Canine bone marrow-derived mesenchymal stromal cells suppress alloreactive lymphocyte proliferation in vitro but fail to enhance engraftment in canine bone marrow transplantation.
Canine bone marrow-derived mesenchymal stromal cells suppress alloreactive lymphocyte proliferation in vitro but fail to enhance engraftment in canine bone marrow transplantation.
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DOI：
10.1016/j.bbmt.2010.04.016
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发表时间：
2011-04
影响因子：
4.3
通讯作者：
Storb, Rainer
中科院分区：
文献类型：
--
作者：
Lee, Won Sik;Suzuki, Yasuhiro;Graves, Scott S.;Iwata, Mineo;Venkataraman, G. M.;Mielcarek, Marco;Peterson, Laura J.;Ikehara, Susumu;Torok-Storb, Beverly;Storb, Rainer
关键词：
在犬白细胞抗原（DLA）一致的骨髓移植前，通过200 cGy的全身照射（TBI）轻度免疫抑制，并在犬白细胞抗原（DLA）一致的骨髓移植后给予麦考酚酸酯（28天）和环孢素（35天）短暂的免疫抑制过程中，稳定的混合造血嵌合体一直被建立。然而，当TBI从200 cGy减少到100 cGy时，移植物在3到12周内几乎一致地被排斥。在这里，我们问是否可以实现稳定的植入后，次优剂量的100 cGy TBI与宿主免疫抑制增强供体来源的间充质基质细胞（MSC）移植后给予。从骨髓细胞培养MSC，并在体外评估抗原表达。它们在混合白细胞反应（MLR）中以细胞剂量依赖性方式显示出深刻的免疫抑制特性，不受DLA的限制。不需要MSC和淋巴细胞接触，表明免疫抑制是由可溶性因子介导的。MSC与MLR共培养时，培养上清中前列腺素E2含量增加。加入吲哚美辛恢复了含有MSC的培养物中的淋巴细胞增殖。MSC表达CD 10、CD 13、CD 29、CD 44、CD 73/SH-3、CD 90/Thy-1和CD 106/VCAM-1。对于体内研究，在骨髓移植当天和移植后环孢素停药的第35天注射MSC。在给予DLA相同移植物的4只狗中，来自相应骨髓供体的MSC在100 cGy的非清髓性条件处理后未能避免骨髓移植物排斥反应，其时间过程与未给予MSC的对照狗无显著差异。虽然MSC在体外表现出与其他物种MSC相似的特征，但其免疫抑制特性未能在该犬模型中维持体内稳定的骨髓植入。
Stable mixed hematopoietic chimerism has been consistently established in dogs mildly immunosuppressed by 200 cGy of total body irradiation (TBI) before and given a brief course of immunosuppression with mycophenolate mofetil (28 days) and cyclosporine (35 days) after dog leukocyte antigen (DLA)-identical marrow transplantation. However, when TBI was reduced from 200 to 100 cGy, grafts were nearly uniformly rejected within 3 to 12 weeks. Here we asked whether stable engraftment could be accomplished after a suboptimal dose of 100 cGy TBI with host immunosuppression enhanced by donor-derived mesenchymal stromal cells (MSC) given after transplantation. MSC were cultured from marrow cells and evaluated in vitro for antigen expression. They showed profound immunosuppressive properties in mixed leukocyte reactions (MLR) in a cell dose-dependent manner not restricted by DLA. MSC and lymphocyte contact was not required, indicating immunosuppression was mediated by soluble factors. Prostaglandin E2 was increased in culture supernatant when MSC were co-cultured in MLR. Adding indomethacin restored lymphocyte proliferation in cultures containing MSC. MSC expressed CD10, CD13, CD29, CD44, CD73/SH-3, CD90/Thy-1, and CD106/VCAM-1. For in vivo studies, MSC were injected on the day of marrow grafting and on day 35, the day of discontinuation of postgrafting cyclosporine. MSC derived from the respective marrow donors failed to avert marrow graft rejection in 4 dogs given DLA-identical grafts after nonmyeloablative conditioning with 100 cGy in a time course not significantly different from control dogs not given MSC. While MSC displayed in vitro characteristics similar to those reported for MSC from other species, their immunosuppressive qualities failed to sustain stable marrow engraftment in vivo in this canine model.
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