Reserch of Clinical

口服他克莫司微球可使他克莫司在小肠派尔集合淋巴结中特异性分布。在这种给药系统中，免疫抑制剂可以在局部肠壁中达到高浓度。将0.04 mg他克莫司微球经口给予小肠移植猪。尽管他克莫司血药浓度低（10.5 ng/ml），但生存期显著延长，无排斥反应或感染。进行了一例活体小肠移植（日本第3例）和一例尸体小肠移植（日本第1例）。通过高倍变焦内窥镜和免疫组化染色监测排斥反应。高倍变焦内镜显示早期排斥绒毛变钝，绒毛数量减少，常规内镜检查无法观察到。免疫组化染色、肥大细胞角蛋白碎片增多、FasL阳性淋巴细胞、穿孔素和颗粒酶B阳性、Ki 67阳性肠上皮细胞减少等有助于早期发现排斥反应。临床上2例患者经监测排异反应均得到较好控制。移植肠功能良好，两例患者均完全脱离肠外营养。应用新型免疫抑制剂FTY 720预防大鼠小肠移植慢性排斥反应。本研究是与国外机构合作研究。建立小肠移植慢性排斥反应模型，移植肠动脉内壁增厚。FTY 720和环孢素联合免疫抑制剂可完全抑制动脉内壁增厚的发展。

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.