Hewitt C W, Strande L, Santos M, Goodman M, Tarnoff M, Zaontz M R, DelRossi A J, Doolin E J
Department of Surgery, Robert Wood Johnson Medical School, Cooper Hospital/University Medical Center, Camden, New Jersey, USA.
Transplant Proc. 1997 Jun;29(4):2183-4. doi: 10.1016/s0041-1345(97)00284-4.
Tolerance was induced in Lewis (LEW) rat renal allograft recipients of Brown Norway kidneys by multiple pretransplant donor-blood transfusions and prior limited cyclosporine A. Rat renal allograft tolerance was associated with the induction of systemic donor T cells (10%), an early phase of nonspecific suppressor-cell generation, followed by maturation of systemic antigen-specific suppressor cells, and renal cellular infiltrates that develop long-term in situ in the kidney graft model. It was hypothesized that these infiltrates represent chimeric immunocytic foci that are locally regulated via a TGF-beta-dependent mechanism. Both immunohistochemical staining and digital image analysis for cellular and extracellular TGF-beta, IL-2 receptor (CD25), and the BN Class I-MHC marker (OX-27) were performed. Control rejecting (REJ) kidneys did not demonstrate any differences with respect to levels of infiltrating immunocyte area vs long-term surviving (TOL) kidneys (3.9% vs 4.5%, P = .303). Immunostaining with the BN Class I MHC marker (OX-27) demonstrated high levels of chimerism within immunocyte foci of the tolerant grafts (OX-27 BN+immunocytes 49.0% +/- 5.1%). In situ cellular IL-2 receptor (CD25) expression was demonstrated in REJ kidney infiltrates but not within TOL immunocytic infiltrating foci, when measured as percent of total lymphocytes (REJ = 5.0% vs TOL = 0.4%, P = .031). Conversely, TGF-beta expression was significantly higher in immunocytes of TOL kidneys when measured as the number of DAB chromogen-staining pixels per total immunocyte area (TOL = .076 vs REJ = .047, P = .003). In conclusion, these results suggested that stable mixed immune chimerism (SMIC) plays an important role in DST-CyA-induced tolerance in situ. SMIC-induced tolerance may involve a local TGF-beta-dependent mechanism that is associated with in situ TGF-beta (+) and IL-2r (-) immunocytes.
通过多次移植前供体输血和预先使用有限剂量的环孢素A，在接受布朗挪威大鼠肾脏移植的Lewis（LEW）大鼠中诱导出耐受。大鼠肾移植耐受与全身供体T细胞的诱导（10%）、非特异性抑制细胞生成的早期阶段相关，随后是全身抗原特异性抑制细胞的成熟，以及在肾移植模型中在肾脏长期原位形成的肾细胞浸润。据推测，这些浸润代表嵌合免疫细胞灶，它们通过一种转化生长因子-β（TGF-β）依赖的机制进行局部调节。对细胞和细胞外TGF-β、白细胞介素-2受体（CD25）以及BN I类主要组织相容性复合体标志物（OX-27）进行了免疫组织化学染色和数字图像分析。对照排斥（REJ）肾脏在浸润免疫细胞面积水平与长期存活（TOL）肾脏方面没有显示出任何差异（3.9%对4.5%，P = 0.303）。用BN I类主要组织相容性复合体标志物（OX-27）进行免疫染色显示，耐受移植物的免疫细胞灶内存在高水平的嵌合现象（OX-27 BN +免疫细胞49.0%±5.1%）。当以总淋巴细胞百分比来衡量时，原位细胞白细胞介素-2受体（CD25）表达在REJ肾脏浸润中可见，但在TOL免疫细胞浸润灶中未观察到（REJ = 5.0%对TOL = 0.4%，P = 0.031）。相反，当以每个总免疫细胞面积的二氨基联苯胺（DAB）显色像素数量来衡量时，TOL肾脏免疫细胞中的TGF-β表达明显更高（TOL = 0.076对REJ = 0.047，P = 0.003）。总之，这些结果表明稳定混合免疫嵌合（SMIC）在去势脾细胞联合环孢素A诱导的原位耐受中起重要作用。SMIC诱导的耐受可能涉及一种局部TGF-β依赖的机制，该机制与原位TGF-β（+）和白细胞介素-2受体（-）免疫细胞相关。
