RESUMO
BACKGROUND: Tumour necrosis factor (TNF) plays a key role in the pathogenesis of Crohn disease (CD). RDP58 is a novel anti-inflammatory decapeptide which was developed using a novel rational design strategy. Recently, RDP58 has proved to be a potent inhibitor of TNF production at a post-transcriptional step. The aims of this study were to investigate the anti-inflammatory properties of RDP58 ex vivo in human CD and in vivo in an experimental model colitis. METHODS: Biopsies and lamina propria mononuclear cells from inflamed colonic mucosa of 18 CD patients were cultured for 24 h in the presence or absence of RDP58. TNF was quantified in a bioassay: interferon (IFN)-gamma and interleukin (IL)-1beta levels were measured by enzyme-linked immunosorbent assays. Colitis was induced by intra-rectal administration of 2, 4, 6 trinitrobenzene sulphonic acid (TNBS) in rats. Inflammation was assessed following 7 days of oral therapy with RDP58 or vehicle alone. RESULTS: RDP58 led to decreased TNF and IFN-gamma (but not IL-1beta) production by biopsies and lamina propria mononuclear cells from CD patients. In rats with TNBS-induced colitis, oral RDP58 therapy reduced weight loss and diarrhoea and improved macroscopic and histological inflammation scores. CONCLUSIONS: Our results suggest that RDP58 may be an effective therapy for CD with the clinical advantage of an oral administration.
Assuntos
Anti-Inflamatórios/farmacologia , Colite/imunologia , Doença de Crohn/imunologia , Antígenos de Histocompatibilidade Classe I/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Peptídeos/farmacologia , Adolescente , Adulto , Idoso , Animais , Anti-Inflamatórios/uso terapêutico , Colite/induzido quimicamente , Doença de Crohn/tratamento farmacológico , Feminino , Antígenos de Histocompatibilidade Classe I/uso terapêutico , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-1/biossíntese , Interleucina-1/imunologia , Masculino , Pessoa de Meia-Idade , Modelos Animais , Peptídeos/uso terapêutico , Estudos Prospectivos , Ratos , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Tumour necrosis factor (TNF) plays a key role in the pathogenesis of Crohn disease (CD). RDP58 is a novel anti-inflammatory decapeptide which was developed using a novel rational design strategy. Recently, RDP58 has proved to be a potent inhibitor of TNF production at a post-transcriptional step. The aims of this study were to investigate the anti-inflammatory properties of RDP58 ex vivo in human CD and in vivo in an experimental model colitis. METHODS: Biopsies and lamina propria mononuclear cells from inflamed colonic mucosa of 18 CD patients were cultured for 24â h in the presence or absence of RDP58. TNF was quantified in a bioassay; interferon (IFN)-γ and interleukin (IL)-1ß levels were measured by enzyme-linked immunosorbent assays. Colitis was induced by intra-rectal administration of 2, 4, 6 trinitrobenzene sulphonic acid (TNBS) in rats. Inflammation was assessed following 7 days of oral therapy with RDP58 or vehicle alone. RESULTS: RDP58 led to decreased TNF and IFN-γ (but not IL-1ß) production by biopsies and lamina propria mononuclear cells from CD patients. In rats with TNBS-induced colitis, oral RDP58 therapy reduced weight loss and diarrhoea and improved macroscopic and histological inflammation scores. CONCLUSIONS: Our results suggest that RDP58 may be an effective therapy for CD with the clinical advantage of an oral administration.
