RESUMEN
OBJECTIVE: Vedolizumab, a monoclonal antibody directed against the integrin heterodimer α4ß7, is approved for the treatment of Crohn's disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNFα antibody infliximab as control. DESIGN: Immunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNFα antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy. RESULTS: Vedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, α4ß7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNFα antibody infliximab, and associated with inhibition of intestinal inflammation. CONCLUSION: Our findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD. TRIAL REGISTRATION NUMBER: NCT02694588.
Asunto(s)
Inmunidad Adaptativa/efectos de los fármacos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Inmunidad Innata/efectos de los fármacos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , Adulto , Biopsia , Estudios de Casos y Controles , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Infliximab/uso terapéutico , Integrinas/antagonistas & inhibidores , Masculino , Fenotipo , Estudios Prospectivos , Análisis de Secuencia de ARN , Linfocitos T/inmunología , Tomografía Computarizada de Emisión de Fotón ÚnicoAsunto(s)
Biomarcadores/análisis , Colitis Ulcerosa/sangre , Enfermedad de Crohn/sangre , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Estudios de Casos y Controles , Colitis Ulcerosa/diagnóstico , Enfermedad de Crohn/diagnóstico , Humanos , Sensibilidad y EspecificidadRESUMEN
Following up on recent genome-wide association studies (GWAS) of Crohn's disease, we investigated 50 previously reported susceptibility loci in a German sample of individuals with Crohn's disease (n = 1,850) or ulcerative colitis (n = 1,103) and healthy controls (n = 1,817). Among these loci, we identified variants in 3p21.31, NKX2-3 and CCNY as susceptibility factors for both diseases, whereas variants in PTPN2, HERC2 and STAT3 were associated only with ulcerative colitis in our sample collection.