| Project/Area Number |
14571267
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Thoracic surgery
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| Research Institution | Yamaguchi University |
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Principal Investigator |
ITO Hiroshi (2003-2004) Yamaguchi University, University Hospital, Research Associate, 医学部附属病院, 助手 (90363100)
鈴木 一弘 (2002) 山口大学, 医学部附属病院, 助手 (40335740)
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| Co-Investigator(Kenkyū-buntansha) |
HAMANO Kimikazu Yamaguchi University, School of Medicine, Professor, 医学部, 教授 (60263787)
伊東 博史 山口大学, 医学部附属病院, 医員(臨床)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | xenotransplantation / tolerance / heart transplantation / mixed chimerism / costimulatory blockade / transplantation immunology |
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| Research Abstract |
Background :
Costimulatory blockade can obviate the need for repeated T cell depletion or thymic irradiation, CD4 depletion in an nonmyeloablative allogeneic bone marrow engraftment that leads to mixed chimerism and donor-specific tolerance. However, the potential of mixed chimerism against xenotransplantation has not been evaluated. Here we analyze the role of mixed chimerism and costimulatory blockade in xenogeneic heart transplantation tolerance.
Methods :
C57BL/6 mice received anti-CD8(2.43) and/or NK-1.1(PK136) plus Thy-1.2(30-H12)mAbs on day-1, total body irradiation(TBI ; 3 Gy)(day 0), and 100 × 10^6 xenogeneic F344 rat bone marrow cells(BMC). One injection of anti-CD40L mAb (MR1; 2mg, day0) was also given. Heterotopic heart transplantation was performed on day0 after BMT to assess induction of donor-specific tolerance. Donor cell engraftment was measured by flow cytometry (FCM) analysis.
Results :
Mice that received no treatment (n=6) rejected rat heart graft by 8 days. Mice receive
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d TBI alone (n=6) showed slightly prolongation of donor heart (MST, median survival time=12). Mice received anti- CD8 mAb (day-1), MR1 (day0) plus TBI/BMT(day0) (n=6) and mice received MR1 (day0) plus TBI/BMT(day0) (n=5) did not developed long-term mixed chimerism, and grafted heart were rejected soon after transplantation (MST=35day and 33day, respectively). Mice received anti-NK1.1/Thy1.2 mAbs (day-1), MR1(day0) plus TBI/BMT(day0) (n=6) developed mixed chimerism only early after BMT, and showed prolongation of graft survival (MST=61day). Mice received anti-CD8/NK1.1/Thy1.2 mAbs (day-1), MR1 (day0) plus TBI/BMT(day0) (n=6) initially developed mixed chimerism, however, those chimerism was also disappear by 10 weeks post BMT. However, those mice accepted donor rat heart (MST>250days). Mice treated only anti-CD8/NK1.1/Thy1.2 mAbs (day-1) and MR1 (day0) (n=5) also showed slight prolongation of donor rat heart (MST=59) and rejected by 105 days after transplantation.
Conclusion :
Prolongation of xenogeneic heart graft survival was achieved using costimulatory blockade and transient mixed chimerism. NK1.1 and Thy1.2 positive cells may play an important role in inducing transient mixed chimerism and rejection of xenogeneic heart graft. Less
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