Role of the ICOS-B7h costimulatory pathway in the pathophysiology of chronic allograft rejection.
BACKGROUND
Inducible costimulator (ICOS) is the third member of the CD28 superfamily and has a unique role in T cell activation and function. Recent studies indicated that the ICOS-B7h pathway plays an important role in alloimmune responses. We further investigated the role of the ICOS pathway in the pathologic process of chronic rejection in vivo.


METHODS
An established major histocompatibility complex class II disparate cardiac transplantation model was used. We treated mice with a blocking anti-B7h monoclonal antibody (mAb) either in the initiation phase (early blockade) or in the progression phase (delayed blockade) of disease. In addition, some mice received mAb in the entire period (whole blockade). At 6 weeks after transplantation, cardiac grafts were evaluated by histopathologic analysis in terms of vasculopathy, fibrosis, and cellular infiltration. The intragraft expressions of cytokines and chemokines were also examined by quantitative real-time polymerase chain reaction analysis.


RESULTS
Early blockade of the ICOS-B7h pathway did not show any protective effect on chronic allograft rejection compared with untreated controls. In contrast, delayed blockade significantly inhibited the development of vasculopathy, fibrosis, and cellular infiltration (P=0.043, P=0.004, and P=0.03 vs. untreated control, respectively). Interestingly, whole blockade did not prevent the chronic rejection process. Furthermore, the inhibitory effect of delayed ICOS blockade on chronic rejection was associated with down-regulation of local intragraft expression of several cytokines and chemokines.


CONCLUSIONS
These data suggest that the ICOS-B7h pathway is critical in the activation of effector/memory T cells that are necessary for the progression of chronic rejection and provide the rationale to develop novel and specific therapies to prevent this process.
Kashizuka
Hisanori
H
Department of Surgery, Nara Medical University School of Medicine, Kashihara, Nara, Japan.
Sho
Masayuki
M
Nomi
Takeo
T
Ikeda
Naoya
N
Kuzumoto
Yukiyasu
Y
Akashi
Satoru
S
Tsurui
Yoshikazu
Y
Mizuno
Takashi
T
Kanehiro
Hiromichi
H
Yagita
Hideo
H
Nakajima
Yoshiyuki
Y
Sayegh
Mohamed H
MH
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D002908:Chronic Disease; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007108:Immune Tolerance; D007156:Immunologic Memory; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology* / Q000473:pathology
D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011506:Proteins