MODULATION OF CHIMERISM FOR INTESTINAL TRANSPLANTATION

近交系大鼠和远系犬模型将用于开发策略，可以将临床肠道和多器官移植手术从目前的过度发病率和死亡率状态提升到更安全和更具成本效益的操作。 该方案基于以下发现：移植后所有器官中的骨髓中的乘客白细胞迁移并产生持续的嵌合体，证据表明这对移植物的持续存活至关重要。 然而，与骨髓相比，肠乘客白细胞具有较差的致耐受性，并且另外具有易患移植物抗宿主病（GVHD）的谱系特征。 该供体白细胞群将通过以对上皮/血管成分无损伤的剂量辐照肠道和多内脏器官来改变，伴或不伴辅助供体骨髓。 终点将是移植后嵌合体的数量和质量、受者的体重、发育和存活;排斥和/或GVHD的临床和组织病理学证据;以及免疫抑制剂停止后的结果。 基础对照组和实验组中的变量将是：（a）辐射和/或辅助骨髓的剂量，（B）用造血生长因子的受体治疗，（c）肠乘客白细胞谱系耗竭的替代（辐射）方法。 该项目要求最初强调近交系大鼠品系组合，其中排斥反应和GVHD可以单独描述。 预期这些实验将更清楚地阐明移植物接受的机制，因为这些适用于所有器官。 根据结果，工作将继续进行到临床上更相关的远交犬模型。

Inbred rat and outbred canine models will be used to develop strategies that can elevate clinical intestinal and multivisceral transplant procedures from their present state of excessive morbidity and mortality to more safe and cost effective operations. The protocols are based on the discovery that passenger leukocytes of bone marrow in all organs migrate after transplantation and produce persistent chimerism, evidence suggests that this is essential for sustained survival of the grafts. However, intestinal passenger leukocytes have inferior tolerogenic qualities compared to bone marrow, and in addition have a lineage profile that predisposes to graft versus host disease (GVHD). This donor leukocyte population will be modified by irradiation of the intestinal and multivisceral organs at doses that are non-injurious to the epithelial/vascular components, with or without adjunct donor bone marrow. The end points will be quantity and quality of the post-transplant chimerism, weight, development, and survival of the recipients; clinical and histopathologic evidence of rejection and/or GVHD; and outcome after discontinuance of immunosuppression. Variables in the basic control and experimental groups will be: (a) the doses of irradiation and/or adjunct bone marrow, (b) recipient treatment with hematolymphopoietic growth factors, (c) alternative (to irradiation) methods of intestinal passenger leukocyte lineage depletion. The project calls for initial emphasis on inbred rat strain combinations in which rejection and GVHD can be delineated separately. These experiments are expected to elucidate more clearly the mechanisms of graft acceptance as these apply to all organs. Based on the results, work will proceed to the clinically more relevant outbred canine models.