MODULATION OF CHIMERISM FOR INTESTINAL TRANSPLANTATION

近交大鼠和近交犬模型将用于制定策略，将临床肠道和多内脏移植手术从目前高发病率和死亡率的状态提升到更安全、更经济的手术。该方案是基于所有器官骨髓的客运白细胞在移植后迁移并产生持续嵌合的发现，有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，肠道旅客白细胞具有较差的耐受性，并且具有易于移植物抗宿主病（GVHD）的谱系特征。在有或没有辅助供体骨髓的情况下，以对上皮/血管成分无害的剂量照射肠道和多内脏器官，可以改变供体白细胞群。终点将是移植后嵌合的数量和质量、受者的体重、发育和生存；排斥反应和/或GVHD的临床和组织病理学证据；停止免疫抑制后的结果。基本对照组和实验组的变量将是：(a)照射和/或辅助骨髓的剂量，(b)受体用造血生长因子治疗，(c)肠道旅客白细胞谱系消耗的替代（辐射）方法。该项目要求最初着重于近亲繁殖的大鼠品系组合，其中排斥反应和GVHD可以分开描述。这些实验有望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。在此基础上，将进行临床更相关的近交系犬模型的研究。

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.