Department of Surgery, UCLA Medical School, Los Angeles, California 90095, USA.
J Heart Lung Transplant. 2010 Mar;29(3):335-41. doi: 10.1016/j.healun.2009.08.003. Epub 2010 Jan 15.
The understanding of chronic rejection (transplant vascular sclerosis, or TVS) mechanisms is a major goal of transplantation. In this study we tested a cardiac transplant model for TVS development in connection with emerging T-regulatory cells (T-regs). We used 40-mer peptides derived from the donor MHC Class I alpha1 helix of the alpha1-domain to make recipients tolerant.
ACI recipients were transplanted with either RT1.A(u) (WF), RT1.A(l) (LEW), RT1.A(c) (PVG), or RT1.A(b) (BUF) cardiac grafts. The grafts were analyzed 120 days later for TVS and development of T-regs.
Donor MHC peptides were injected through the portal vein (0.1 mg) into ACI recipients of WF hearts in addition to sub-therapeutic cyclosporine (CsA, 10 mg/kg for 3 days post-operatively). Peptide treatment specifically prolonged graft survival for >100 days (n = 31). ACI recipients of WF or LEW hearts treated with PVG peptides promptly rejected the transplanted grafts (15 +/- 4 and 20 +/- 1 days, respectively). Presence of T-regs in tolerant recipients was confirmed by the adoptive transfer of T cells into a new cohort of syngeneic recipients (mean survival time [MST] >100 days, n = 3). CD4(+) and FoxP3(+) cells were detected in 70% of the chronically rejected grafts vs 38% (CD4) and 22% (FoxP3) in the well-preserved transplants. IgG and IgM deposits were found in only half of surviving cardiac grafts with a high level of TVS. Blood vessels in grafts with attenuated TVS were 80% IgG and IgM positive. Interleukin (IL)-4 and IL-2 were markedly down-regulated in the hearts with high TVS compared with well-preserved grafts. Long-term-surviving hearts demonstrated increased IL-10 expression. Interferon-gamma (IFN-gamma) was more evident in the grafts with a high TVS.
Donor MHC Class I peptides can specifically prolong transplant survival and generate T-regs. The level of intragraft T-regs correlates with severity of TVS and IL-2/IL-4 down-regulation.
了解慢性排斥反应（移植血管硬化，或 TVS）的机制是移植的主要目标。在这项研究中，我们测试了心脏移植模型中与新兴的 T 调节细胞（Tregs）相关的 TVS 发展。我们使用源自供体 MHC 类 I alpha1 螺旋的 alpha1 结构域的 40 个氨基酸肽使受者耐受。
ACI 受者接受 RT1.A(u)（WF）、RT1.A(l)（LEW）、RT1.A(c)（PVG）或 RT1.A(b)（BUF）心脏移植物。120 天后分析移植物的 TVS 和 Treg 发育情况。
除了术后给予亚治疗剂量环孢素（CsA，10mg/kg，3 天）外，通过门静脉（0.1mg）将供体 MHC 肽注射到 WF 心脏的 ACI 受者体内。肽治疗特异性地延长了移植物的存活时间>100 天（n=31）。用 PVG 肽处理的 WF 或 LEW 心脏的 ACI 受者迅速排斥移植的移植物（分别为 15 +/- 4 和 20 +/- 1 天）。在新的同基因受者中，通过过继转移 T 细胞证实了耐受受者中 Treg 的存在（MST >100 天，n=3）。在慢性排斥的移植物中检测到 70%的 CD4(+)和 FoxP3(+)细胞，而在保存完好的移植物中分别为 38%（CD4）和 22%（FoxP3）。仅在伴有高 TVS 的存活心脏移植物中发现 IgG 和 IgM 沉积。TVS 减弱的移植物中血管 IgG 和 IgM 阳性率为 80%。与保存完好的移植物相比，具有高 TVS 的心脏中白细胞介素（IL）-4 和 IL-2 明显下调。长期存活的心脏表现出 IL-10 表达增加。高 TVS 移植物中 IFN-γ更为明显。
供体 MHC 类 I 肽可特异性延长移植存活时间并产生 Treg。移植物内 Treg 的水平与 TVS 的严重程度和 IL-2/IL-4 下调相关。
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