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International Immunology Advance Access published online on May 17, 2005
International Immunology, doi:10.1093/intimm/dxh256
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
Received February 3, 2005
Accepted March 10, 2005

Article

Prolonged skin allograft survival by IL-10 gene-introduced CD4 T cell administration

Takeshi Miyamoto 1, Takaaki Kaneko 2, Masakatsu Yamashita 2, Yoshiyuki Tenda 2, Masamichi Inami 2, Akane Suzuki 2, Sohtaro Ishii 2, Motoko Kimura 2, Kahoko Hashimoto 3, Hideaki Shimada 4, Hiroshi Yahata 5, Takenori Ochiai 4, Izumu Saito 6, James DeGregori 7, and Toshinori Nakayama 2*

1 Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan; Department of Academic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan
2 Department of Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan
3 Department of Life and Environmental Sciences and High Technology Research Center, Chiba Institute of Technology, Narashino, Tsudanuma, Chiba 275-0016, Japan
4 Department of Academic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuo-ku, Chiba 260-8670, Japan
5 Second Department of Surgery, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
6 Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
7 Department of Biochemistry and Molecular Genetics, University of Colorado Denver Health Sciences Center, Aurora, CO 80045, USA

* To whom correspondence should be addressed.
Toshinori Nakayama, E-mail: tnakayama{at}faculty.chiba-u.jp


  Abstract

Both CD4 and CD8 T cells play crucial roles in immune responses in transplantation. Immunosuppressive drugs, such as FK506 and cyclosporin A, block the priming of alloreactive CD4 Th cells and the subsequent induction of allospecific CD8 cytotoxic effector T cells and inhibit allograft rejection. However, the desire to minimize chronic complications that may arise from the use of immunosuppressive agents drives the search for additional strategies for immunosuppression of allograft rejection. In this study, CD4 or CD8 T cells into which the IL-10 gene is introduced using an adenovirus vector containing human IL-10 (hIL-10) cDNA (Ad-hIL-10) and into mouse T cells transgenic for the Coxsackie virus and adenovirus receptor form a model system to study the effect of administration of IL-10-secreting T cells on the survival of the allogenic skin grafts. Ad-hIL-10-infected CD4 and CD8 T cells secreted a large amount of hIL-10 for 3-4 days in culture in vitro. Ad-hIL-10-infected CD4 T cells administered in vivo could be detected in the spleen for 7 days post-transfer. Significantly prolonged survival of grafts was observed in animals that received either Ad-hIL-10-infected activated CD4 T cells or Th2-skewed CD4 T cells as compared with controls. Furthermore, substantial enhancement of the effect was observed in B6.C-H2bm1/ByJ transplants. Thus, a direct manipulation of T cells through the introduction of the immunosuppressive cytokine gene IL-10 may be a novel strategy for the control of allograft rejection.

Keywords: Bm1; CAR Tg; gene therapy; skin graft.
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