Nagasaki Kazuhito, Obara Hideaki, Xiong Anming, Kambham Neeraja, Strober Samuel, Esquivel Carlos O, Millan Maria T
Department of Surgery, Division of Transplantation, Stanford University School of Medicine, Stanford, CA, USA.
Transplantation. 2007 Sep 15;84(5):619-28. doi: 10.1097/01.tp.0000278104.15002.64.
Posttransplant total lymphoid irradiation (TLI) treatment has been applied to tolerance induction protocols in heart and kidney transplantation models.
We examined the efficacy and mechanism of posttransplant TLI treatment in the induction and maintenance of tolerance in a rat orthotopic liver transplantation model.
Posttransplant TLI prolonged ACI (RT1(a)) liver allograft survival in Lewis (RT1(b)) hosts, with 50% long-term engraftment without immunosuppression and without evidence of chronic rejection. Injection of donor-type liver mononuclear cells (LMCs) facilitated the prolongation of graft survival, with more than 70% of grafts in LMC recipients surviving more than 100 days without chronic rejection. Recipients with long-term liver allograft survival accepted ACI but not PVG skin grafts. In TLI-conditioned recipients with accepted grafts, apoptosis occurred predominantly in graft-infiltrating leukocytes. In contrast, there were few apoptotic leukocytes in rejecting grafts. Recipients with long-term graft acceptance (>100 days of survival) demonstrated evidence of immune deviation; mixed lymphocyte reaction to ACI stimulator cells was vigorous, but secretion of interferon-gamma and interleukin-2 was reduced. In tolerant recipients, the number of Foxp3(+) CD25(+) CD4(+) regulatory T cells was increased in the liver allograft as well as in the peripheral blood.
We conclude that posttransplant TLI induces tolerance to liver allografts via a mechanism involving apoptotic cell-deletion and immunoregulation.
移植后全淋巴照射（TLI）治疗已应用于心脏和肾脏移植模型的免疫耐受诱导方案。
我们研究了移植后TLI治疗在大鼠原位肝移植模型中诱导和维持免疫耐受的疗效及机制。
移植后TLI延长了Lewis（RT1(b)）宿主中ACI（RT1(a)）肝同种异体移植物的存活时间，50%的移植物在无免疫抑制且无慢性排斥证据的情况下长期存活。注射供体型肝脏单个核细胞（LMCs）促进了移植物存活时间的延长，LMCs受体中超过70%的移植物存活超过100天且无慢性排斥。长期存活肝同种异体移植物的受体接受ACI皮肤移植但不接受PVG皮肤移植。在接受移植的TLI预处理受体中，凋亡主要发生在移植物浸润白细胞中。相比之下，排斥移植物中凋亡白细胞很少。长期接受移植物（存活>100天）的受体表现出免疫偏离的证据；对ACI刺激细胞的混合淋巴细胞反应强烈，但干扰素-γ和白细胞介素-2的分泌减少。在耐受受体中，肝脏同种异体移植物以及外周血中Foxp3(+) CD25(+) CD4(+)调节性T细胞数量增加。
我们得出结论，移植后TLI通过涉及凋亡细胞清除和免疫调节的机制诱导对肝同种异体移植物的耐受。
