Llull R, Ramsamooj R, Black K S, Hewitt C W
Department of Surgery, UMDNJ/Cooper Hospital, Camden, NJ 08103, USA.
Transpl Int. 1994;7 Suppl 1:S453-6. doi: 10.1111/j.1432-2277.1994.tb01417.x.
It has been demonstrated that the development of stable mixed lymphocyte chimerism is associated with alloimmune tolerance induction in vascularized bone marrow transplant (VBMT) recipients. The underlying mechanisms of immune non-responsiveness in tolerant VBMT chimeras remains unclear. Our VBMT model involves the transplantation of a parental donor limb (Lewis rats) onto a hybrid (Lewis x Brown Norway) F1 recipient. Tolerogenic mechanisms and cellular immune regulation to self and host allodeterminants were investigated during the early post-transplant phase of tolerance induction. Flow cytometric analysis of sIg+-depleted experimental peripheral blood lymphocytes from tolerant VBMT recipients demonstrated low level stable mixed immune chimerism. Chimeric cells tested for responsiveness against self-LEW determinants showed activated proliferation and immune dysregulation 30 days post-transplantation. However, direct immunocytolytic activity against LEW determinants was not found. Tolerant chimeras also demonstrated elevated cellular proliferation and cytolytic responses against host-specific BN allodeterminants at 30 days. Consistent with these in vitro findings, limited clinical signs compatible with GVH reactivity were evident in vivo at this time. Following this initial period, the tolerant VBMT animals returned to normal clinical condition and remained otherwise healthy throughout the study. Consistent with these results, VBMT chimeras then showed declining proliferative responses from the elevated values seen at 30 days against self-LEW determinants. Proliferative and immunocytolytic responses also decreased against host-specific BN allodeterminants from peak levels at 30 days. In conclusion, these results provide evidence that the initial phases of tolerance induction in VBMT chimeras consist of self- and alloimmune regulation that follow an early period of immune dysregulation. Sequential phases of immune dysregulation and re-regulation elucidated in VBMT stable mixed chimeras within the first 100-day period may represent important mechanisms of tolerance induction.
已证明，稳定混合淋巴细胞嵌合体的形成与血管化骨髓移植（VBMT）受者的同种免疫耐受诱导相关。耐受的VBMT嵌合体中免疫无反应性的潜在机制仍不清楚。我们的VBMT模型涉及将亲代供体肢体（Lewis大鼠）移植到杂种（Lewis×Brown Norway）F1受体上。在耐受诱导的移植后早期阶段，研究了对自身和宿主同种异体决定簇的致耐受机制和细胞免疫调节。对耐受的VBMT受者的sIg + 耗尽的实验外周血淋巴细胞进行流式细胞术分析，显示出低水平的稳定混合免疫嵌合体。测试针对自身LEW决定簇反应性的嵌合细胞在移植后30天显示出活化增殖和免疫失调。然而，未发现针对LEW决定簇的直接免疫细胞溶解活性。耐受的嵌合体在30天时也显示出针对宿主特异性BN同种异体决定簇的细胞增殖和细胞溶解反应升高。与这些体外研究结果一致，此时在体内明显可见与移植物抗宿主反应性相符的有限临床体征。在此初始阶段之后，耐受的VBMT动物恢复到正常临床状态，并在整个研究过程中保持健康。与这些结果一致，VBMT嵌合体随后显示出针对自身LEW决定簇的增殖反应从30天时的升高值下降。针对宿主特异性BN同种异体决定簇的增殖和免疫细胞溶解反应也从30天时的峰值水平下降。总之，这些结果提供了证据，表明VBMT嵌合体中耐受诱导的初始阶段包括在免疫失调早期之后的自身和同种免疫调节。在VBMT稳定混合嵌合体中阐明的免疫失调和重新调节的连续阶段可能代表耐受诱导的重要机制。
