角膜异种移植是解决人类角膜供体短缺的有效方法,并且猪角膜可以是供体角膜的合适候选物,因为其与人类的光学相似性。然而,有必要施用额外的免疫抑制剂以克服抗原差异。我们旨在研究在临床适用的猪到非人灵长类动物角膜异种移植模型中使用抗CD40抗体介导的共刺激阻断的猪角膜的可行性。
五只中国恒河猴使用临床上可接受的大小(直径7.5mm)的猪角膜移植物进行了深层状角膜移植。抗CD40抗体以程序化的时间表静脉内施用。移植物存活,中央角膜厚度,并评估眼压。在血液中研究了效应和记忆T和B细胞亚群以及抗αGal和供体特异性抗体的变化,并评估了房水和血液中补体水平的变化。将抗CD40抗体治疗组的记忆细胞谱与抗CD154抗体治疗组的记忆细胞谱或我们先前报告中提出的拒绝对照的记忆细胞谱进行比较。抗αGal的变化,非αGal,6个月后的供体特异性抗体与基线值进行比较.
抗CD40抗体介导的共刺激阻断导致异种角膜移植物成功存活(>389、>382、>236、>201和>61天),80%的人可存活6个月。抗CD40抗体的注射显著减少了炎性细胞向移植物中的浸润,并且显著阻断了房水中的补体应答(P=.0159,Mann-WhitneyU检验)。与排斥对照中的那些(P<.05,Mann-WhitneyU检验)或在抗CD154抗体处理的灵长类动物中的那些(P>.05,Mann-WhitneyU检验)相比,在抗CD40抗体处理的灵长类动物中消除了中枢或效应记忆T细胞的系统扩增。抗αGal的水平,非αGal,与基线水平相比,6个月时的供体特异性抗体没有显着增加(P>.05,Wilcoxon符号秩检验)。
抗CD40抗体介导的阻断似乎是灵长类动物猪角膜深层异种移植的有效免疫抑制方法。
Corneal xenotransplantation is an effective solution for the shortage of human donor corneas, and the porcine cornea may be a suitable candidate for the donor cornea because of its optical similarity with humans. However, it is necessary to administer additional immunosuppressants to overcome antigenic differences. We aimed to investigate the feasibility of porcine corneas with anti-CD40 antibody-mediated costimulation blockade in a clinically applicable pig-to-non-human primate corneal xenotransplantation model.
Five Chinese rhesus macaques underwent deep-lamellar corneal transplantation using clinically acceptable sized (7.5 mm diameter) porcine corneal grafts. The anti-CD40 antibody was intravenously administered on a programmed schedule. Graft survival, central corneal thickness, and intraocular pressure were evaluated. Changes in effector and memory T and B cell subsets and anti-αGal and donor-specific antibodies were investigated in the blood, and the changes in complement levels in the aqueous humor and blood were evaluated. Memory cell profiles in the anti-CD40 antibody-treated group were compared with those from the anti-CD154 antibody-treated group or rejected controls presented in our previous report. The changes in anti-αGal, non-αGal, and donor-specific antibodies after 6 months were compared with baseline values.
Anti-CD40 antibody-mediated costimulation blockade resulted in the successful survival of xenocorneal grafts (>389, >382, >236, >201, and >61 days), with 80% reaching 6 months of survival. Injection of anti-CD40 antibody considerably reduced the infiltration of inflammatory cells into the grafts and significantly blocked the complement response in the aqueous humor (P=.0159, Mann-Whitney U test). Systemic expansion of central or effector memory T cells was abrogated in the anti-CD40 antibody-treated primates compared with those in the rejected controls (P<.05, Mann-Whitney U test) or those in the anti-CD154 antibody-treated primates (P>.05, Mann-Whitney U test). The levels of anti-αGal, non-αGal, and donor-specific antibodies at 6 months were not significantly increased compared with baseline levels (P>.05, Wilcoxon signed rank test).
An anti-CD40 antibody-mediated blockade appears to be effective immunosuppressive approach for porcine corneal deep-lamellar xenotransplantation in primates.