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A Novel Peptide Mimotope Identified As a Potential Immunosuppressive Vaccine for Organ Transplantation

Kuei-Chen Chiang^1,*, Yayoi Shimada^1,*, Toshiaki Nakano, Chia-Yun Lai, Li-Wen Hsu, Shigeru Goto^,¶, Naoya Ohmori^*,, Kenji Mori^*,, Takamitsu Miyagi^*,, Seiji Kawamoto, Kazuhisa Ono, Chao-Long Chen, Takeshi Goto^2,*, and Shuji Sato^*,

^* Kazusa Institute for Drug Discovery, Josai International University, Kisarazu, Chiba, Japan; Faculty of Pharmaceutical Sciences, Josai International University, Togane, Chiba, Japan; Liver Transplantation Program, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Niao-Sung, Kaohsiung, Taiwan; Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan; and ^¶ Iwao Hospital, Yufuin, Oita, Japan

We reported that anti-histone H1 autoantibody is one of the main immunosuppressive factors in serum that is induced after orthotopic liver transplantation in a rat tolerogenic model. We generated a novel anti-histone H1 IgM mAb produced by hybridoma 16G9 (16G9 mAb) that shows MLR-inhibitory activity. Identification of a functional epitope responsible for the immunosuppressive activity of 16G9 mAb may lead to the establishment of a novel therapeutic strategy. We used a combinatorial phage display peptide library to screen for peptides that bind to 16G9 mAb. Consequently, two peptides that bind to 16G9 mAb, SSV and LPQ, were selected from the library. The binding of 16G9 mAb to histone H1 was inhibited by SSV. SSV was recognized by rat tolerogenic post-orthotopic liver transplantation serum and the binding to SSV was inhibited by histone H1. Mice were immunized with keyhole limpet hemocyanin-conjugated SSV and LPQ. Abs induced by SSV immunization inhibited Con A-stimulated splenocyte proliferation, and the inhibition was neutralized by preincubation with SSV. Splenocytes stimulated by anti-CD3 Ab were inhibited by SSV-induced Abs using CFSE labeling. SSV immunization in rats before heterotopic heart transplantation resulted in significant prolonged allograft survival. These findings suggested that SSV is a functional histone H1-binding epitope for 16G9 mAb. SSV is capable of determining serum immunoreactivity against histone H1 as an index marker for tolerance. The inhibitory activity of SSV-induced Abs on blast cell proliferation and the prolonged graft survival that results from SSV immunization imply a potential for the development of an immunosuppressive vaccine.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ K.-C.C. and Y.S. contributed equally to this work.

² Address correspondence and reprint requests to Dr. Takeshi Goto, Kazusa Institute for Drug Discovery, Josai International University, 2-1-6 Kazusa-Kamatari, Kisarazu, Chiba 292-0818, Japan. E-mail address: tgoto{at}jiu.ac.jp

³ Abbreviations used in this paper: OLT, orthotopic liver transplantation; HHT, heterotopic heart transplantation; KLH, keyhole limpet hemocyanin; MHCH, MHC haplotype; 7-AAD, 7-aminoactinomycin D.