Yamada Jun, Hamuro Junji, Terai Kazuto, Kinoshita Shigeru
Department of Ophthalmology, Meiji University of Oriental Medicine, Hinotani6-1, Honoda, Nantan-shi, Kyoto, Japan.
Transplantation. 2007 Oct 15;84(7):899-907. doi: 10.1097/01.tp.0000284731.22247.a3.
Corneal allograft rejection is mediated by a Th1-type response. Because major histocompatibility complex (MHC)-compatible allografts are the prerequisite for efficient graft survival by reducing the Th1 response, we explored a new strategy for the acceptance of (MHC+minor H)-disparate allografts.
N,N'-diacetyl-L-cystine dimethylester (NM2) reduces the intracellular glutathione content (icGSH) in antigen-presenting cells (APCs) and down-regulates Th1 responses. Therefore, we subconjunctivally (scj) injected NM2 into donor- and/or recipient mice on days 1, 4, and 7 before penetrating keratoplasty. C57BL/10, B10.D2, or CBF1 corneal allografts were then placed on neovascularized graft beds of BALB/c mice. Corneal grafting was also performed between CBF1 and B6C3F1 mice.
The saline-injected controls rejected all allografts within 3 weeks. Minor H-only-disparate B10.D2 allografts survived indefinitely after the intraperitoneal (ip) (65.0%) and scj (71.4%) injection of NM2 (P<0.0001). MHC+minor H-disparate C57BL/10 allograft survival was prolonged only by scj injection of NM2 (median survival time [MST]=43.6+/-1.5, P<0.001); there was no indefinite allograft survival. Allelic-gene semi-matched CBF1 grafts survived indefinitely after ip (75.0%) or scj (86.6%) delivery of NM2 and 50% of the B6C3F1 grafts survived indefinitely only after scl NM2 injection; no control grafts survived (MST=18.9+/-1.1, P<0.0001).
The local application of NM2 improved the survival of MHC-disparate allografts. Allelic-gene semi-matching, combined with the local induction of APCs with reduced icGSH, resulted in allograft survival comparable to the survival of MHC-matched grafts.
角膜同种异体移植排斥反应由Th1型应答介导。由于主要组织相容性复合体（MHC）相容的同种异体移植是通过降低Th1应答实现有效移植物存活的前提条件，我们探索了一种接受（MHC+次要组织相容性抗原）不相合同种异体移植的新策略。
N，N'-二乙酰-L-胱氨酸二甲酯（NM2）可降低抗原呈递细胞（APC）内的细胞内谷胱甘肽含量（icGSH）并下调Th1应答。因此，我们在穿透性角膜移植术前第1、4和7天经结膜下（scj）向供体和/或受体小鼠注射NM2。然后将C57BL/10、B10.D2或CBF1角膜同种异体移植物置于BALB/c小鼠的新生血管化移植床上。还在CBF1和B6C3F1小鼠之间进行了角膜移植。
注射生理盐水的对照组在3周内排斥了所有同种异体移植物。仅次要组织相容性抗原不相合的B10.D2同种异体移植物在腹腔内（ip）（65.0%）和经结膜下（scj）（71.4%）注射NM2后无限期存活（P<0.0001）。MHC+次要组织相容性抗原不相合的C57BL/10同种异体移植物仅通过经结膜下注射NM2存活时间延长（中位存活时间[MST]=43.6±1.5，P<0.001）；没有同种异体移植物无限期存活。等位基因半匹配的CBF1移植物在腹腔内（75.0%）或经结膜下（86.6%）注射NM2后无限期存活，50%的B6C3F1移植物仅在经结膜下注射NM2后无限期存活；没有对照移植物存活（MST=18.9±1.1，P<0.0001）。
NM2的局部应用提高了MHC不相合同种异体移植物的存活率。等位基因半匹配，结合局部诱导icGSH降低的APC，导致同种异体移植物存活情况与MHC匹配的移植物相当。
