Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease
Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease
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DOI：
10.1172/jci200214793
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发表时间：
2002-05-01
影响因子：
15.9
通讯作者：
Ferrara, JLM
中科院分区：
文献类型：
--
作者：
Ordemann, R;Hutchinson, R;Ferrara, JLM
老年骨髓移植（BMT）受者在同种异体骨髓移植后发生急性移植物抗宿主病（GVHD）的风险增加，但这种关联的原因尚不清楚。使用具有良好特征的小鼠BMT模型，我们探索了老年小鼠GVHD增加的机制。老龄受者GVHD死亡率、发病率及病理生化指标均较差。老年小鼠的抗原呈递细胞（APCs）在体内和体外刺激下，供体T细胞反应均显著增加，LPS刺激后，APCs分泌更多的tnf - α和IL-12。在B6 -> B6D2F1模型中，CD4（+）供体T细胞介导老年小鼠更严重的GVHD，而不是CD8(+) T细胞。我们通过使用年老或年轻的骨髓基质构建的B6D2F1骨髓嵌合体，证实了衰老APCs在GVHD中的作用。嵌合体产生4个月后，来自B6供体的同种异体骨髓移植在旧骨髓嵌合体中引起的GVHD明显恶化。来自这些小鼠的apc也刺激了体外同种异体细胞的更大反应。这些数据表明，在BMT模型中，老年异体宿主apc放大供体T细胞反应，增加老年受体急性GVHD的机制迄今未被怀疑。
Older bone marrow transplantation (BMT) recipients are at heightened risk for acute graft-versus-host disease (GVHD) after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality, morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-alpha and IL-12 after LPS stimulation. In a B6 --> B6D2F1 model, CD4(+) donor T cells but not CD8(+) T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2F1 BM chimeras created with either old or young BM. Four months after chimera creation, allogeneic BMT from B6 donors caused significantly worse GVHD in old BM chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model.