title: Further study of anti-ICOS immunotherapy for rat cardiac allograft rejection.
abstract: OBJECTIVE
  To study the effect of B7-CD28 costimulatory signal blockade by adenovirus-mediated cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin (AdCTLA-4Ig) on cardiac allograft survival in DA (RT1(a)) to LEW (Lewis RT1(l)) rat combinations.
  
  
  METHODS
  We evaluated the effect of combined AdCTLA-4Ig and anti-inducible costimulator (ICOS) antibody immunotherapy on rat cardiac allograft acceptance.
  
  
  RESULTS
  Unlike AdCTLA-4Ig alone, anti-ICOS immunotherapy combined with AdCTLA-4Ig induced stable tolerance without causing chronic rejection. The combined immunotherapy also prevented the accelerated cardiac rejection caused by donor-type test skin grafting. Immunohistochemical analyses revealed remarkable inflammatory mononuclear cell infiltration with typical vasculopathy, especially ICOS-positive cells in the grafts, in recipients treated with AdCTLA-4Ig alone. In contrast, anti-ICOS therapy combined with AdCTLA-4Ig reduced the ICOS-positive inflammatory cell infiltration of the graft significantly. The most important finding is that possible cardiac arrest caused by secondary donor-type skin graft was prevented by combined immunotherapy of AdCTLA-4Ig and anti-ICOS antibody, despite skin graft rejection.
  
  
  CONCLUSIONS
  Our results identified a major role played by the ICOS-ICOSL pathway in chronic and accelerated cardiac allograft rejection, providing a novel approach to preventing the chronic rejection of vascularized organ allografts.
authors.affiliation: Department of Artificial Organ and Transplantation Surgery, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Xuan-Chao
authors.initials: XC
authors.lastname: Pan
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Ying-Bing
authors.initials: YB
authors.lastname: Deng
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Naruse
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kimura
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Sugawara
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Makuuchi