Reserch of Clinical

通过口服含有他克莫司的微球，他克莫司可以特异性地分布在小肠的Peyer斑块中。在这种给药系统中，局部肠壁可以获得高浓度的免疫抑制剂。他克莫司微球0.04 mg灌胃给猪小肠移植。尽管他克莫司的血液浓度很低(10.5 ng/ml)，但存活时间显著延长，没有排斥反应或感染。行活体小肠移植1例(日本第3例)和身体小肠移植1例(日本第1例)。通过高倍变焦内窥镜和免疫组织化学染色监测排斥反应。高倍变焦内窥镜检查可见早期绒毛变钝，绒毛数目减少，这是常规内窥镜检查无法观察到的。活检标本的免疫组织化学染色、细胞凋亡性角化片断增多、FasL染色的淋巴细胞、穿孔素和颗粒酶B阳性发现、Ki67染色的肠上皮细胞减少有助于发现早期排斥反应。通过新的监测，上述2例临床排斥反应得到了较好的控制。移植肠功能良好，均完全脱离肠外营养。应用新型免疫抑制剂FTY720预防小肠移植大鼠的慢性排斥反应。这项研究是国外研究所的合作研究。建立了移植小肠慢性排斥反应模型，移植肠动脉内壁增厚。FTY720和环孢素联合免疫抑制可完全抑制动脉壁增厚。

By oral intake of microsphere containing tacrolimus, tacrolimus can be distributed specifically in Peyer patches of small intestine. In this drug delivery system, high concentration of immunosuppressive agent can be achieved in local intestinal wall. Microsphere at the dose of 0.04 mg of tacrolimus was administered orally to small bowel transplant porcine. Survival was dramatically prolonged without rejection or infection in spite of low blood concentration of tacrolimus (10.5 ng/ml). One living donor small bowel transplantation (the 3rd case in Japan) and one cadaveric small bowel transplantation ( the 1st case in Japan) were performed. Monitoring of rejection was instituted by high-power zoom endoscopy and immunohistochemical staining. High-power zoom endoscopy demonstrated blunting of villi and decreased number of villi as an early stage of rejevtion, which could not be observed by ordinal endoscopy examination. III immunohistochemical staining of biopsy specimen, increase of apopstosis induced keratine fragments, FasL-staining lymphocytes, positive finding of perforin and granzymeB, decrease of Ki67-staining enterocytes were useful for detecting very early stage of rejection. The rejection was controlled well in the above clinical 2 cases by those new monitoring. Intestinal grafts functioned well, and both of them were weaned from parenteral nutrition completely. The new immunosuppresive agent (FTY720) was used for prevention of chronic rejection in small bowel transplant rats. This research is co-operative study in foreign institute. Chronic rejection model in small intestine transplantation was achieved, in which thickning of internal wall of artery was demonstrated in intestinal grafts. Combined immunosuppression with FTY720 and cyclosporine inhibited completely development of internal wall of thichning of artery.