dense eosinophilic infiltrate in the mucosa. There was no response to therapy for reflux. Symptoms quickly resolved with corticosteroid therapy. Subsequent manometric values recorded after corticosteroid therapy showed resolution of the dysmotility. Biopsies showed normal mucosa. Adult asthmatic subjects with noncardiac chest pain should receive further investigation if reflux therapy fails to resolve the symptoms.
Asunto(s)
Dolor en el Pecho/etiología , Eosinofilia/complicaciones , Trastornos de la Motilidad Esofágica/etiología , Esofagitis/complicaciones , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Aspirina/efectos adversos , Asma/complicaciones , Eosinofilia/patología , Esofagitis/patología , Humanos , Masculino , ManometríaRESUMEN
Globally, schistosomes infect 1 in 30 people. Tourists travel to endemic areas, whereas students, workers, and expatriates travel to nonendemic areas. Physicians around the world need to remain aware of this common parasitic infection. Pathology results from parasite eggs that lodge in the intestines and liver. Intestinal schistosomiasis is most often asymptomatic and presents with occult gastrointestinal bleeding. Hepatosplenic schistosomiasis develops insidiously because of cumulative fibrotic injury. Stigmata of liver failure are absent unless comorbid viral or alcoholic hepatitis is present. Patients with end-stage hepatosplenic schistosomiasis die from variceal hemorrhage. Diagnosis of schistosomiasis is confirmed by finding eggs in stool or biopsy specimens. Antischistosome antibodies may identify infected tourists returning from endemic areas. Circulating schistosome antigens distinguish current from past infections. Praziquantel is the schistosomicidal drug of choice. Most cases of hepatosplenic schistosomiasis resolve after effective treatment. Prophylactic propranolol may prevent hemorrhage in praziquantel-treated patients with high-grade varices. Sclerotherapy is also efficacious. When necessary, patients with hepatosplenic schistosomiasis tolerate decompressive surgery well.
Asunto(s)
Schistosoma/fisiología , Esquistosomiasis/parasitología , Animales , Humanos , Masculino , Persona de Mediana Edad , Esquistosomiasis/diagnóstico , Esquistosomiasis/tratamiento farmacológico , Esquistosomiasis/epidemiología , Esquistosomiasis/fisiopatología , Esquistosomicidas/uso terapéuticoRESUMEN
The role of somatostatin (SRIF) in controlling the granulomatous inflammatory response to infection with the parasite Schistosoma mansoni was explored in mice. The murine granulomas contain SRIF-14. Immunoreactive SRIF and prepro SRIF localize in the cytoplasmic granules of macrophages within the granulomas. The granulomas contain mRNA for prepro SRIF and are not innervated. The production of SRIF by the inflammatory cells appears to be inducible. The granulomas contain mRNA for the SRIF receptors sst2A and sst2B, which are expressed mainly on CD4- T lymphocytes and bind SRIF-14 with high affinity. Antigens from the schistosome eggs stimulate granuloma T lymphocytes to produce cytokines. Interferon-gamma (IFN-gamma) is one such cytokine made by CD4+ T lymphocytes. SRIF-14 suppresses antigen-induced IFN-gamma production from granuloma cells, and this effect is blocked by anti-sst2 antibody. SRIF was shown to inhibit IFN-gamma-induced immunoglobulin G2a (lgG2a) synthesis in murine schistosomiasis. SRIF also blocks substance P (SP)-stimulated IFN-gamma and lgG2a secretion. Schistosome-infected animals treated with the SRIF analog octreotide form smaller granulomas that secrete substantially less IFN-gamma and lgG2a. Unpublished observations suggest that SRIF does not modulate schistosome egg antigen- or concanavalin A-stimulated granuloma lymphocyte proliferation in murine schistosomiasis. In conclusion, SRIF may be an important factor in the control of the granulomatous inflammatory response in murine schistosomiasis.
Asunto(s)
Granuloma/inmunología , Granuloma/fisiopatología , Sistema Inmunológico/fisiopatología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/fisiopatología , Somatostatina/fisiología , Animales , RatonesRESUMEN
Schistosomiasis mansoni is a disease characterized by liver and intestinal granulomas. Previous investigations in our laboratory showed that nylon wool-adherent CD4+ T lymphocytes isolated from murine hepatic schistosome granulomas express receptors for somatostatin 1-14. Moreover, somatostatin 1-14 substantially decreased IFN-gamma and IgG2a, but not IL-5 secretion by dispersed granuloma cells. This paper extends these observations by defining the somatostatin receptor (SSTR) isoform most likely expressed by granuloma inflammatory lymphocytes. Amplification of mRNA by reverse transcription PCR shows SSTR1, SSTR2, and SSTR3 mRNA in normal mouse brain and other tissues. Nevertheless, only the SSTR2 PCR product was amplified from granuloma cell RNA. The nucleotide sequence of the granuloma SSTR2 PCR product from inflammatory cells is identical to the CBA murine brain SSTR2 cDNA sequence. Granuloma-derived T cell lines, FACS-isolated granuloma CD4+ T cells, thymocytes, splenocytes, and cloned T cell lines all contain mRNA for SSTR2 by reverse transcription PCR. Moreover, both SSTR2A and the splice variant SSTR2B can be amplified from dispersed granuloma cells, granuloma T cell lines, thymocytes, and splenocytes. This is the first demonstration that inflammatory cells produce mRNA for an authentic somatostatin receptor. It is probable that the lymphocyte SSTR2 receptor mediates somatostatin-induced modulation of IFN-gamma secretion.
Asunto(s)
Receptores de Somatostatina/genética , Esquistosomiasis mansoni/inmunología , Linfocitos T/inmunología , Animales , Secuencia de Bases , Linfocitos T CD4-Positivos/fisiología , Cartilla de ADN/química , ADN Complementario/genética , Femenino , Expresión Génica , Granuloma/genética , Granuloma/inmunología , Hígado/parasitología , Ratones , Ratones Endogámicos CBA , Datos de Secuencia Molecular , ARN Mensajero/genética , Linfocitos T Colaboradores-Inductores/fisiologíaRESUMEN
Atypical vancomycin pharmacokinetics were observed in an immunoglobulin A myeloma patient. Drug concentrations in serum were extremely elevated, the elimination half-life was prolonged despite normal renal function, and the vancomycin therapy was ineffective. Extensive binding of vancomycin, presumably by high concentrations of an aberrant immunoglobulin A protein, may have accounted for these observations.
Asunto(s)
Inmunoglobulina A/metabolismo , Mieloma Múltiple/metabolismo , Vancomicina/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Proteínas Sanguíneas/metabolismo , Femenino , Semivida , Humanos , Persona de Mediana Edad , Mieloma Múltiple/complicaciones , Mieloma Múltiple/inmunología , Proteínas de Mieloma/inmunología , Proteínas de Mieloma/metabolismo , Unión Proteica , Vancomicina/uso terapéuticoRESUMEN
T-lymphocyte-adherent mononuclear cell interaction was analyzed in the vigorous and immunomodulated liver granulomas of Schistosoma mansoni-infected mice. Collagenase-dispersed granulomas contained 15% lymphocytes, 30% macrophages, 50% eosinophilis, and some neutrophils. Dispersed granuloma cells stimulated with concanavalin A or soluble worm egg antigens (SEA) did not proliferate unless plate-adherent, esterase-positive mononuclear cells were removed before culture. To analyze the granuloma adherent cell-mediated suppression, vigorous granuloma cell cultures partially depleted of adherent mononuclear cells were supplemented with indomethacin, catalase, superoxide dismutase, levamisole, and anti-murine alpha/beta interferon antiserum. In concanavalin A and SEA-stimulated cultures, only the addition of indomethacin or anti-alpha/beta interferon antiserum alleviated the adherent cell-mediated suppression of vigorous granuloma lymphocyte response. In contrast, these agents only minimally alleviated the suppressed response of SEA-stimulated, immunomodulated granuloma lymphocytes. Moreover, coculture of equal numbers of vigorous and immunomodulated granuloma cells partially depleted of adherent suppressor cells abrogated the alleviated response of vigorous granuloma lymphocytes. These findings indicate that, within the schistosome egg-induced vigorous granulomas, the adherent mononuclear cells exert regulation over lymphocyte responsiveness by alpha/beta-interferon and an indomethacin-sensitive, probably prostaglandin-mediated pathway. Within the immunomodulated granulomas, the adherent suppressor cell-mediated regulation of lymphocyte proliferation appears to play a lesser role.
Asunto(s)
Leucocitos Mononucleares/inmunología , Linfocitos/inmunología , Esquistosomiasis mansoni/inmunología , Animales , Antígenos Helmínticos/inmunología , Concanavalina A/farmacología , Granuloma/inmunología , Granuloma/patología , Tolerancia Inmunológica , Indometacina/farmacología , Interferón Tipo I/fisiología , Hepatopatías/inmunología , Hepatopatías/patología , Activación de Linfocitos , Ratones , Ratones Endogámicos CBA , Esquistosomiasis mansoni/patologíaRESUMEN
Previously it was shown that macrophages (M phi) isolated from the vigorous (Vig) or modulated (Mod) liver granulomas (Gr) of Schistosoma mansoni-infected mice restored mitogen and parasite egg antigen-induced proliferative responses to accessory cell-depleted lymphocytes. Furthermore, supraoptimal concentrations of highly activated VigGrM phi suppressed lymphoproliferation to a greater extent than did the lesser activated ModGrM phi. In this study we investigated the role of soluble mediators in GrM phi accessory/regulatory activity. Indomethacin released VigGrM phi-mediated inhibition of mitogen but not antigen-induced lymphoproliferation. Extensively dialyzed serum-free GrM phi culture supernatant nonspecifically suppressed SEA- or KLH-induced blastogenesis. Culture supernatants also reduced vesicular stomatitis virus-induced plaque formation in supernatant-pretreated L-929 fibroblasts. The 20 to 45 Kd GrM phi-derived lymphoproliferation suppressive factor (SF) and the 20 to 50 Kd viral plaque-reducing factor (PRF) were stable at low pH, but became inactivated by heat and trypsin digestion. Although freshly isolated Vig or ModGrM phi contained preformed SF and PRF, in vitro production of the factors were depressed by protein synthesis inhibitors. Moreover, SF was active only when added to cultures before day 3 of the 6-day proliferation assay. Both SF and PRF were specifically retained on rabbit anti-murine IFN-alpha/beta immunoaffinity columns. Thus, the suppressive activity of Vig or ModGrM phi is in part mediated by a monokine that shares physical, biological, and antigenic characteristics with murine IFN-alpha/beta. In contrast to the suppression of antigen-driven proliferation, GrM phi culture supernatant costimulated PHA-induced mitogenesis. The 13 to 21 Kd GrM phi-derived lymphocyte-activating factor (LAF) was stable to heat, low pH, and trypsin digestion. Freshly isolated Vig or ModGrM phi contained preformed LAF, although its in vitro production was depressed by protein synthesis inhibitors. The physical and biological characteristics of GrM phi-derived LAF appear similar to IL 1. It is concluded that both Vig and ModGrM phi secrete regulatory/accessory monokines that may contribute to the initiation and maintenance of the focal inflammatory granulomatous response.