| Co-Investigator(Kenkyū-buntansha) |
FUJISATO Toshiya National Cardiovascular Center, Regenerative medicine and tissue engineering, Laboratory chief, 再生医療部, 室長 (60270732)
TAKAHARA Shiro Osaka University Graduate School of Medicine, Advanced technology for Transplantation, Professor, 大学院・医学系研究科・先端移植基盤医療学, 教授 (70179547)
YAMADA Kazuhiko Harvard University School of Medicine, Surgery, Associated Professor (40241103)
OTA Masao Shinshu University School of Medicine, Legal medicine, Instructor (50115333)
ANDO Asako Tokai University School of Medicine, Molecular medicine, Instructor (40101935)
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| Research Abstract |
To induction of tolerance for organ transplantation, we have performed on analysis of SLA antigens in miniature swine, full SLA antigens mismatched organ transplantation and co-transplantation of vascularized thymic lobe administrated short-term immunosuppression in miniature swine. In inbred Clawn miniature swine, three haplotypes have been assined by RT-PCR of SLA class I and II genes. To determine of SLA antigens of Clawn miniature swine, we have developed a polymerase chain reaction-sequence specific primer (PCR-SSP) method for SLA class I (SLA-1,-2,-3 genes) and SLA class II (DRB1 gene), and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for SLA class II (DQB1 gene). Based on allele analysis of SLA class I and II genes, eleven different phenotype pattern and two new haplotypes were identified of this study. We have established pure-bred Clawn miniature swine, twenty-two of identified SLA gene homozygotes and nineteen of heterozygotes. We have
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transplanted seventeen hearts heterotopically across either minor mismatched or MHC-class II mismatched MHC-inbred miniature swine to assess (1)whether a short course of FK560 induces tolerance and prevents the development of cardiac allograft vasculopathy (CAV), and (2)whether a new immunosuppressant, FK778,which has been shown to have inhibitory effects on the cellular and humoral immune responses. The 12-day course of FK506 failed to induce tolerance in this model, but it did prolong the mean graft survival across a MHC-class II mismatched barrier compared with control model. The co-administration of FK778 with FK506 further prolong the mean graft survival, induced donor specific hyporesponsineness in vitro, and inhibited the development of CAV. We have previously reported the ability of vascularized thymic lobe (VTL) allografts to induce transplantation tolerance across full MHC mismatch in thymectomized miniature swine. In this study, we have investigated the mechanism of long-term acceptance in recipient swine following cotransplantation of VLT in fully MHC-mismatched cardiac transplantation heterotopically. All recipients that received a VTL maintained their grafts significantly longer than only heart graft, and those receiving 28days of tacrolimus maintained their heart graft long-term. Cytotoxic T-lymphocyte responses against third-party antigens by cells from tolerant animals showed restriction by both self and donor MHC, whereas responses of controls were restricted to self MHC only. The presence of donor dendritic cells in VTL grafts and results of co-culture assays suggested both central and regulatory mechanisms were involved an achieving long-term acceptance. Less
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