Tolerance induction by intrathymic injection of allopeptides.

Research Project

Project/Area Number	07807109
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	General surgery
Research Institution	The University of Tokyo
Principal Investigator	ANDO Yuichi The University of Tokyo, The Institute of Medical Science, Research Associate, 医科学研究所, 教務職員 (00262080)
Co-Investigator(Kenkyū-buntansha)	TAKIGUCHI Masafumi The University of Tokyo, The Institute of Medical Science, Research Associate, 医科学研究所, 助手 (00183450) BECK Yoshifumi The University of Tokyo, The Institute of Medical Science, Research Associate, 医科学研究所, 助手 (70199454)
Project Period (FY)	1995 – 1996
Project Status	Completed (Fiscal Year 1996)
Budget Amount *help	¥2,400,000 (Direct Cost: ¥2,400,000) Fiscal Year 1996: ¥900,000 (Direct Cost: ¥900,000) Fiscal Year 1995: ¥1,500,000 (Direct Cost: ¥1,500,000)
Keywords	synthetic peptide / MHC class I / transgenic mice / intrathimic injection / heart transplantation / 合成アプチド
Research Abstract	PURPOSE : One of possible methods to achieve donor specific tolerance is intrathymic injection of donor antigen, but no report was available about intrathymic injection of peptides of donor MHC class I molecules. In order to analyze the role of HLA class I molecules on graft rejection, two different HLA class I transgenic mice were selected and transplantation was performed. In addition, peptides from one of the HLA class I were injected intrathymically to the other HLA class I transgenic mouse to study the possibility of specific tolerance induction. METHODS : A skin graft from an HLA-B35 transgenic mouse (HLA-B35TGM), in which the HLA-B35^01 gene is transfected to C3H/He, was transplanted to HLA-B51 transgenic mice (HLA-B51TGM), in which the HLA-B51^01 gene is transfected to C3H/He. Seven kinds of 23 to 25 mer synthetic peptides, representing full sequences of the polymorphic lesion of HLA-B35, were injected to the thymus of HLA-B51TGM.Two days after intrathymic injection, HLA-B35TG … More M heart was transplanted. Rejection of the heart graft was judged by palpation and histopathological findings. Standard CML assay was performed between the transgenic mice to study the specific cellular cytotoxity. RESULTS : Skin grafts from HLA-B35TGM transplanted to HLA-B51TGM were rejected 12.6 (]SY.+-。[) 4.2 days (mean (]SY.+-。[) SD) after transplantation. Specific cytotoxity was detected by CML assay and this effect was significant when responder cells were primed by skin grafting. Heart grafts from HLA-B35 TGM transplanted into HLA-B51TGM was rejected on 22.8 (]SY.+-。[) 4.2 days after transplantation, whereas mean heart graft survival was more than 60 days when some HLA-B35 peptides were injected intrathymically to HLA-B51TGM prior to heart transplantation. CONCLUSIONS : 1. HLA-B51TGM reject HLA-B35TGM skin and heart graft mainly by cellular mechanism, and these mice are useful to study the role of HLA class I molecules on graft rejection. 2. Intrathymic injection of peptides derivedfrom donor HLA class I molecules has a great chance to induce donor specific tolerance. Less