IOVS Am. J. Pathology
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(Investigative Ophthalmology and Visual Science. 2004;45:448-454.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0939
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Promotion of Corneal Allograft Survival by the Induction of Oxidative Macrophages

Jun Yamada,1,2 Kazuichi Maruyama,2 Yoichiro Sano,2 Shigeru Kinoshita,2 Yukie Murata,3 and Junji Hamuro3

1From the Department of Ophthalmology, Meiji University of Oriental Medicine, Kyoto, Japan; 2Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan; and 3Basic Research Laboratories, Ajinomoto Co. Inc., Kawasaki, Japan.

PURPOSE.A Th1-type immune response was detected in allotransplanted, rejected corneas. Because the intracellular thiol redox status of antigen-presenting cells (APCs) reportedly regulates the Th1/Th2 balance through distinctive cytokine production by APCs, this study was conducted to investigate the effect of the intracellular thiol redox status of macrophages (Mps) on corneal allograft survival.

METHODS.N,N'-diacetyl-L-cystine dimethylester (NACOMe)2 was injected intraperitoneally into BALB/c (H-2d) mice to induce Mps with a low intracellular glutathione content (icGSH). Corneal grafts from C57BL/10 (H-2b), B10.D2 (H-2d), and DBA/2 (H-2d) donor mice were placed on neovascularized BALB/c graft beds for assessment. B10.D2-grafted recipients were evaluated for donor-specific delayed-type hypersensitivity (DTH), and the cytokines produced by their lymphocytes were examined (IFN-{gamma}, IL-4, and IL-10). In other experiments, naïve BALB/c mice, injected intravenously with Mps of low icGSH content, received B10.D2 corneal grafts.

RESULTS.In (NACOMe)2-treated mice, 13 of 20 B10.D2 grafts and 6 of 10 DBA/2 grafts survived indefinitely. No grafts survived in the control mice (P < 0.0001). (NACOMe)2 treatment did not enhance C57BL/10 graft survival. At 2 weeks after B10.D2 grafting, control mice exhibited DTH, but (NACOMe)2-treated mice did not (P < 0.01). Lymphocytes from (NACOMe)2-treated mice did not respond to donor splenocytes. Those of control mice showed Th1-type cytokine secretion. The intravenous transfer of peritoneal Mps from (NACOMe)2-treated mice prolonged corneal allograft survival (P < 0.003).

CONCLUSIONS. The observed enhanced graft acceptance may be due to the suppression of alloantigen-induced Th1 polarization through the induction of Mps with reduced icGSH levels.






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