Ameliorating effect of anti-inducible costimulator monoclonal antibody in a murine model of chronic colitis.
OBJECTIVE
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(+)CD45RB(high) T cells from normal mice into SCID mice. The ability of CD4(+)CD45RB(high) 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(+)CD45RB(high) 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.
Totsuka
Teruji
T
Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Japan.
Kanai
Takanori
T
Iiyama
Ryoichi
R
Uraushihara
Koji
K
Yamazaki
Motomi
M
Okamoto
Ryuichi
R
Hibi
Toshifumi
T
Tezuka
Katsunari
K
Azuma
Miyuki
M
Akiba
Hisaya
H
Yagita
Hideo
H
Okumura
Ko
K
Watanabe
Mamoru
M
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D017209:Apoptosis; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10 / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D016513:Mice, SCID; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D016207:Cytokines; C556694:Icos protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10; D017493:Leukocyte Common Antigens