Kraus M D, Shahsafaei A, Antin J, Odze R D
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Hum Pathol. 1998 Aug;29(8):869-75. doi: 10.1016/s0046-8177(98)90459-2.
Graft versus host disease (GVHD) occurs in up to 75% of patients who have had an allogeneic bone marrow transplant (BMT). However, the pathophysiology of this disorder, including the mechanisms responsible for enhanced apoptosis, are poorly understood. Bcl-2 is a cellular protein known to inhibit apoptosis in a variety of human tissues. Therefore, the aim of this study was to evaluate the expression of Bcl-2 in colonic GVHD and to determine its relationship to cell proliferation and apoptosis in this disease. Routinely processed colonic mucosal biopsy specimens from 47 allogeneic BMT patients with diarrhea were evaluated histologically for the grade of GVHD (0-4) and for the degree of apoptosis (apoptosis index). Immunohistochemical staining for Bcl-2 and MIB-1, a cell proliferation marker, was performed, and the results were correlated with the histological findings and with each other. Normal-appearing colonic mucosal biopsy specimens from 10 age-matched patients with noncolonic diarrhea served as controls. Also evaluated were 13 colonic biopsy specimens from 13 patients with chronic ulcerative colitis (three inactive, four mild chronic-active, six moderately severe chronic active) to test the specificity of our findings. When compared with controls, a slight trend toward increased Bcl-2 expression was noted in patients with high-grade GVHD (grade 3 or 4) (P=.09). However, Bcl-2 expression did not correlate with the degree of apoptosis in these patients. In contrast, the degree of Bcl-2 staining correlated positively with the crypt proliferative rate (P=.04). Furthermore, crypt proliferation was significantly higher in the GVHD patients in comparison with controls (MIB-1 index, 27.7+/-17.1 v 15.6+/-11.4, =.02), and increased progressively with each successively higher grade of GVHD, and with the degree of apoptosis. Similar to GVHD, Bcl-2 expression was increased in biopsy specimens of CUC patients with higher grades of active injury and epithelial regeneration. This immunohistochemical study does not provide support for Bcl-2 in the pathogenesis of GVHD-induced apoptosis in the colon, but instead, indicates that this protein may play a nonspecific role in the generalized response to cellular injury in GVHD.
移植物抗宿主病（GVHD）发生在高达75%接受异基因骨髓移植（BMT）的患者中。然而，这种疾病的病理生理学，包括导致凋亡增强的机制，目前仍知之甚少。Bcl-2是一种已知能在多种人体组织中抑制凋亡的细胞蛋白。因此，本研究的目的是评估Bcl-2在结肠GVHD中的表达，并确定其与该疾病中细胞增殖和凋亡的关系。对47例异基因BMT后出现腹泻的患者常规处理的结肠黏膜活检标本进行组织学评估，以确定GVHD的分级（0 - 4级）和凋亡程度（凋亡指数）。进行了Bcl-2和细胞增殖标志物MIB-1的免疫组织化学染色，并将结果与组织学发现以及彼此之间进行关联。10例年龄匹配的非结肠性腹泻患者外观正常的结肠黏膜活检标本作为对照。还评估了13例慢性溃疡性结肠炎（CUC）患者的13份结肠活检标本（3例静止期、4例轻度慢性活动期、6例中度重度慢性活动期），以检验我们研究结果的特异性。与对照组相比，在高级别GVHD（3级或4级）患者中观察到Bcl-2表达有轻微增加的趋势（P = 0.09）。然而，在这些患者中，Bcl-2表达与凋亡程度无关。相反，Bcl-2染色程度与隐窝增殖率呈正相关（P = 0.04）。此外，与对照组相比，GVHD患者的隐窝增殖明显更高（MIB-1指数，27.7±17.1对15.6±11.4，P = 0.02），并且随着GVHD级别升高以及凋亡程度增加而逐渐升高。与GVHD相似，在具有更高级别活动性损伤和上皮再生的CUC患者活检标本中，Bcl-2表达增加。这项免疫组织化学研究不支持Bcl-2在结肠GVHD诱导的凋亡发病机制中的作用，相反，表明该蛋白可能在GVHD对细胞损伤的全身性反应中起非特异性作用。
