Effect of recipient age /graft vs host disease post BMT

小鼠造血干细胞移植模型将用于研究年龄增长与更严重的移植物vs之间的关系。-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GVHD严重程度的增加是否由更大的肠道组织损伤导致内毒素易位增强和随后的促炎细胞因子释放引起的；(2)确定受体年龄的增长是否与更严重的GVHD相关，无论是H2 II类抗原介导的GVHD还是H2 I类抗原介导的GVHD都成立。为了验证调节治疗导致的更严重的胃肠道损伤会导致更严重的GVHD的假设，我们将在一个具有良好特征的造血干细胞移植模型（C57BU6 -+ B6D2F1）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生存。内毒素和tnf - α阻滞剂将被用于体内实验，以验证阻断促炎细胞因子级联将降低老龄动物GVHD发病率和死亡率的假设。最后，为了验证年龄增长与更严重GVHD的关联主要是由于胃肠道损伤，并且与T细胞效应物的类型无关的假设，我们将评估cd4介导和cd8介导的GVHD模型，以评估衰老对GVHD评分、胃肠道和肝脏组织病理学、血清tnf - α水平和生存率的影响。

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.