Study for improvement of islet cell transplantation by renal transplantation with micro cell chimerism

即使严格控制血糖水平，大多数IDDM患者仍因糖尿病肾病而需要肾移植。临床上多采用胰腺(器官)联合肾移植治疗，但侵袭性大，并发症不少。目前较为理想的治疗方法是胰岛联合肾移植，但由于其强烈的排斥反应，其临床应用仍受到限制。因此，我们明确了在胰岛细胞移植中，通过诱导受体微细胞嵌合体进行移植物修饰是否可以提高移植物的存活率。供体和受体分别为Inbrecd大鼠、F344和LEW。肾移植前4周，供体行全身照射(TBI)。伤后1周，将受者的骨髓细胞和脾细胞输注给同一供者(BMTX)。用TBI和BMTX诱导受体细胞嵌合的移植肾，在F344胰岛细胞移植前移植给受体。非嵌合组(以高血糖判断排斥反应)的胰岛存活时间为7~14d，比单纯胰岛移植的存活时间长，排斥后各受者血糖均升高500 mg/dl以上。另一方面，嵌合组的存活时间为11~25天，提示通过这种方法可以获得更长的生存时间。嵌合移植物可诱导供体TBI和BMTX免疫耐受。目前正在研究理想的条件：照射强度、骨髓细胞数量以及每次治疗和移植之间的间隔时间。此外，通过研究微细胞嵌合体的数量/强度与移植物存活之间的关系，将有助于阐明其机制。

The most of the IDDM patients needs renal transplantation because of diabetic nephropathy even if their blood sugar level was strictly controlled by insulin therapy. Clinically, the simultaneous pancreas (organ) and renal transplantation is applied for this disease, but this therapy is very invasive and its complications are not rare. The more ideal therapy must be the islet transplantation with renal transplantation but its clinical application is still limited because of its strong rejection. Therefore, we clarify whether graft modification by inducing the recipient micro cell chimerism improve the graft survival in islet cell transplantation. Inbrecd rats, F344 and LEW were used for the donor and the recipient. Four weeks before kidney transplantation, the donor total body irradiation (TBI) was performed. One week after TBI, the recipient bone marrow cells and splenocytes were infused to the same donor (BMTX). the renal graft in which the recipients cell chimerism was induced by TBI and BMTX, is transplanted to the recipient before F344 islet cell transplantation. The islet survivals of non-chimerism group (rejection was judged by hyperglycemia) are 7 to 14 days, which is longer than those of the islet transplantation alone, the blood sugar level of each recipient were elevated over 500 mg/dl after rejection. On the other hands, the survival of chimerism group were 11 to 25 days, which suggests the more longer survival could be obtained by this procedures. Immunological tolerance by donor TBI and BMTX could induced by the chimeric graft. The ideal condition ; strength of irradiation, number of bone marrow cells and intervals between each therapy and transplantation is now under investigation. Moreover, mechanism will be clarified by investigating the relationships between the number/strength of micro cell chimerism and graft survivals.