Prolonged survival in rat liver transplantation with mouse monoclonal antibody against an inducible costimulator (ICOS).
BACKGROUND
An inducible costimulator (ICOS), a recently identified costimulatory receptor with a close structural homology to CD28 and CTLA4, is expressed on activated T cells. Interaction with its ligand on antigen-presenting cells stimulates T-cell proliferation to produce a different spectrum of cytokine. The inhibition of ICOS-mediated signal transduction by an anti-ICOS antibody is considered to be capable of protecting against graft rejection in organ transplantation.


METHODS
An anti-rat ICOS antibody was intravenously administered into recipients of dark Agouti-to-Lewis liver transplantations. The recipient lymphocytes from mesenteric lymph nodes were harvested on day 7 after transplantation for fluorescence-activated cell sorting analysis, and tissue specimens from the grafts were removed for histologic evaluation. Antigen-specific T-cell proliferation responses were assessed in vitro with anti-ICOS antibody.


RESULTS
Monotherapy with the antibody significantly prolonged the graft survival time by inhibiting T-cell activation and its proliferation response. The graft-infiltrating cells, both CD4 and CD8 T cells, were not completely reduced even when rats were administered the antibody, whereas the expression of ICOS almost completely disappeared in these cells.


CONCLUSIONS
T-cell activation through the ICOS costimulatory pathway plays an important role in graft rejection, and manipulating its pathway is an effective method for modulating transplantation immunity.
Guo
Lei
L
Department of Experimental Surgery and Bioengineering, National Children's Medical Research Center, Tokyo, Japan.
Li
Xiao-Kang
XK
Funeshima
Naoko
N
Fujino
Masayuki
M
Nagata
Yuhko
Y
Kimura
Hiromitsu
H
Amemiya
Hiroshi
H
Enosawa
Shin
S
Tsuji
Takashi
T
Harihara
Yasushi
Y
Makuuchi
Masatoshi
M
Suzuki
Seiichi
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology; D006085:Graft Survival; D007150:Immunohistochemistry; D060889:Inducible T-Cell Co-Stimulator Protein; D016031:Liver Transplantation; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C556694:Icos protein, mouse; C556695:Icos protein, rat; D060889:Inducible T-Cell Co-Stimulator Protein; D015375:Receptors, Interleukin-2