移植早期宿主成熟T细胞的灭活在诱导特异性免疫耐受中的作用

目的探讨参与早期急性排斥反应并导致非清髓性治疗诱导特异性免疫耐受失败的主要免疫细胞。方法通过动态观察受者三种不同预处理方案的骨髓移植后早期各阶段在外周血、脾脏、胸腺中的嵌合状态，再用T细胞敲除小鼠作为受者，以验证宿主成熟T细胞在急性排斥反应与诱导特并性免疫耐受中的重要作用。结果亚致死量全身放射治疗TBI（450cGy）4-BMT骨髓移植治疗组的BALB／C受者移植心脏均出现排斥反应，存活时间〈38d，骨髓移植后第7天在受者的外周血、脾脏中仍存活一定数量的宿主成熟T细胞（分别为0．23％与0．48％）。T细胞基因敲除c57BL／6小鼠作为受者，给予单次TBI（450cGy）＋BMT治疗，其移植心脏获长期存活，并获得完全嵌合状态。结论移植早期彻底清除或灭活宿主成熟T细胞是预防早期排斥反应的关键，也有利于供者骨髓T细胞植活，这对临床制定诱导特异性免疫耐受冶疗方案有着重要意义。

Inactivation of host mature T cells in induction of immune tolerance at early stage after transplantation

Objective To observe the role of immune cells which possibly leads to failure of nonmyeloablative immune tolerance in acute rejection at the early stage after bone marrow transplantation. Methods BALB/c (WT) recipients were divided into three groups which were conditioned respectively with TBI (800 cGy) +BMT, TBI(450cGy) + BMT, ATS + TBI (450cGy) + BMT. Chimera was examined respectively in peripheral blood, spleen, thymus of the hosts 7,14,21,28,42 days after bone marrow transplantation (BMT). Recipients,C 57 BL/6 TCRα-KO and wild-type C 57 BL/6, were treated by the same conditioning regimenTBI (450cGy) +BMT], and then were performed heart transplantation from BALB/C donor. We evaluated the important role of host mature T cells in acute rejection and induction of immune tolerance. Results In TBI(450cGy) + BMT group, some host T cells still survived in peripheral blood and spleen (respectively 0.23% and 0.48% of the whole white blood cells) and a lot of host cells survived in Thymus (99%) on the 7th day after BMT. All the heat allografts in this group had rejection within 38 days after heart transplantation. In TBI (800 cGy) + BMT and ATS + TBI(450cGy) +BMT groups, very few host T cells survived in peripheral blood and spleen (respectively 0.02%, 0.05% and 0.01% ,0.05% ) and chimeric index of donor cells was 30% in the host thymus on 7th day after BMT. Most of heart allografts in these groups didn t have rejection. All C 57 BL/6 TCRα-KO hosts treated by TBI(450cGy) + BMT regimen accepted allogeneic heart grafts (graft survival time > 100 days) and got complete chimera of donor cells ( chimeric index 99.4% ). Conclusion Depletion or dysfunction of anti-donor-antigen host mature T cells at early stage of transplantation not only prevented acute rejection, but also contributed to donor bone marrow cell engraftment and creation of stable chimerism that produced central immunologic cell clonal deletion and induced long-term specific immune tolerance. It is important to set up non-myeloablative conditioning regimen in clinical transplantation.