Ameliorating effect of anti-inducible costimulator monoclonal antibody in a murine model of chronic colitis

Teruji Totsuka, Takanori Kanai, Ryoichi Iiyama, Koji Uraushihara, Motomi Yamazaki, Ryuichi Okamoto, Toshifumi Hibi, Katsunari Tezuka, Miyuki Azuma, Hisaya Akiba, Hideo Yagita, Ko Okumura, Mamoru Watanabe

Research output: Contribution to journalArticlepeer-review

65 Citations (Scopus)

Abstract

Background & Aims: Inducible costimulator (ICOS)/B7RP-1 represents a newly described receptor/ligand pair involved in costimulation of T cells by antigen-presenting cells. We investigated the involvement of the ICOS/B7RP-1 interaction in the pathogenesis of colitis and the therapeutic potential of anti-ICOS monoclonal antibody (mAb) in experimental colitis. Methods: We administered anti-ICOS or anti-B7RP-1 mAb to mice with experimental colitis induced by transfer of CD4+CD45RBhigh T cells from normal mice into SCID mice. The ability of CD4+CD45RBhigh cells derived from ICOS-/- mice to induce colitis was assessed. Th2 cytokine production and apoptosis in infiltrating T cells was examined after administration of anti-ICOS mAb. Results: ICOS was strongly induced on CD4+ T cells, and B7RP-1 was expressed by macrophages in the inflamed mucosa of colitic mice. Anti-ICOS mAb, but not anti-B7RP-1, ameliorated chronic colitis when administered in prevention or therapeutic protocols. Transfer of CD4+CD45RBhigh T cells from ICOS-/- mice induced colitis. Treatment with anti-ICOS mAb did not enhance the production of Th2 cytokines, but a single dose of anti-ICOS mAb induced massive apoptosis of infiltrating ICOS-expressing T cells. Conclusions: ICOS/B7RP-1 interactions are not required for the development of colitis. However, treatment with anti-ICOS mAb can prevent and reverse intestinal inflammation by inducing apoptosis of ICOS-expressing T lymphocytes.

Original languageEnglish
Pages (from-to)410-421
Number of pages12
JournalGastroenterology
Volume124
Issue number2
DOIs
Publication statusPublished - 2003 Feb 1
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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