RESUMEN
T helper type (Th17) cytokines such as interleukin (IL)-17A and IL-22 are important in maintaining mucosal barrier function and may be important in the pathogenesis of inflammatory bowel diseases (IBDs). Here, we analyzed cells from the colon of IBD patients and show that Crohn's disease (CD) patients had significantly elevated numbers of IL-17+, CD4+ cells compared with healthy controls and ulcerative colitis (UC) patients, but these numbers did not vary based on the inflammatory status of the mucosa. By contrast, UC patients had significantly reduced numbers of IL-22+ cells in actively inflamed tissues compared with both normal tissue and healthy controls. There was a selective increase in mono-IL-17-producing cells from the mucosa of UC patients with active inflammation together with increased expression of transforming growth factor (TGF)-ß and c-Maf. Increasing concentrations of TGF-ß in lamina propria mononuclear cell cultures significantly depleted Th22 cells, whereas anti-TGF-ß antibodies increased IL-22 production. When mucosal microbiota was examined, depletion of Th22 cells in actively inflamed tissue was associated with reduced populations of Clostridiales and increased populations of Proteobacteria. These results suggest that increased TGF-ß during active inflammation in UC may lead to the loss of Th22 cells in the human intestinal mucosa.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/metabolismo , Interleucinas/biosíntesis , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/microbiología , Mucosa Intestinal/citología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/patología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Microbiota , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Interleucina-22RESUMEN
BACKGROUND: Adalimumab, at an induction dose of 160/80 mg followed by 40 mg every other week is approved for treatment of refractory Crohn's disease (CD) and for patients with loss of response to infliximab. AIM: To evaluate the indications for adalimumab, the proportion of inflammatory bowel disease patients who require dose escalation and to identify whether this strategy is effective in inducing or maintaining remission. METHODS: Patients prescribed adalimumab for CD were identified and included for analysis, if they had follow-up of at least 6 weeks. Adalimumab dose was escalated if patients had return of symptoms prior to next dose. Clinical judgment was used to determine severity of disease. A second GI physician confirmed disease severity as determined by the first physician. RESULTS: A total of 48 out of 60 patients met inclusion criteria. Adalimumab was used to treat CD in 47/48 (98%) and ulcerative colitis in one (2%). Most patients had moderate 30/48 (63%) or severe 17/48 (35%) disease. Prior infliximab exposure was present in 42/48 (88%). Adalimumab dose escalation occurred in 14/48 (29%) within an average time of 2.2 months (s.d. 1.5 months). A majority of patients who required dose escalation, nine of 14 (64%) did not improve clinically. Steroids could be discontinued in three of 16 (18.8%). Clinical improvement was noted in 21/48 (43.8%) and one of 48 (2%) patients achieved clinical remission. Adverse drug reactions necessitated drug discontinuation in four of 48 (8%) of patients. CONCLUSIONS: This retrospective review from a single academic medical centre suggests that a minority of patients, who cannot be maintained on 40 mg every other week, of adalimumab benefit from an increased dose. This suggests the need for a treatment with an alternative mode of action in anti-TNF failures.
Asunto(s)
Antiinflamatorios/farmacocinética , Anticuerpos Monoclonales/farmacocinética , Enfermedad de Crohn/tratamiento farmacológico , Adalimumab , Adolescente , Antiinflamatorios/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infliximab , Masculino , Inducción de Remisión/métodos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenAsunto(s)
Trastornos Cerebrovasculares/fisiopatología , Sistema Digestivo/fisiopatología , Animales , Colon/fisiopatología , Trastornos de Deglución/fisiopatología , Sistema Digestivo/inervación , Duodeno/fisiopatología , Esófago/fisiopatología , Humanos , Trastornos Nutricionales/fisiopatología , Estómago/fisiopatologíaRESUMEN
This paper describes a new canine segmental spinal fusion model for the comparison of bone-grafting materials. The test sites in the model are three separate posterior interfacet-interlaminar fusion sites in the lumbar spine (L1-2, L3-4, and L5-6). The outcome was assessed by scoring of the fusion sites for union and by mechanical testing of fused segments. The results from two experiments are presented. Autogenous cancellous bone was the most effective material tested and had a statistically superior score for union compared with all other materials (p = 0.01). The results with an osteoconductive matrix of collagen and ceramic alone were no better than those with the controls (no graft). However, addition of an extract of matrix-derived proteins (15-30 kDa) to the collagen-ceramic carrier appeared to improve the score for union. The inclusion of nonresorbed ceramic granules had no evident effect on the mechanical properties of fusions, with a comparable score for union. This model appears to be a sensitive and efficient method for the comparison of graft materials. Advantages over previously described models are discussed.