Vallera D A, Taylor P A, Sprent J, Blazar B R
University of Minnesota, Minneapolis.
Transplantation. 1994 Jan;57(2):249-56. doi: 10.1097/00007890-199401001-00017.
An expanded pool of unrelated donors (URD) is now being utilized for clinical allogeneic bone marrow transplantation. Because URD transplants can involve a mismatch at least at one genotypic MHC locus, we developed a C57BL/6 congenic mouse model to better understand graft rejection based exclusively on MHC class I or class II disparities. T cell-depleted (TCD) BM from class II-disparate mutant bm12 mice was transplanted into irradiated C57BL/6-Ly5.2 congenic hosts. These mice express a different allelic form of the Ly5 (CD45) marker than bm12 and thus permit definitive typing of reconstituted mice by flow cytometry. Peripheral blood typing indicated that host-mediated graft rejection was restricted to class II-reactive CD4+ cells since an anti-CD4 monoclonal antibody significantly inhibited rejection by enhancing the level of mean donor cell engraftment from 13% to 53%. The administration of anti-CD8 had no inhibitory effect on the ability of the recipient to reject the donor graft. Hematologic reconstitution studies revealed that there was a direct relationship between the level of donor cell engraftment and the extent of lymphoid, myeloid, and erythroid recovery. Mice that did not engraft had sustained reductions in in hematologic recovery. In other studies, TCD BM from bm1 mice mutated only in the MHC class I region was rejected by C57BL/6-Ly5.2 recipients. Anti-CD8 mAb infusion prevented the class I response resulting in an increase in the level of mean donor cell engraftment from 1% to 78%. Anti-CD4 alone had no effect. A CD4/CD8 T cell interaction could be important since the combination of anti-CD4 and anti-CD8 mAb resulted in significantly better donor engraftment than with the individual antibodies. Since the role of NK cells in these models has not been previously established and there is a reported association between NK cells and the rejection of BM cells that lack the expression of self-MHC antigens, we tested the role of NK cells. The elimination of NK cells using anti-NK mAb had no effect on graft rejection in either the bm1 or bm12 model. In addition to their value in exploring mechanisms of graft rejection, these models may prove useful for evaluating the efficacy of anti-BM rejection agents exclusively against class I- or class II-restricted disparities.
目前，扩大的无关供体库（URD）正被用于临床异基因骨髓移植。由于无关供体移植可能至少在一个基因型MHC位点存在错配，我们建立了一个C57BL/6同源小鼠模型，以更好地理解仅基于MHC I类或II类差异的移植物排斥反应。将来自II类不相合突变体bm12小鼠的T细胞清除（TCD）骨髓移植到经照射的C57BL/6-Ly5.2同源宿主中。这些小鼠表达的Ly5（CD45）标记的等位基因形式与bm12不同，因此可以通过流式细胞术对重建小鼠进行明确分型。外周血分型表明，宿主介导的移植物排斥反应仅限于II类反应性CD4+细胞，因为抗CD4单克隆抗体通过将平均供体细胞植入水平从13%提高到53%，显著抑制了排斥反应。抗CD8的给药对受体排斥供体移植物的能力没有抑制作用。血液重建研究表明，供体细胞植入水平与淋巴、髓系和红系恢复程度之间存在直接关系。未植入的小鼠血液恢复持续降低。在其他研究中，仅在MHC I类区域发生突变的bm1小鼠的TCD骨髓被C57BL/6-Ly5.2受体排斥。抗CD8 mAb输注阻止了I类反应，导致平均供体细胞植入水平从1%提高到78%。单独使用抗CD4没有效果。CD4/CD8 T细胞相互作用可能很重要，因为抗CD4和抗CD8 mAb的联合使用比单独使用抗体能显著提高供体植入率。由于NK细胞在这些模型中的作用此前尚未确定，并且有报道称NK细胞与缺乏自身MHC抗原表达的骨髓细胞排斥之间存在关联，我们测试了NK细胞的作用。使用抗NK mAb清除NK细胞对bm1或bm12模型中的移植物排斥均无影响。除了在探索移植物排斥机制方面的价值外，这些模型可能被证明有助于评估抗骨髓排斥药物仅针对I类或II类限制差异的疗效。
