title: Elimination of colonic patches with lymphotoxin beta receptor-Ig prevents Th2 cell-type colitis.
abstract: Past studies have shown that colonic patches, which are the gut-associated lymphoreticular tissues (GALT) in the colon, become much more pronounced in hapten-induced murine colitis, and this was associated with Th2-type T cell responses. To address the role of GALT in colonic inflammation, experimental colitis was induced in mice either lacking organized GALT or with altered GALT structures. Trinitrobenzene sulfonic acid was used to induce colitis in mice given lymphotoxin-beta receptor-Ig fusion protein (LTbetaR-Ig) in utero, a treatment that blocked the formation of both Peyer's and colonic patches. Mice deficient in colonic patches developed focal acute ulcers with Th1-type responses, whereas lesions in normal mice were of a diffuse mucosal type with both Th1- and Th2-type cytokine production. We next determined whether LTbetaR-Ig could be used to treat colitis in normal or Th2-dominant, IFN-gamma gene knockout (IFN-gamma(-/-)) mice. Four weekly treatments with LTbetaR-Ig resulted in deletion of Peyer's and colonic patches with significant decreases in numbers of dendritic cells. This pretreatment protected IFN-gamma(-/-) mice from trinitrobenzene sulfonic acid-induced colitis; however, in normal mice this weekly treatment was less protective. In these mice hypertrophy of colonic patches was seen after induction of colitis. We conclude that Th2-type colitis is dependent upon the presence of colonic patches. The effect of LTbetaR-Ig was mediated through prevention of colonic patch hypertrophy in the absence of IFN-gamma. Thus, LTbetaR-Ig may offer a possible treatment for the Th2-dominant form of colitis.
authors.affiliation: Department of Gastroenterology, Research Institute, International Medical Center of Japan, Tokyo, Japan. dohi@ri.imcj.go.jp
authors.forename: T
authors.initials: T
authors.lastname: Dohi
authors.forename: P D
authors.initials: PD
authors.lastname: Rennert
authors.forename: K
authors.initials: K
authors.lastname: Fujihashi
authors.forename: H
authors.initials: H
authors.lastname: Kiyono
authors.forename: Y
authors.initials: Y
authors.lastname: Shirai
authors.forename: Y I
authors.initials: YI
authors.lastname: Kawamura
authors.forename: J L
authors.initials: JL
authors.lastname: Browning
authors.forename: J R
authors.initials: JR
authors.lastname: McGhee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology; D003092:Colitis / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007136:Immunoglobulins / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D053259:Lymphotoxin beta Receptor; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D011247:Pregnancy; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D016207:Cytokines; D007136:Immunoglobulins; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma