Tolerance induction in xenogeneic transplantation using anti-CD27 antibody

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 15591347
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: Yamaguchi University
• Principal Investigator: ENOKI Tadahiko Yamaguchi University, Hospital, Assistant Professor, 医学部附属病院, 講師 (80311819)
• Co-Investigator(Kenkyū-buntansha): HAMANO Kimikazu Yamaguchi Universyty, Faculty of Medicine, Professor, 医学部, 教授 (60263787) ; ITO Hiroshi Yamaguchi University, Hospital, Research Assistant, 医学部附属病院, 助手 (90363100)
• Project Period (FY): 2003 – 2005
• Keywords: xenotransplantation / tolerance / CD27

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 CD27-CD70 blockade in xenogeneic heart transplantation.
Methods :
C57BL/6 mice received anti-CD8(2.43) or anti-CD27 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, day 0) was also given. Heterotopic heart transplantation was performed on day 0 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 receiv ed TBI alone (n=6) showed slightly prolongation of donor heart (MST, median survival time=12). Mice received anti- CD8 mAb (day-1), MR1 (day 0) plus TBI/BMT(day 0)(n=6) and mice received MR1 (day 0) plus TBI/BMT(day 0)(n=5) did not developed long-term mixed chimerism, and grafted heart were rejected soon after transplantation (MST=35day and 33 day, respectively). Mice received anti-NK1.1/Thy1.2 mAbs (day-1), MR1(day 0) plus TBI/BMT(day 0)(n=6) developed mixed chimerism only early after BMT, and showed prolongation of graft survival (MST=61 day). Mice received anti-CD8/NK1.1/Thy1.2 mAbs (day-1), MR1 (day 0) plus TBI/BMT(day 0)(n=6) initially developed mixed chimerism, however, those chimerism was also disappear by 10 weeks post BMT. Those mice accepted donor rat heart (MST>250 days). Mice received anti-CD27 antibody plus MR1/NK1.1/Thy1.2 mAb did not developed mixed chimerism and tolerance(n=4). In allotransplantation model, anti-CD27 plus MR1 could not developed mixed chimerism (n=5).
Conclusion :
Blocking of CD27-CD70 interaction could not prevent CD8 mediated allo and xeno rejection in transplantation model using mixed chimerism.