Wekerle Thomas, Blaha Peter, Koporc Zvonimir, Bigenzahn Sinda, Pusch Michael, Muehlbacher Ferdinand
Department of Surgery, Vienna General Hospital, Waehringer Guertel 18, A 1090 Vienna, Austria.
Transplantation. 2003 May 15;75(9 Suppl):21S-25S. doi: 10.1097/01.TP.0000067947.90241.66.
The transplantation of donor hematopoietic stem cells has been used successfully in numerous experimental settings to induce donor-specific tolerance. After appropriate host conditioning, hematopoietic stem-cell transplantation leads to a lasting state of donor macrochimerism that is associated with a robust form of tolerance. One of the key factors in the success of this approach is its reliance on intrathymic clonal deletion to ensure lifelong tolerization of newly developing T cells. Evidence for ongoing central deletion comes from studies following superantigen-reactive T cells and from experiments using mice transgenic for an alloreactive T-cell receptor. In protocols inducing tolerance through macrochimerism, the preexisting mature T-cell repertoire is controlled by either globally destroying all T cells before the hematopoietic cell transplantation or, in more recent models, by tolerizing it through co-stimulation blockade. The peripheral mechanisms induced by hematopoietic stem-cell transplantation and co-stimulation blockade include both extrathymic clonal deletion and the nondeletional mechanisms anergy, suppression, or both. In addition to these immunologic hurdles, a physiologic engraftment barrier has to be surmounted for the successful induction of mixed chimerism. This can be achieved by cytoreductive host treatment or by the infusion of high numbers of donor hematopoietic cells. A detailed delineation of the mechanisms responsible for tolerance induction after hematopoietic stem-cell transplantation is expected to help in the translation of these experimental protocols to clinical organ transplantation.
供体造血干细胞移植已在众多实验环境中成功用于诱导供体特异性耐受。经过适当的宿主预处理后，造血干细胞移植会导致持久的供体大嵌合状态，这与一种强大的耐受形式相关。这种方法成功的关键因素之一是其依赖胸腺内克隆清除来确保新发育的T细胞终身耐受。持续的中枢清除的证据来自对超抗原反应性T细胞的跟踪研究以及使用同种异体反应性T细胞受体转基因小鼠的实验。在通过大嵌合诱导耐受的方案中，预先存在的成熟T细胞库通过在造血细胞移植前全局破坏所有T细胞来控制，或者在最近的模型中，通过共刺激阻断使其耐受。造血干细胞移植和共刺激阻断诱导的外周机制包括胸腺外克隆清除以及无反应性、抑制或两者兼有的非清除机制。除了这些免疫障碍外，为成功诱导混合嵌合还必须克服生理植入障碍。这可以通过减体细胞宿主治疗或输注大量供体造血细胞来实现。详细描述造血干细胞移植后耐受诱导的机制有望有助于将这些实验方案转化为临床器官移植。
