TNFalpha blockade prevents the development of inflammatory bowel disease in HLA-B27 transgenic rats.
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.
Milia
Anna Franca
AF
Department of Biomedicine, Division of Rheumatology, University of Florence, Florence, Italy.
Manetti
Mirko
M
Generini
Sergio
S
Polidori
Lucia
L
Benelli
Gemma
G
Cinelli
Marina
M
Messerini
Luca
L
Ibba-Manneschi
Lidia
L
Matucci-Cerinic
Marco
M
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
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