Gammie J S, Li S, Zeevi A, Demetris A J, Ildstad S T, Pham S M
Division of Cardiothoracic Surgery, University of Pittsburgh Medical Center, PA 15261, USA.
Circulation. 1998 Nov 10;98(19 Suppl):II163-8; discussion II168-9.
Thoracic organ transplantation remains limited by the reciprocal problems of rejection and the toxicities of nonspecific immunosuppression. Mixed bone marrow chimerism reliably produces donor-specific transplantation tolerance without immunosuppressive drugs. We have previously described a nonmyeloablative conditioning regimen based on recipient treatment with antilymphocyte serum, tacrolimus, and low-dose total-body irradiation that yields long-term multilineage allogeneic bone marrow chimerism in the rat. We have now investigated whether mixed bone marrow chimerism that arises from this partial conditioning strategy produces permanent acceptance of donor-specific cardiac allografts.
Mixed allogeneic chimeras (ACI-->WF) were prepared by treating Wistar Furth recipients with a single dose of antilymphocyte serum 5 days before bone marrow transplantation and tacrolimus 1 mg/kg/d from days -1 to 10. Five hundred cGy total-body irradiation was administered immediately before infusion of 1 x 10(8) donor (ACI) T-cell depleted marrow cells. All recipients were chimeric, with a mean level of donor chimerism = 26.3 +/- 3.5%. Chimeras underwent heterotopic cardiac transplantation 4 weeks after bone marrow transplantation. All donor-specific (ACI) grafts were permanently accepted (follow-up, 230 to 360 days). Third-party grafts were rapidly rejected. Histology of long-surviving donor-specific grafts was without evidence of acute or chronic rejection. Second-set donor-specific skin grafts transplanted to chimeras 135 days after heart transplantation showed long-term survival (> 130 days), whereas third-party skin grafts were rapidly rejected. Mixed lymphocyte reaction demonstrated in vitro donor-specific hyporeactivity.
A tacrolimus-based nonmyeloablative recipient conditioning regimen produces mixed bone marrow chimerism and donor-specific tolerance to cardiac allografts in the rat.
胸段器官移植仍然受到排斥反应和非特异性免疫抑制毒性等相互关联问题的限制。混合骨髓嵌合体能够在不使用免疫抑制药物的情况下可靠地产生供体特异性移植耐受。我们之前描述了一种基于受体接受抗淋巴细胞血清、他克莫司和低剂量全身照射的非清髓性预处理方案，该方案可在大鼠中产生长期多谱系异基因骨髓嵌合体。我们现在研究了这种部分预处理策略产生的混合骨髓嵌合体是否能使供体特异性心脏异体移植物被永久接受。
通过在骨髓移植前5天给Wistar Furth受体单次注射抗淋巴细胞血清，并在第-1天至第10天给予1mg/kg/d的他克莫司，制备混合异基因嵌合体（ACI→WF）。在输注(1×10^8)个供体（ACI）去除T细胞的骨髓细胞前立即给予500cGy全身照射。所有受体均形成嵌合体，供体嵌合率平均为26.3±3.5%。嵌合体在骨髓移植后4周接受异位心脏移植。所有供体特异性（ACI）移植物均被永久接受（随访230至360天）。第三方移植物被迅速排斥。长期存活的供体特异性移植物的组织学检查未发现急性或慢性排斥反应的证据。心脏移植后135天移植到嵌合体的第二次供体特异性皮肤移植物显示长期存活（>130天），而第三方皮肤移植物被迅速排斥。混合淋巴细胞反应显示体外供体特异性低反应性。
基于他克莫司的非清髓性受体预处理方案可在大鼠中产生混合骨髓嵌合体和对心脏异体移植物的供体特异性耐受。
