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1.
环孢素A缓释系统植入前房抑制鼠角膜移植免疫排斥反应机制的研究 总被引:24,自引:13,他引:11
目的 探讨前房植入环孢素A(cyclosporineA ,CsA)缓释系统抑制鼠角膜移植免疫排斥反应的机制。方法 (1)环孢素A缓释系统的制备 :为CsA粉剂与已交酯 丙交酯 已内酯的三元共聚物混合体 ,每粒含环孢素A 0 5mg。 (2 )对 90只 (90只眼 )BALB c鼠 (受体 )行穿透性角膜移植术 ,将其分为A、B、C组 ,每组 30只。供体为C5 7BL 6鼠。A组术中鼠前房植入CsA缓释系统 ;B组术中鼠前房植入不含CsA的空白缓释系统 ;C组术后不作任何处理作为正常对照组。术后 3d用裂隙灯显微镜观察角膜植片情况 ,记录角膜植片免疫排斥反应发生的时间和程度。各组分别于术后 1、2、4及 6周随机取 2只鼠眼行组织病理学检查 ,并用CD4、CD8及CD11B单克隆抗体行免疫组织化学染色 ,观察各组T淋巴细胞的迁移和数量。结果 A组鼠角膜植片排斥时间平均 (35± 3)d ,较B、C组 (14± 3)d明显延长 (P <0 0 0 1)。前房植入的CsA缓释系统体积缩小前 ,A组角膜植片均保持透明 ;当前房植入的CsA缓释系统消失后 ,角膜出现免疫排斥反应 ,植片逐渐混浊、增厚、血管化。B、C组免疫排斥反应均在术后 2周发生。组织病理学和免疫组织化学检查 :A组在术后 14d仅于植床角膜可见少量CD+ 4 和CD+ 8 细胞浸润 ,在虹膜和睫状体中未见CD+ 11B、CD+ 4 、CD+ 8 T淋 相似文献
2.
Effect of local macrophage depletion on cellular immunity and tolerance evoked by corneal allografts 总被引:2,自引:0,他引:2
Slegers TP van der Gaag R van Rooijen N van Rij G Streilein JW 《Current eye research》2003,26(2):73-79
Corneal graft rejection can be prevented by local macrophage depletion, via subconjunctival injections with clodronate liposomes. To unravel the underlying immunological mechanism responsible for prolonged graft survival in this circumstance, the effect of this regimen on induction of donor-specific delayed type hypersensitivity (DTH) and anterior chamber associated immune deviation (ACAID) was determined. The study showed that although subconjunctival clodronate liposome-treatment failed to alter systemically induced DTH and ACAID, both types of immune response were absent in clodronate liposome-treated rats after corneal transplantation. Thus, elimination of macrophages from the corneal transplant site renders corneal allografts immunologically "invisible" to the recipient. PURPOSE: To determine whether local macrophage depletion, via administration of clodronate liposomes, alters delayed type hypersensitivity (DTH) responses and induction of anterior chamber associated immune deviation (ACAID) after corneal allotransplantation. METHODS: Clodronate liposome-treated and untreated rats received orthotopic corneal allografts and were tested for DTH responses and induction of ACAID towards donor antigens. Also in subconjunctivally treated and untreated rats, DTH responses were measured after subcutaneous immunization or induction of ACAID with allogeneic spleen cells. RESULTS: Subconjunctival injected clodronate liposomes prevented grafted rats from developing donor-specific DTH as well as ACAID. By contrast, subconjunctivally injected clodronate liposomes had no effect on donor-specific DTH responses after systemic immunization or on the induction of ACAID with allogeneic cells. CONCLUSIONS: Depletion of macrophages at the time of corneal allografting seems to render the grafts immunologically invisible to the recipients. This could explain why these grafts survive "indefinitely" without any other form of therapy. 相似文献
3.
Adhesion molecule expression in local-macrophage-depleted rats bearing orthotopic corneal allografts 总被引:1,自引:0,他引:1
BACKGROUND: Rejection of corneal grafts is dependent on influx of T lymphocytes and macrophages. This process is partly regulated by adhesion molecules. Earlier investigations showed that corneal graft rejection in rats could be prevented by clodronate liposomes that selectively eliminate macrophages. In the present study the effect of macrophage depletion on adhesion molecule expression after corneal allotransplantation was investigated. METHODS: Orthotopic corneal allografts were performed, after which rats received subconjunctival injections with clodronate liposomes or remained untreated. On various postoperative days, grafted rats were killed and mid-eye sections were stained for expression of ICAM-1 (CD54) and beta(2)-integrins (CD18 and CD11b/c). RESULTS: In the clodronate liposome-treated group grafts were not rejected, while in untreated rats grafts had a mean survival time of 12 days. During the first postoperative days a slightly enhanced expression of ICAM-1 in the conjunctiva and allografted cornea of clodronate liposome-treated recipients was seen. On day 12, however, ICAM-1 expression was markedly downregulated in the allografts of this treated group. The expression of beta(2)-integrins was also significantly decreased in the allografts and recipient corneas of treated rats at this time point. CONCLUSION: Prolonged corneal graft survival in rats, obtained via local depletion of macrophages, correlates with diminished expression of adhesion molecules. 相似文献
4.
ACAID induced by allogeneic corneal tissue promotes subsequent survival of orthotopic corneal grafts 总被引:2,自引:0,他引:2
Sonoda A Sonoda Y Muramatu R Streilein JW Usui M 《Investigative ophthalmology & visual science》2000,41(3):790-798
PURPOSE: To determine whether immune deviation is induced by allogeneic corneal tissue implanted in the anterior chamber and whether survival of subsequent orthotopic corneal allografts is thereby enhanced. METHODS: Corneal tissue from C57BL/6 mice was implanted in the anterior chamber of eyes of BALB/c mice. The fate of these implants was assessed histologically, and the donor-specific immune response of recipient mice was tested for donor-specific delayed hypersensitivity and the capacity to accept or reject C57BL/6 corneas grafted orthotopically into the fellow eye. RESULTS: C57BL/6 cornea implants in the anterior chamber failed to induce donor-specific delayed hypersensitivity but impaired donor-specific delayed hypersensitivity in a proportion of recipients with implants in place for 2 weeks. Mice with donor-specific delayed hypersensitivity rejected the intraocular implants. Mice bearing C57BL/6 cornea implants in the anterior chamber for 2 (but not 4) weeks accepted the C57BL/6 corneas grafted orthotopically into the fellow eye at a high rate and with few rejection reactions. CONCLUSIONS: Implantation of allogeneic corneal tissue in the anterior chamber of the eye has the transient capacity to alter the recipient alloimmune response in a manner that promotes survival of subsequent orthotopic corneal allografts. 相似文献
5.
前房植入环孢素A缓释系统抑制鼠高危角膜移植术后的免疫排斥反应 总被引:12,自引:1,他引:11
目的 探讨前房内植入环孢素A缓释系统 (cyclosporineAdrugdeliverysystem ,CsADDS)抑制高危角膜移植术后免疫排斥反应的有效性和可行性。方法 (1)对 6 0只Wistar大鼠 (6 0只眼 )用缝线法诱导角膜新生血管增生。 (2 )将发生角膜新生血管化的 4 0只Wistar大鼠 (40只眼 )随机分为4组 :对照组 ,1%CsA滴眼组 ,CsADDS结膜下植入组 ,CsADDS前房内植入组。每组均接受同种异系(Spregue Dawley大鼠 )角膜供体 ,行穿透性角膜移植术 ,术后比较各组大鼠免疫排斥反应发生的时间 ,并定期检测各组大鼠房水中CsA的浓度。 (3)正常Wistar大鼠 8只 (16只眼 ) ,随机分为 2组 ,分别在结膜下和前房内植入CsADDS ,术后 2和 4周行眼的组织病理学检查。结果 (1) 5 1只Wistar大鼠 (5 1只眼 )经角膜基质缝线 ,成功诱导角膜新生血管增生。 (2 ) 4组共 4 0只Wistar大鼠角膜移植术后免疫排斥反应的发生时间分别为 :对照组 (8 2 0± 1 4 8)d ,1%CsA滴眼组 (10 6 0± 1 90 )d ,CsADDS结膜下植入组 (11 4 0± 2 5 0 )d ,CsADDS前房内植入组 (17 0 0± 6 0 5 )d。房水中CsA浓度均值分别为 :对照组 0 μg/L ;1%CsA滴眼组 (47 90± 3 4 8) μg/L ;CsADDS结膜下植入组术后 1、2、4周 ,房水中CsA浓度均值分别为 (5 9 0 0± 3 6 6 ) μg/ 相似文献
6.
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 总被引:4,自引:1,他引:3
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CsA 1mg)、0.1%FK506眼液滴眼组及FK506 DDS前房植入组(含FK5060.5mg)。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%FKS06眼液滴眼组和FKS06 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a(IL-2Bot)、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180d,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FKS06眼液滴眼组(T=21.00,P=0.0022)。FKS06 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.2Bet和MCP-1mRNA的表达,而CsADDS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-2Pux和MCP-1mRNA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。 相似文献
7.
Immunity and immune privilege elicited by autoantigens expressed on syngeneic neonatal neural retina grafts. 总被引:2,自引:0,他引:2
Achieving the long-term goal of successful engraftment of retinal tissues into eyes blinded by endogenous retinal failure will depend, at least in part, on controlling the immune response to antigens expressed on retinal grafts. Since histoincompatible tissues will have to be used for such transplants, methods to control immune rejection directed at transplantation alloantigens must be devised. In addition, it has recently been observed in mice that developing neural retinal tissues express retina-specific antigens that have the potential to contribute to graft failure. To examine the potential risk of this contribution, syngeneic neonatal neural retinas were implanted into the anterior chamber, vitreous cavity, and subconjunctival space of adult BALB/c mice. During two weeks post-implantation, the fate of these grafts was observed clinically and histologically, and the retina-specific immune responses of the recipients were evaluated. Whereas grafts placed intraocularly thrived, carried out their inherent developmental potential, and were healthy and intact at the end of the observation interval. Grafts placed extraocularly expressed their differentiation program poorly. These grafts underwent rapid decline and attrition, although the process was not accompanied by significant inflammation. Recipients of subconjunctival, but not AC or VC, implants developed retina-specific delayed hypersensitivity. Alternatively, mice bearing AC and VC implants of neonatal neural retina developed retina-specific anterior chamber associated immune deviation. It is concluded that retinal autoantigens are expressed on developing neural retinal tissues and these antigens are highly immunogenic when retinal grafts are placed at conventional body sites. When similar grafts are placed in immune privileged compartments of the normal eye, they enjoy significant survival. Circumstantial evidence indicates that intraocular retinal grafts are protected and maintained in part by the emergence of systemic retinal auto-antigen-specific immune suppression. 相似文献
8.
CD95 ligand expression on corneal epithelium and endothelium influences the fates of orthotopic and heterotopic corneal allografts in mice 总被引:4,自引:0,他引:4
PURPOSE: To determine the extent to which CD95 ligand (CD95L) expressed on corneal epithelium and endothelium influences survival of cornea grafts placed orthotopically and heterotopically in the anterior chamber (AC), an immune-privileged site. METHODS: Corneas from eyes of C57BL/6 (B6) and B6.gld (CD95L deficient) mice were (1) rendered into small full-thickness fragments, with or without an epithelial layer, and placed behind recipient corneas in the ACs of BALB/c eyes, while BALB/c corneas were similarly implanted in eyes of B6 and B6.lpr (CD95 deficient) mice; or (2) corneas were grafted orthotopically in BALB/c eyes as intact corneas or as composite corneas in which epithelium from one donor source was layered in vitro onto epithelium-deprived stroma+endothelium from another donor source before grafting. The fate of the grafts was assessed clinically and histologically, and the capacity of the grafts to sensitize recipient mice to donor alloantigens (delayed hypersensitivity, DH) was evaluated. RESULTS: Allogeneic, full-thickness B6.gld corneal fragment grafts placed in the AC of BALB/c mice were rejected and sensitized their recipients, whereas epithelium-deprived B6.gld cornea fragments survived indefinitely and failed to sensitize their recipients. BALB/c corneal fragment grafts placed in the AC of C57BL/6 or B6.lpr eyes were rejected. Orthotopic cornea grafts composed of B6.gld epithelium layered onto wild-type B6 stroma and endothelium were rejected at a tempo and incidence similar to full-thickness B6 grafts, whereas orthotopic composite cornea grafts containing B6 epithelium layered onto B6.gld stroma+endothelium were vigorously rejected. CONCLUSIONS: CD95L expression on epithelium of full-thickness cornea fragment grafts placed in the anterior chamber of BALB/c eyes protects these heterotopic grafts from rejection but has only a trivial role to play in determining the fate of orthotopic corneal grafts. In the latter type of corneal grafts, CD95L expression on the endothelium plays an essential role in preventing graft rejection. 相似文献
9.
Role of recipient epithelium in promoting survival of orthotopic corneal allografts in mice 总被引:5,自引:0,他引:5
PURPOSE. To determine whether epithelium-deprived corneal allografts covered with syngeneic epithelium display immune privilege in orthotopic transplantation and whether syngeneic epithelium containing antigen-presenting cells nullifies this effect. METHODS. Epithelium-deprived allogeneic corneas (C57BL/6) and epithelium-deprived allogeneic corneas reconstituted with syngeneic (BALB/c) epithelium (containing or deprived of Langerhans' cells) were transplanted orthotopically into normal eyes of BALB/c mice. Graft survival was assessed clinically and evaluated histologically. RESULTS. Epithelium-deprived corneal grafts survived in syngeneic recipients but were swiftly rejected in allogeneic recipients. These allografts incited intense stromal inflammation and neovascularization. Epithelium-deprived allografts that were resurfaced in vivo by syngeneic epithelium derived from immune-incompetent SCID mice also underwent intense acute rejection when placed in normal eyes of BALB/c mice. The epithelium of in vivo resurfaced grafts was replete with Langerhans' cells. By contrast, most of the epithelium-deprived allografts reconstituted in vitro with fresh, normal BALB/c corneal epithelium survived indefinitely when placed in eyes of BALB/c mice. Similar grafts reconstituted with BALB/c epithelium containing Langerhans' cells were swiftly rejected. CONCLUSIONS. Replacement of donor epithelium with Langerhans' cell-deficient syngeneic epithelium protects orthotopic allogeneic cornea grafts (stroma plus endothelium) from immune-mediated rejection. The presence of an intact, histocompatible layer of corneal epithelium has two important effects on orthotopic corneal allografts: It suppresses nonspecific inflammation and neovascularization within the graft, and it blunts the alloimmunogenicity of the histoincompatible stroma and endothelium. 相似文献
10.
Intraocular dexamethasone delivery system for corneal transplantation in an animal model 总被引:3,自引:0,他引:3
PURPOSE: To assess the efficacy of a new intraocular biodegradable polymer dexamethasone drug delivery system (DEX DDS) in a high-risk corneal transplantation model. METHODS: Lewis rats that received orthotopic corneal transplants (Balb/c mice donors) were divided into three groups (six rats in each); group 1 received no treatment and served as controls, group 2 was treated with 0.1% betamethasone eyedrops three times daily for 6 weeks, and group 3 received DEX DDS in the anterior chamber at the time of transplantation. RESULTS: All grafts in the untreated control group were rejected within 8 days. In the betamethasone eyedrop group, five eyes (83%) were rejected during the 8-week study period. None of the grafts in the DEX DDS group was rejected. The administration of DEX DDS significantly prolonged the survival rate of the corneal grafts (p < 0.001, log-rank test). CONCLUSION: DEX DDS is effective in suppressing graft rejection in high-risk corneal transplantation. 相似文献