Induction of stable long-term mixed hematopoietic chimerism following nonmyeloablative conditioning with T cell-depleting antibodies, cyclophosphamide, and thymic irradiation leads to donor-specific in vitro and in vivo tolerance
Induction of stable long-term mixed hematopoietic chimerism following nonmyeloablative conditioning with T cell-depleting antibodies, cyclophosphamide, and thymic irradiation leads to donor-specific in vitro and in vivo tolerance
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DOI：
10.1053/bbmt.2001.v7.pm11787527
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发表时间：
2001-01-01
影响因子：
4.3
通讯作者：
Sykes, M
中科院分区：
文献类型：
--
作者：
Mapara, MY;Pelot, M;Sykes, M
背景：成功的实体器官移植依赖于长期的免疫抑制来预防移植排斥反应。在同种异体骨髓移植后，可以观察到供体特异性耐受，而无需持续的免疫抑制。然而，到目前为止，由于标准BMT方案的高调节相关毒性，其常规用于耐受性诱导一直被排除在外。我们的实验室最近建立了环磷酰胺（CTX）加胸腺照射（TI）为基础的非清髓调理方案治疗血液系统恶性肿瘤。我们最近描述了该方法在活体肾移植患者中诱导供体特异性耐受性的成功临床应用，该方法在没有长期免疫抑制的情况下导致移植物接受。本研究的目的是在小鼠模型中评估ctx + ti方案对宿主抗移植物耐受的诱导和维持。方法：在全主要组织相容性复合体(MHC)-错配的B10A (H2(a))- > B6 （H2(b)）菌株组合中，研究基于CTX的非清髓调节方案（200mg /kg CTX，体内t细胞耗散[抗cd4单克隆抗体（MoAb） GK1.5和抗cd8 MoAb 2.43]和7 Gy TI）诱导混合造血嵌合和供者特异性耐受的发展。调节方案允许异体骨髓移植，并在几乎所有受者中持续（bb0 - 30周）混合淋巴造血嵌合。TI对于移植和耐受性的发展至关重要，这在所有持久嵌合体中都很明显。与接受类似的基于tbi的调节方案的动物相比，嵌合的总体水平。在ctx + ti条件下的动物中显著降低。然而，体外和体内的供体特异性耐受性在ctx + ti条件嵌合体中是明显的。通过Mtv-8和Mtv-9超抗原介导的V β 11（+）和V β 5/1.2(+) T细胞的缺失，可以确定耐受性与胸腺中供体型MHC II+细胞的存在和供体反应性细胞的缺失有关。结论：在不诱导GVHD的情况下，在nmc完全不匹配的BMT受体中，使用非清髓性ctx调节方案可以实现移植、长期嵌合和诱导供者特异性耐受。
Background: Successful transplantation of solid organs relies on long-term immunosuppression for the prevention of graft rejection. Donor-specific tolerance without the need for continuous immunosuppression can he observed after allogeneic BMT. However, its routine use for tolerance induction has been precluded so far by the high conditioning-related toxicity of standard BMT regimens. Our laboratory has recently established a cyclophosphamide (CTX) plus thymic irradiation (TI)-based nonmyeloablative conditioning protocol for the treatment of hematologic malignancies. We have recently described the successful clinical application of this approach for the induction of donor-specific tolerance in a patient receiving a living-related kidney transplant, which resulted in graft acceptance without long-term immunosuppression. The aim of this study was to evaluate the induction and maintenance of host-versus-graft tolerance following this CTX-plus-TI-based regimen in a mouse model.Methods: Induction of mixed hematopoietic chimerism and development of donor-specific tolerance following the CTX-based nonmyeloablative conditioning regimen (200 mg/kg CTX, in vivo T-cell depletion [anti-CD4 monoclonal antibody (MoAb) GK1.5 and anti-CD8 MoAb 2.43], and 7 Gy TI) was studied in the fully major histocompatibility complex (MHC)-mismatched B10A (H2(a))--> B6 (H2(b)) strain combination.Results. The conditioning regimen allowed allogeneic bone marrow engraftment and persistent (>30 weeks) mixed lymphohematopoietic chimerism in almost all recipients. TI was essential to allow engraftment and development of tolerance, which was evident in all lasting chimeras. Compared to animals receiving a similar TBI-based conditioning regimen, overall levels of chimerism. were significantly lower in the CTX-plus-TI-conditioned animals. However, donor-specific tolerance in vitro and in vivo was evident in CTX-plus-TI-conditioned chimeras. Tolerance was associated with the presence of donor-type MHC class II+ cells in the thymus and deletion of donor-reactive cells, as determined by Mtv-8 and Mtv-9 superantigen-mediated deletion of V beta 11(+) and V beta5/1.2(+) T cells.Conclusion: Engraftment, long-term chimerism, and induction of donor-specific tolerance can be achieved using a nonmyeloablative CTX-based conditioning regimen in fully NMC-mismatched BMT recipients without the induction of GVHD.