Eicosapentenoic Acid Attenuates Allograft Rejection in an HLA-B27/EGFP Transgenic Rat Cardiac Transplantation Model

Zhong Liu; Naoyuki Hatayama; Lin Xie; Ken Kato; Ping Zhu; Takahiro Ochiya; Yukitoshi Nagahara; Xiang Hu; Xiao-Kang Li

doi:10.3727/215517912X639379

Eicosapentenoic Acid Attenuates Allograft Rejection in an HLA-B27/EGFP Transgenic Rat Cardiac Transplantation Model

Cell Med. 2012 May 8;3(1-3):63-74. doi: 10.3727/215517912X639379. eCollection 2012 Jan.

Authors

Zhong Liu¹, Naoyuki Hatayama², Lin Xie², Ken Kato³, Ping Zhu², Takahiro Ochiya⁴, Yukitoshi Nagahara⁵, Xiang Hu⁶, Xiao-Kang Li²

Affiliations

¹ Division of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development, Tokyo, Japan; §Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, China.
² Division of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development , Tokyo , Japan.
³ Division of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development, Tokyo, Japan; †Department of Biomedical Sciences, Tokyo Denki University, Saitama, Japan.
⁴ ‡ Section for Studies on Metastasis, National Cancer Center Research Institute , Tokyo , Japan.
⁵ † Department of Biomedical Sciences, Tokyo Denki University , Saitama , Japan.
⁶ § Department of General Surgery, First Affiliated Hospital of Dalian Medical University , Dalian , China.

Abstract

The development of an animal model bearing definite antigens is important to facilitate the evaluation and modulation of specific allo-antigen responses after transplantation. In the present study, heterotopic cardiac transplantation was performed from F344/EGFPTg and F344/HLA-B27Tg rats to F344 rats. The F344 recipients accepted the F344/EGFPTg transplants, whereas they rejected the cardiac tissue from the F344/HLA-B27Tg rats by 39.4 ± 6.5 days, due to high production of anti-HLA-B27 IgM- and IgG-specific antibodies. In addition, immunization of F344 rats with skin grafts from F344/HLA-B27Tg rats resulted in robust production of anti- HLA-B27 IgM and IgG antibodies and accelerated the rejection of a secondary cardiac allograft (7.4 ± 1.9 days). Of interest, the F344 recipients rejected cardiac grafts from double transgenic F344/HLA-B27&EGFPTg rats within 9.0 ± 3.2 days, and this was associated with a significant increase in the infiltration of lymphocytes by day 7, suggesting a role for cellular immune rejection. Eicosapentenoic acid (EPA), one of the ω-3 polyunsaturated fatty acids in fish oil, could attenuate the production of anti-HLA IgG antibodies and B-cell proliferation, significantly prolonging double transgenic F344HLA-B27&EGFPTg to F344 rat cardiac allograft survival (36.1 ± 13.6 days). Moreover, the mRNA expression in the grafts was assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR), revealing an increase in the expression of the HO-1, IL-10, TGF-β, IDO, and Foxp3 genes in the EPA-treated group. Hence, our data indicate that HLA-B27 and/or GFP transgenic proteins are useful for establishing a unique animal transplantation model to clarify the mechanism underlying the allogeneic cellular and humoral immune response, in which the transplant antigens are specifically presented. Furthermore, we also demonstrated that EPA was effective in the treatment of rat cardiac allograft rejection and may allow the development of novel immunomodulatory strategies for organ transplantation.

Keywords: Allograft; GFP; HLA-B27; Regulatory T cell; Tolerance; Transgenic rat.