Open AccessTNFα blockade prevents the development of inflammatory bowel disease in HLA‐B27 transgenic rats
Author(s) -
Milia Anna Franca,
Manetti Mirko,
Generini Sergio,
Polidori Lucia,
Benelli Gemma,
Cinelli Marina,
Messerini Luca,
IbbaManneschi Lidia,
MatucciCerinic Marco
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00310.x
Subject(s) - tumor necrosis factor alpha , medicine , inflammatory bowel disease , inflammation , apoptosis , necrosis , immunology , gastroenterology , disease , biology , biochemistry
Rats transgenic for HLA‐B27 and human β2microglobulin (B27TR) develop a multi‐systemic disease resembling inflammatory bowel disease (IBD) and spondyloarthritis. TNFα has a crucial role in chronic inflammation. Our objective was to evaluate the effect of anti‐TNFα treatment on spontaneous IBD in B27TR. Nine‐week‐old B27TR received monoclonal anti‐TNFα 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‐TNFα or IgG2 a,k treatment. Each rat was monitored for clinical IBD manifestations. After sacrifice, the colon was examined for pathological changes. TNFα 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‐TNFα‐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‐TNFα 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‐TNFα‐treated animals. TNF‐R2 immunopositivity was strongly evident in IgG2a,k‐treated B27TR, whereas was absent in anti‐TNFα‐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‐TNFα treatment increased Fas‐L expression, whereas Fas increased only with the early treatment. TNFα blockade is effective in preventing inflammation in early phase of IBD, maintaining the homeostatic balance of apoptosis.