MODULATION OF CHIMERISM FOR INTESTINAL TRANSPLANTATION

近交系大鼠和近交犬模型将被用来开发策略，将临床肠道和多脏器移植手术从目前过高的发病率和死亡率提升到更安全和更具成本效益的手术。这些方案是基于这样一个发现，即所有器官的骨髓中的乘客白细胞在移植后都会迁移并产生持续的嵌合体，有证据表明这对移植物的持续存活是必不可少的。然而，与骨髓相比，肠道乘客白细胞的耐受性较差，而且具有易患移植物抗宿主病(GVHD)的谱系特征。这种供者白细胞群体将通过照射肠道和多个内脏器官来改变，照射剂量对上皮/血管成分没有损害，无论有没有辅助供者骨髓。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/或移植物抗宿主病的临床和组织病理学证据；以及停用免疫抑制后的结果。基本控制组和试验组的变量将是：(A)照射和/或辅助骨髓的剂量，(B)受者使用造血生长因子治疗，(C)替代照射的肠道乘客白细胞谱系去除方法。该项目呼吁首先强调近交系大鼠品系组合，其中排斥反应和移植物抗宿主病可以分开描述。这些实验有望更清楚地阐明移植物接受的机制，因为这些机制适用于所有器官。根据结果，工作将继续进行到临床上更相关的近交犬模型。

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.