Ilan Y, Gotsman I, Pines M, Beinart R, Zeira M, Ohana M, Rabbani E, Engelhardt D, Nagler A
Liver Unit, Department of Medicine, and Department of Bone Marrow Transplantation, Hadassah University Hospital, Jerusalem, Israel.
Blood. 2000 Jun 1;95(11):3613-9.
Chronic graft versus host disease (cGVHD) is a major complication that can develop after bone marrow transplantation. It involves an immune-mediated attack by transplanted donor lymphocytes, and often results in inflammatory damage of host target organs. Immune hyporesponsiveness induced by oral antigen administration has been recently shown to prevent the development of cGVHD in a murine model. The aim of this study was to evaluate whether tolerance induction in bone marrow transplant (BMT) recipients after transplantation, toward their pretransplant antigens, can alleviate preexisting cGVHD in a mouse model. cGVHD was generated by infusing 2.5 x 10(7) splenocytes from B10.D2 donor mice, to sublethally irradiated (6 Gy) BALB/c recipient mice, which differ by minor histocompatibility antigens. Transplantation resulted in cGVHD, with characteristic scleroderma-like cutaneous fibrosis, increased skin collagen content, decreased body weight, and hepatic and small bowel inflammation. Oral tolerance was induced by feeding recipient BALB/c mice with proteins extracted from BALB/c splenocytes for 11 days after B10.D2 splenocyte transplantation. Tolerance induction was evidenced by a significant reduction in mixed lymphocyte response of effector splenocytes from tolerant BALB/c mice transplanted with B10.D2 splenocytes against BALB/c target splenocytes. Oral tolerance decreased skin collagen deposits. Reduction of collagen alpha1(I) gene expression and skin collagen were shown by in situ hybridization and histochemistry, respectively. Liver and bowel biopsy specimens revealed less inflammation. Serum IL-10 levels were higher in tolerant mice than in controls, whereas IFNgamma was significantly reduced. Oral tolerance of BMT recipients toward their pretransplant antigens after splenocyte transplantation down-regulated the immune attack by transplanted cells, thus ameliorating cGVHD.
慢性移植物抗宿主病（cGVHD）是骨髓移植后可能出现的一种主要并发症。它涉及移植的供体淋巴细胞介导的免疫攻击，常导致宿主靶器官的炎症性损伤。最近研究表明，口服抗原给药诱导的免疫低反应性可在小鼠模型中预防cGVHD的发生。本研究的目的是评估骨髓移植（BMT）受者在移植后对其移植前抗原的耐受性诱导是否能减轻小鼠模型中已存在的cGVHD。通过将来自B10.D2供体小鼠的2.5×10⁷个脾细胞输注到经亚致死剂量照射（6 Gy）的BALB/c受体小鼠体内来诱导cGVHD，这两种小鼠在次要组织相容性抗原方面存在差异。移植导致了cGVHD，其特征为硬皮病样皮肤纤维化、皮肤胶原蛋白含量增加、体重减轻以及肝脏和小肠炎症。在B10.D2脾细胞移植后，通过给受体BALB/c小鼠喂食从BALB/c脾细胞中提取的蛋白质11天来诱导口服耐受。耐受性诱导表现为，用B10.D2脾细胞移植的耐受BALB/c小鼠的效应脾细胞对BALB/c靶脾细胞的混合淋巴细胞反应显著降低。口服耐受减少了皮肤胶原蛋白沉积。原位杂交和组织化学分别显示胶原蛋白α1（I）基因表达和皮肤胶原蛋白减少。肝脏和肠道活检标本显示炎症减轻。耐受小鼠血清IL-10水平高于对照组，而IFNγ显著降低。脾细胞移植后BMT受者对其移植前抗原的口服耐受下调了移植细胞的免疫攻击，从而改善了cGVHD。
