Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease.
OBJECTIVE
To investigate the role of inducible costimulator (ICOS), a new member of the CD28 family involved in regulation of T-cell activation and chronic intestinal inflammation, we assessed its expression and functional role in patients with inflammatory bowel disease (IBD).


METHODS
Expression of ICOS, CD28, and cytotoxic T-lymphocyte antigen (CTLA) 4 on intestinal lamina propria mononuclear cells (LPMC) from patients with ulcerative colitis (UC), Crohn's disease (CD), and normal controls was determined using flow cytometry and immunohistochemistry. Expressions of the ICOS ligand, B7h, on lamina propria B cells, macrophages, and epithelial cells (EC) in the intestinal mucosa were also determined using flow cytometry. The functional costimulatory effect of ICOS on LPMC was assessed by the proliferative response and cytokine production.


RESULTS
CD4(+) LPMC expressing ICOS was significantly increased in the inflamed mucosa of IBD patients but not in inflammatory or normal controls. B7h was also significantly up-regulated on B cells, macrophages, and EC in inflamed mucosa of IBD patients. Proliferative responses of anti-CD3/ICOS costimulation were significantly higher compared with those of anti-CD3 monoclonal antibody (mAb) alone. Anti-CD3/ICOS-stimulated-LPMC from UC secreted significantly increased amounts of interleukin (IL)-5 among the 3 groups. In contrast, anti-CD3/ICOS-stimulated-LPMC from CD secreted significantly increased amounts of interferon (IFN)-gamma in the presence of IL-12.


CONCLUSIONS
Highly expressed ICOS in activated CD4(+) LPMC of IBD patients contributes to the dysregulated immune responses in IBD. Because ICOS hyperexpression was limited to inflammatory sites in IBD patients, ICOS would be a feasible therapeutic target for the treatment of IBD.
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Toshiro
T
Sato
Takanori
T
Kanai
Mamoru
M
Watanabe
Atsushi
A
Sakuraba
Susumu
S
Okamoto
Takaaki
T
Nakai
Akira
A
Okazawa
Nagamu
N
Inoue
Teruji
T
Totsuka
Motomi
M
Yamazaki
Richard A
RA
Kroczek
Tsuneo
T
Fukushima
Hiromasa
H
Ishii
Toshifumi
T
Hibi
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism*; D017252:CD3 Complex / Q000276:immunology; D016022:Case-Control Studies; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D004357:Drug Synergism; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018664:Interleukin-12 / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D007700:Kinetics; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D016207:Cytokines; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D018664:Interleukin-12