Major histocompatibility complex semi-matching improves murine corneal allograft survival under oxidative macrophage dominancy.
BACKGROUND
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.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Yamada
Jun
J
Department of Ophthalmology, Meiji University of Oriental Medicine, Hinotani6-1, Honoda, Nantan-shi, Kyoto, Japan. jyamada@ophth.kpu-m.ac.jp
Hamuro
Junji
J
Terai
Kazuto
K
Kinoshita
Shigeru
S
D000818:Animals; D000938:Antigen-Presenting Cells; D016039:Corneal Transplantation / Q000379:methods*; D005978:Glutathione / Q000378:metabolism; D006085:Graft Survival; D006650:Histocompatibility Testing; D008264:Macrophages / Q000378:metabolism; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D018417:Th1 Cells / Q000378:metabolism; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D005978:Glutathione