Gorczynski Reginald M, Hadidi Sima, Yu Gary, Clark David A
Transplant Research Division, The Toronto Hospital, Ontario, Canada.
Am J Reprod Immunol. 2002 Jul;48(1):18-26. doi: 10.1034/j.1600-0897.2002.01094.x.
At least two dendritic cell-associated molecules have been shown to contribute to the successful outcome of organ and tissue allografts in mice, namely CD200 and MD-1. CD200 is up-regulated in rodent transplantation models where successful inhibition of rejection is accomplished, and is believed to signal immunosuppression following engagement of a receptor, CD200R, on macrophages and/or gammadelta T-cell receptor (gammadelta TCR+ cells MD-1 is implicated in controlling expression of costimulatory molecules including CD80/CD86 which induce an immunorejection response, and thus inhibition of MD-1 expression also facilitates increased graft survival MD-1 also stabilizes expression of CD14, part of the receptor complex for LPS. As well as the inhibition of rejection which follows blockade of MD-1 expression and/or augmentation of CD200 expression, an altered polarization in cytokine production is seen, with increased expression of interleukin-4 (IL-4), IL-10 and transforming growth factor-beta (TGF-beta), and decreased IL-2, interferon-gamma (IFN-gamma) and tumor nerosis factor-alpha (TNF-alpha). Successful pregnancy in allopregnant mice also depends upon control of graft rejection mechanisms. Proinflammatory T-helper 1 (Th1) cytokines (TNF-alpha + IFN-gamma + IL-1) have been shown to cause spontaneous abortion in mice by activating a novel prothrombinase, fibrinogen-like peptide (fibroleukin) fgl2, which may promote fibrin deposition in the graft rejection process; expression of IL-10, TGF-beta, and progesterone-induced blocking factor (PIBF) in contrast leads to lowering of abortion rates. Interestingly, the spontaneous abortion rates in abortion-prone CBA x DBA/2 matings and in the low abortion rate CBA x BALB/c matings were lower than the frequency of implantation sites showing fibrin(hi) + fgl2 (mRNA)hi, implying regulation of the pro-abortion consequences of fgl2 expression.
We have investigated, by in situ hybridization, CD200, MD-1 and fgl2 expression in implantation sites in different strains of mice, and studied the effects of anti-MD-1, anti-CD200 and CD200Fc immunoadhesin on fetal and allograft survival. The role of indoleamine dioxygenase (IDO) was evaluated.
CD200 mRNA expression occurred in the same sites as fgl2 mRNA. Anti-CD200 antibody raised the abortion rate to predicted levels, and infusion of a CD200 immunoadhesin reduced the abortion rate, as did an anti-MD-1 antibody. The latter also improved organ and tissue graft survival. Suppression by antigen-presenting macrophages triggered by CD200 is dependent upon intact IDO activity.
Regulation of CD200 and MD-1 expression may control both pregnancy and allograft survival.
至少有两种与树突状细胞相关的分子已被证明有助于小鼠器官和组织同种异体移植的成功，即CD200和MD-1。在啮齿动物移植模型中，当成功抑制排斥反应时，CD200会上调，并且据信在与巨噬细胞和/或γδT细胞受体（γδTCR+细胞）上的受体CD200R结合后会发出免疫抑制信号。MD-1与控制共刺激分子的表达有关，包括诱导免疫排斥反应的CD80/CD86，因此抑制MD-1的表达也有助于提高移植物存活率。MD-1还能稳定脂多糖受体复合物一部分CD14的表达。除了MD-1表达阻断和/或CD200表达增强后对排斥反应的抑制外，还观察到细胞因子产生的极化改变，白细胞介素-4（IL-4）、IL-10和转化生长因子-β（TGF-β）表达增加，而IL-2、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）表达减少。同种异体妊娠小鼠的成功妊娠也取决于移植排斥机制的控制。促炎辅助性T细胞1（Th1）细胞因子（TNF-α+IFN-γ+IL-1）已被证明通过激活一种新型凝血酶原酶、纤维蛋白原样肽（纤维白细胞介素）fgl2在小鼠中导致自然流产，这可能在移植排斥过程中促进纤维蛋白沉积；相反，IL-10、TGF-β和孕酮诱导的阻断因子（PIBF）的表达导致流产率降低。有趣的是，易流产的CBA×DBA/2交配和低流产率的CBA×BALB/c交配中的自然流产率低于显示纤维蛋白（高）+fgl2（mRNA）高的着床部位频率，这意味着对fgl2表达的流产前后果有调节作用。
我们通过原位杂交研究了不同品系小鼠着床部位的CD200、MD-1和fgl2表达，并研究了抗MD-1、抗CD200和CD200Fc免疫粘附素对胎儿和同种异体移植物存活的影响。评估了吲哚胺双加氧酶（IDO）的作用。
CD200 mRNA表达与fgl2 mRNA出现在相同部位。抗CD200抗体将流产率提高到预测水平，输注CD200免疫粘附素降低了流产率，抗MD-1抗体也有同样效果。后者还提高了器官和组织移植物的存活率。由CD200触发的抗原呈递巨噬细胞的抑制作用取决于完整的IDO活性。
CD200和MD-1表达的调节可能控制妊娠和同种异体移植物存活。
