FK506缓释系统前房植入抑制兔高危角膜移植术后的免疫排斥反应  

Implantation of FK506 drug delivery system into the anterior chamber for inhibiting corneal rejection in high risk rabbit corneal allograft

作　　者：史伟云[1] 刘廷[1] 谢立信[1] 王身国[2] 

机构地区：[1]山东省眼科研究所山东省眼科学重点实验室-省部共建国家重点实验室培育基地,青岛266071 [2]中国科学院化学研究所

出　　处：《中华眼科杂志》2006年第4期299-304,共6页Chinese Journal of Ophthalmology

基　　金：山东省科技厅发展计划重大项目资助(021100105);国家重点基础研究发展项目(973计划)(2003CB515500);青岛市科技局院士科研项目(02KGYSH-01);国家高技术研究发展计划(863计划)(30271239)

摘　　要：目的探讨前房植入FK506药物缓释系统(DDS)对兔高危角膜移植术后免疫排斥反应的抑制作用和FK506房水药物浓度与免疫排斥反应的关系。方法107只新西兰白兔中随机数字法选取73只兔进行角膜新生血管化模型的制作,其中68只兔作为受体成功建立高危角膜移植动物模型,随机数字法分为对照组、空白DDS前房植入组、环孢素A(CsA)DDS前房植入组(含CsA1 mg)、0.1%FK506眼液滴眼组及FK506 DDS前房植入组(含FK506 0.5 mg)。角膜移植术后观察各组角膜植片排斥发生的时间,移植术后1周取各组实验兔眼房水和静脉血进行FK506药物浓度检测。0.1%FK506眼液滴眼组和FK506 DDS前房植入组在移植术后的不同时间点抽取实验兔眼房水和静脉血,进行FK506药物浓度的检测。观察各组兔移植术后4周和观察期结束时角膜植片的病理变化,同时应用原位杂交的方法检测各组角膜植片内白细胞介素2受体α(IL-2Rα)、单核细胞趋化蛋白1(MCP-1)、Fas及FasL mRNA的表达。结果FK506 DDS前房植入组角膜植片存活时间超过180 d,明显优于其他各组(F=926.37,P=0.0000),其房水和角膜组织中的FK506药物浓度明显高于FK506眼液滴眼组(T=21.00,P=0.0022)。FK506 DDS前房植入组在术后24周内均能在房水中检测出FK506。术后4周对照组和空白DDS前房植入组有大量的炎性细胞浸润,并有明显的IL-2Rα和MCP-1 mRNA的表达,而CsA DDS前房植入组、FK506眼液滴眼组及FK506 DDS植入组角膜未见明显的炎性细胞浸润,未见IL-2Rα和MCP-1 mRNA的表达。各组均未见明显的Fas和FasL mRNA的表达。结论前房植入FK506 DDS可有效地抑制高危角膜移植术后免疫排斥反应的发生,房水中较高的FK506药物浓度是防治术后发生免疫排斥反应的重要因素。Objective To study the effects of a biodegradable FK506 drug delivery system （DDS） on the inhibition of corneal rejection, to measure the concentration of FK506 in the aqueous humor and to study the relationship between intraocular concentration of FK.506 and its immunosuppressive effects on corneal rejection. Methods Corneal neo-vascularization was induced by 5-0 silk sutures in 68 New Zealand rabbits to establish a high risk corneal transplantation model A unilateral 7 mm diameter central penetrating corneal transplantation was performed with 7.5 nun diameter grafts from health New Zealand rabbit donor~ Grafted rabbits were randomized into five groups as follows： Group A： untreated control animals; Group B： DDS anterior chamber recipients without drug; Group C： 1 mg cyclosporine DDS anterior chamber recipients; Group D： 0.1% FK.506--olive oil drop recipients; Group E： 0.5 mg FKS06 DDS anterior chamber recipients. Grafts were examined with a slit lamp every other day and clinical conditions were scored for up to 28 weeks. The aqueous humor and cornea of Group D and Group E were collected, and the concentration of FKS06 was determined. The expression of cytokines IL-2Rα, MCP-1, Fas and FasL mRNA was detected with in situ hybridization method. Results The median survival time was （17.9±4. 7） d in Group A （untreated corneal allograft）, （20. 0±3.7） d in Group B, （56. 3±8. 8） d in Group C, （78. 1±7.2） d in Group D, and over 180 d in Group E. Statistically significant difference （F =926.37, P = 0. 0000 ） in the survival time of allograft has been found between Group E and other groups. The concentration of FKS06 in aqueous humor was （ 15.7 ± 2.6） ng/ml in Group E at one week and remained stable for at least 24 weeks, much higher than that in Group D （ 〈0. 3 ng/ml）. The concentration of FK506 in cornea was also higher in Group E than that in Group D. The expression of cytokines IL-2Rα and MCP-1 mRNA was detected, but the expression of Fas and FasL mRNA was not de

关 键 词：角膜移植 他罗利姆 药物缓释系统 免疫抑制 兔 免疫排斥反应 

分 类 号：R779.65[医药卫生—眼科]