Watson Debbie, Zhang Geoff Yu, Sartor Mary, Alexander Stephen I
Center for Kidney Research, The Children's Hospital at Westmead, New South Wales, Australia.
J Immunol. 2004 Dec 1;173(11):6574-82. doi: 10.4049/jimmunol.173.11.6574.
Removal of alloreactive cells by either thymic deletion or deletion/anergy in the periphery is regarded as crucial to the development of tolerance. Dyes, such as CFSE, that allow monitoring of cell division suggest that in vitro proliferation could be a used as a way of "pruning" alloreactive cells while retaining a normal immune repertoire with retention of memory to previously encountered pathogens. This would overcome the problems occurring as a result of therapies that use massive depletion of T cells to allow acceptance of organ transplants or bone marrow grafts. We therefore used a skin graft model of CD4-mediated T cell rejection across a major H-2 mismatch (C57BL/6 (H-2(b)) to BALB/c (H-2(d)) mice) to evaluate whether nondividing CD4(+) T cells derived from a mixed lymphocyte culture would exhibit tolerance to a skin graft from the initial stimulator strain. We demonstrate that selective removal of dividing alloreactive CD4(+) T cells resulted in marked specific prolongation of allogeneic skin graft survival, and that the nondividing CD4(+) T cells retained a broad TCR repertoire and the ability to maintain memory. This novel way of depleting alloreactive T cells may serve as a useful strategy in combination with other mechanisms to achieve transplant tolerance.
通过胸腺缺失或外周缺失/失能来清除同种反应性细胞被认为是耐受形成的关键。诸如CFSE等能监测细胞分裂的染料表明，体外增殖可作为一种“修剪”同种反应性细胞的方法，同时保留正常的免疫库并维持对先前遇到病原体的记忆。这将克服因使用大量T细胞耗竭疗法以促进器官移植或骨髓移植接受而出现的问题。因此，我们使用了一个主要H-2不匹配（从C57BL/6（H-2(b)）到BALB/c（H-2(d)）小鼠）的CD4介导的T细胞排斥皮肤移植模型，以评估来自混合淋巴细胞培养的不分裂CD4(+) T细胞是否会对来自初始刺激菌株的皮肤移植表现出耐受性。我们证明，选择性清除分裂的同种反应性CD4(+) T细胞导致同种异体皮肤移植存活时间显著延长，并且不分裂的CD4(+) T细胞保留了广泛的TCR库和维持记忆的能力。这种清除同种反应性T细胞的新方法可能作为一种有用的策略，与其他机制结合以实现移植耐受。
