Prolonged survival in rat liver transplantation with mouse monoclonal antibody against an inducible costimulator (ICOS)1.
Guo, Lei 2,3; Li, Xiao-Kang 2; Funeshima, Naoko 2; Fujino, Masayuki 2; Nagata, Yuhko 2; Kimura, Hiromitsu 2; Amemiya, Hiroshi 2; Enosawa, Shin 2; Tsuji, Takashi 4; Harihara, Yasushi 3; Makuuchi, Masatoshi 3; Suzuki, Seiichi 2,5
73(7):1027-1032, April 15, 2002.
(Format: HTML, PDF)
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.
(C) 2002 Lippincott Williams & Wilkins, Inc.