title: TNFalpha blockade prevents the development of inflammatory bowel disease in HLA-B27 transgenic rats.
abstract: Abstract Rats transgenic for HLA-B27 and human beta2microglobulin (B27TR) develop a multi-systemic disease resembling inflammatory bowel disease (IBD) and spondyloarthritis. TNFalpha has a crucial role in chronic inflammation. Our objective was to evaluate the effect of anti-TNFalpha treatment on spontaneous IBD in B27TR. Nine-week-old B27TR received monoclonal anti-TNFalpha or an isotypic IgG2a,k up to age of 18 weeks. A second group was monitored up to 18 weeks and then randomly assigned to anti-TNFalpha or IgG2 a,k treatment. Each rat was monitored for clinical IBD manifestations. After sacrifice, the colon was examined for pathological changes. TNFalpha receptors (TNF-R1, TNF-R2), Fas/Fas-L expression and apoptosis were evaluated. IgG2a,k-treated and untreated B27TR presented signs of IBD at 11 weeks, whereas in anti-TNFalpha-treated B27TR no IBD signs were detected. In the late treatment, IBD signs improved after 1 week. Histopathological analysis of IgG2a,k-treated B27TR colon showed inflammatory signs that were widely prevented by early anti-TNFalpha treatment. Late treatment did not significantly reduce inflammation. TNF-R1 was weakly expressed in intestinal epithelial cells of IgG2a,k-treated B27TR, while it was comparable to controls in anti-TNFalpha-treated animals. TNF-R2 immunopositivity was strongly evident in IgG2a,k-treated B27TR, whereas was absent in anti-TNFalpha-treated rats. RT-PCR confirmed these results. IgG2a,k-treated B27TR showed, at 18 weeks, few Fas-positive cells and an increase of Fas-L-positive cells. At 27 weeks, Fas-/Fas-L-positive cell number was significantly low. Anti-TNFalpha treatment increased Fas-L expression, whereas Fas increased only with the early treatment. TNFalpha blockade is effective in preventing inflammation in early phase of IBD, maintaining the homeostatic balance of apoptosis.
authors: Department of Biomedicine, Division of Rheumatology, University of Florence, Florence, Italy.
authors: Anna Franca
authors: AF
authors: Milia
authors: Mirko
authors: M
authors: Manetti
authors: Sergio
authors: S
authors: Generini
authors: Lucia
authors: L
authors: Polidori
authors: Gemma
authors: G
authors: Benelli
authors: Marina
authors: M
authors: Cinelli
authors: Luca
authors: L
authors: Messerini
authors: Lidia
authors: L
authors: Ibba-Manneschi
authors: Marco
authors: M
authors: Matucci-Cerinic
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D003106:Colon / Q000166:cytology / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D053222:Fas Ligand Protein / Q000276:immunology; D015796:HLA-B27 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000276:immunology; D025241:Spondylarthritis / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology; D019014:fas Receptor / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D053222:Fas Ligand Protein; D015796:HLA-B27 Antigen; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor