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Further study of anti-ICOS immunotherapy for rat cardiac allograft rejection

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Abstract

Purpose

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 (RT1a) to LEW (Lewis RT1l) 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.

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Authors and Affiliations

  1. Department of Artificial Organ and Transplantation Surgery, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan

    Xuan-Chao Pan, Lei Guo, Ying-Bing Deng, Katsutoshi Naruse, Yasuhiko Sugawara & Masatoshi Makuuchi

  2. Department of Research Surgery, Division of Collaborative Research, National Research Center for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo, 157-8535, Japan

    Xuan-Chao Pan & Hiromitsu Kimura

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  1. Xuan-Chao Pan
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Pan, XC., Guo, L., Deng, YB. et al. Further study of anti-ICOS immunotherapy for rat cardiac allograft rejection. Surg Today 38, 815–825 (2008). https://doi.org/10.1007/s00595-007-3734-y

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  • DOI: https://doi.org/10.1007/s00595-007-3734-y

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