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J. Yamada, J. Hamuro, S. Kinoshita; MHC semi–matching improves corneal allograft survival . Invest. Ophthalmol. Vis. Sci. 2004;45(13):606.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Corneal allograft rejection is mediated by Th1–type immune response and suppressed by Th2–type. We previously reported that oxidative macrophage (reduced intracellular glutathione content) induction could suppress Th1–mediated allograft rejection. Since only MHC–compatible donor allografts showed improved survival in this system, we wished to determine a new strategy for avoiding MHC + minor H–disparate allograft rejection. Methods: N,N’–diacetyl–L–cystine dimethylester (NM2) reduces intracellular glutathione content and induces Th2 type immune circumstance. NM2 was injected either intraperitoneally (i. p.) (200 µg) into recipient mice or subconjunctivally (s. con.) (8 µg) into both donor and recipient mice on days 1, 4 and 7 prior to penetrating keratoplasty. Saline was injected into control mice. C57BL/10 (H2b, MHC and minor H–disparate), B10.D2 (H2d, MHC–matched) or CBF1 (H2b/d, semi–matched) corneal allografts were placed on neovascularized graft beds of BALB/c (H2d) recipients. For living related combinations, B6C3F1 (H2b/k) donor allografts were also placed on neovascularized graft beds of CBF1 (H2b/d) recipients. Results:In the control mice, all allografts were swiftly rejected. (B10.D2: Mean survival time (MST) = 15.4 ± 0.6; C57BL/10: MST = 16.1 ± 1.1; CBF1: MST = 20.2 ± 1.6) Minor H–only–disparate B10.D2 allografts significantly survived with i. p. (65.0%) and s. con. (71.4%) injection of NM2 (p < 0.0001). MHC + minor H–disparate C57BL/10 allograft survival was not improved with i. p. injection of NM2 (MST = 19.1 ± 1.2). S. con. injection of NM2 improved C57BL/10 allograft survival (MST = 43.6 ± 1.5, p < 0.001), but still none survived indefinitely. Surprisingly, semi–matched CBF1 allografts significantly survived with i. p. (75.0%) and with s. con. (86.6%) injection of NM2. Additionally, 50% of B6C3F1 allografts survived indefinitely with s. con. injection of NM2, though no control allografts survived (MST = 18.9 ± 1.1, p < 0.0001). Conclusions: First, local application of NM2 in both donor and recipient improved MHC–disparate allografts survival, suggesting that NM2 treatment affects the intracellular thiol redox status of ocular antigen–presenting cells. Second, allelic gene–matched allografts, such as living related allografts, can promote allograft survival similar to that of MHC–matched allografts. These findings may explain the clinical benefit of MHC matching in regard to allograft survival, which has thus far been a matter of controversy.
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