RDP58, a novel immunomodulatory peptide with anti-inflammatory effects. A pharmacological study in trinitrobenzene sulphonic acid colitis and Crohn disease.
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.
Bourreille
A
A
Dept. of Gastroenterology, INSERM U 539 and CIC/INSERM, Hôtel Dieu, Nantes, France.
Doubremelle
M
M
de la Blétière
D Raingeard
DR
Segain
J P
JP
Toquet
C
C
Buelow
R
R
Galmiche
J P
JP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
D000893:Anti-Inflammatory Agents; D015395:Histocompatibility Antigens Class I; D007375:Interleukin-1; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C092373:allotrap; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid