Morrissey N J, Blom D, Ryan C K, Fisher T, Bronsther O, Orloff M S
Department of Surgery, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Transpl Immunol. 1999 Mar;7(1):19-25. doi: 10.1016/s0966-3274(99)80015-x.
The induction of tolerance to organ allografts would eliminate acute and chronic rejection as well as the need for nonspecific immunosuppression. We have shown that tolerance induced through the creation of mixed allogeneic bone marrow chimeras allows for the long-term engraftment of cardiac and small bowel allografts across strong multiple major histocompatibility barriers. The possibility that tolerance might render the host susceptible to graft-versus-host disease (GVHD) has not been investigated in this or other models of tolerance. To test this possibility chimeras were created by transplantation of T-cell depleted ACI and Lewis bone marrow into lethally irradiated Lewis rats. Chimerism was determined post bone marrow transplant (BMTx) by flow cytometry of lymphocytes from reconstituted animals. ACI/Lew chimeras (ALC), Lewis/ACI F1 (LACF1), and Lewis (LEW) rats all received heterotopic ACI vascularized small bowel grafts. A second group of chimeras received small bowel grafts from ACI rats pretreated with low dose irradiation to eliminate T-cells from the graft. LEW-->LEW small bowel isografts were also performed. Animals were examined for evidence of GVHD by clinical signs and histologic examination of biopsied tissues. GVHD was quantified using the popliteal lymph node enlargement assay. All LACF1 rats developed severe lethal GVHD following ACI small bowel transplant. Bone marrow chimeras, ALC (n = 6), developed fatal GVHD in a similar fashion after receiving a small bowel transplant. LEW-->LEW isografts and chimeras receiving bowel from irradiated ACI rats survived long term without GVHD while ACI-->LEW allogeneic transplants all underwent acute rejection. GVHD or its absence was confirmed histologically. Popliteal lymph node enlargement indices reflected the presence of GVHD in the chimeras (1.87) and LACF1 (5.4) receiving allografts, but not in isografts or chimeras receiving irradiated allogeneic transplants. Analysis of cytokines in the tongues of rats undergoing GVHD showed elaboration of Th1 type proinflammatory cytokines which was not seen in isografted rats or rats receiving preirradiated small bowel. These results demonstrate that tolerance induction through mixed chimerism results in susceptibility to small bowel induced GVHD. Preirradiating the donor bowel prior to SBTx can prevent GVHD.
诱导对器官异体移植的耐受可消除急性和慢性排斥反应，以及对非特异性免疫抑制的需求。我们已经表明，通过创建混合异体骨髓嵌合体诱导的耐受能够使心脏和小肠异体移植在强大的多个主要组织相容性屏障下长期存活。在这种或其他耐受模型中，尚未研究耐受是否会使宿主易患移植物抗宿主病（GVHD）。为了测试这种可能性，通过将T细胞去除的ACI和Lewis骨髓移植到经致死性照射的Lewis大鼠体内来创建嵌合体。在骨髓移植（BMTx）后，通过对重建动物的淋巴细胞进行流式细胞术来确定嵌合状态。ACI/Lew嵌合体（ALC）、Lewis/ACI F1（LACF1）和Lewis（LEW）大鼠均接受了异位ACI血管化小肠移植。第二组嵌合体接受了经低剂量照射预处理以去除移植物中T细胞的ACI大鼠的小肠移植。还进行了LEW→LEW小肠同基因移植。通过临床体征和活检组织的组织学检查来检查动物是否有GVHD的迹象。使用腘窝淋巴结肿大试验对GVHD进行量化。所有LACF1大鼠在接受ACI小肠移植后均发生了严重的致死性GVHD。骨髓嵌合体ALC（n = 6）在接受小肠移植后也以类似方式发生了致命性GVHD。LEW→LEW同基因移植和接受经照射ACI大鼠小肠的嵌合体长期存活，无GVHD，而ACI→LEW异体移植均发生了急性排斥反应。通过组织学证实了GVHD的存在与否。腘窝淋巴结肿大指数反映了接受异体移植的嵌合体（1.87）和LACF1（5.4）中GVHD的存在，但在同基因移植或接受经照射异体移植的嵌合体中未出现。对发生GVHD的大鼠舌头中的细胞因子分析表明，Th1型促炎细胞因子有所增加，而同基因移植大鼠或接受预照射小肠的大鼠中未观察到这种情况。这些结果表明，通过混合嵌合诱导的耐受会导致对小肠诱导的GVHD易感。在小肠移植（SBTx）前对供体小肠进行预照射可预防GVHD。
