Effect of recipient age /graft vs host disease post BMT

将利用造血干细胞移植的鼠类模型来研究年龄增长与更严重的移植物抗肿瘤之间的关联。宿主病（GVHD）。这项工作的长期目标是了解老年移植受者GVHD的病理生理学，从而制定干预措施，降低严重GVHD的风险，增加造血干细胞移植在老年受者中的适用性。这项工作的具体目的是（1）确定老年小鼠中GVHD严重程度的增加是否是由更大的肠组织损伤引起的，从而导致内毒素的移位增加和随后促炎细胞因子的释放，以及（2）确定更严重的GVHD与受体年龄的增加之间的关联是否适用于H2 II类抗原-介导的GVHD和H2 I类抗原介导的GVHD。为了检验由于预处理治疗引起的更严重的胃肠道损伤将导致更严重的GVHD的假设，将在充分表征的造血干细胞移植模型（C57 BU 6-+ B6 D2 F1）中评估临床GVHD评分、血清内毒素和TNF-α水平、胃肠道和肝脏组织病理学以及存活率。将在体内使用内毒素和TNF-α阻断剂来检验促炎性细胞因子级联反应的中断将降低老年动物中GVHD发病率和死亡率的假设。最后，为了检验年龄增长与更严重的GVHD的关联主要是由于胃肠道损伤而与T细胞效应物的类型无关的假设，将评价CD 4介导和CD 8介导的GVHD模型的衰老对GVHD评分、胃肠道和肝脏组织病理学、血清TNF-α水平和存活率的影响。

Murine models of hematopoietic stem cell transplantation will be utilized to investigate the association between advancing age and more severe graft-vs.-host disease (GVHD). The long-term objective of this work is to understand the pathophysiology of GVHD in aged transplant recipients and thereby to develop interventions which will decrease the risk of severe GVHD and increase the applicability of hematopoietic stem cell transplantation in aging recipients. The specific aims of this work are (1) to determine whether the increased severity of GVHD in older mice is caused by greater intestinal tissue injury resulting in enhanced translocation of endotoxins and subsequent release of proinflammatory cytokines and (2) to determine whether the association of more severe GVHD with advancing age of the recipient holds true both for H2 class II antigen- mediated GVHD and for H2 class I antigen-mediated GVHD. In order to test the hypothesis that more severe GI tract damage due to conditioning therapy will lead to more severe GVHD, clinical GVHD scores, serum endotoxin and TNF-alpha levels, GI tract and liver histopathology, and survival will be assessed in a well characterized hematopoietic stem cell transplantation model (C57BU6 -+ B6D2F1). Endotoxin and TNF-alpha blockers will be employed in vivo to test the hypothesis that interruption of the proinflammatory cytokine cascade will decrease GVHD morbidity and mortality in aged animals. Finally, to test the hypothesis that the association of advancing age with more severe GVHD is primarily due to GI tract damage and is independent of the type of T cell effector, both CD4-mediated and CD8-mediated models of GVHD will be evaluated for the effects of aging upon GVHD scores, GI tract and liver histopathology, serum TNF-alpha levels, and survival.