Further study of anti-ICOS immunotherapy for rat cardiac allograft rejection.
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.
Pan
Xuan-Chao
XC
Department of Artificial Organ and Transplantation Surgery, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Guo
Lei
L
Deng
Ying-Bing
YB
Naruse
Katsutoshi
K
Kimura
Hiromitsu
H
Sugawara
Yasuhiko
Y
Makuuchi
Masatoshi
M