Induction of Xeno-transplantation tolerance using mixed chimerism

背景：在非清髓性异基因骨髓移植中，共刺激因子阻断可以避免重复T细胞耗竭或胸腺照射，CD 4耗竭，导致混合嵌合体和供体特异性耐受。然而，尚未评估混合嵌合体对抗异种移植的潜力。方法：C57 BL/6小鼠在第1天接受抗CD 8（2.43）和/或NK-1.1（PK 136）+Thy-1.2（30-H12）单抗，第0天接受全身照射（TBI ; 3戈伊），第1天接受100 × 10^6异种F344大鼠骨髓细胞（BMC）。还注射了一次抗CD 40 L mAb（MR 1; 2 mg，第0天）。在骨髓移植后第0天进行异位心脏移植，以评估供体特异性耐受的诱导。供体细胞植入通过流式细胞术（FCM）analysis.Results：未接受治疗的小鼠（n=6）在8天内排斥大鼠心脏移植物。小鼠接受 ...更多信息 d单纯TBI（n=6）显示供体心脏稍有延长（MST，中位存活时间=12）。接受抗CD 8 mAb（第-1天）、MR 1（第0天）+TBI/BMT（第0天）（n=6）和MR 1（第0天）+TBI/BMT（第0天）（n=5）的小鼠未形成长期混合嵌合体，并且移植心脏在移植后不久（MST分别为35天和33天）即发生排斥反应。接受抗NK 1.1/Thy 1. 2单抗（第-1天）、MR 1（第0天）和TBI/BMT（第0天）（n=6）的小鼠仅在BMT后早期出现混合嵌合体，并显示移植物存活时间延长（MST= 61天）。接受抗CD 8/NK1.1/Thy1.2 mAb（第-1天）、MR 1（第0天）和TBI/BMT（第0天）的小鼠（n=6）最初出现混合嵌合体，然而，这些嵌合体在BMT后10周也消失。但这些小鼠接受供体大鼠心脏（MST> 250天）。仅用抗CD 8/NK1.1/Thy1.2单克隆抗体（第1天）和MR 1（第0天）处理的小鼠（n=5）也表现出供体大鼠心脏（MST=59）的轻微延长，并在移植后105天出现排斥反应。NK 1.1和Thy1.2阳性细胞在诱导异种心脏移植物一过性混合嵌合体和排斥反应中可能起重要作用。少

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 … More 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