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J Yamada, K Maruyama, Y Sano, S Kinoshita, Y Murata, J Hamuro; Promoting Corneal Allograft Survival Through Oxidative Macrophage Induction . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2270.
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Purpose: On the basis of functional distinction and intracellular content of glutathione, macrophages are categorized into reductive macrophages (RMp) and oxidative macrophages (OMp). The balance between the two types is known to regulate Th1/Th2 balance through the cytokine production differential. Since Th2 bias promotes corneal allograft survival, we examined the fate of corneal allografts in mice subject to the influence of OMp, which can lead Th2 type differentiation. Methods: Either 200 µg of OMp inducer (N,N'-diacetyl-L-cystine dimethylester ((NACOMe)2)) or saline alone (control) was injected intraperitoneally into BALB/c (H-2d) recipients on days 0, 4 and 7 prior to penetrating keratoplasty. C57BL/10 (H-2b, MHC and minor H disparate) or B10.D2 (H-2d, MHC-matched) corneal grafts were placed on neovascularized recipient graft beds and assessed clinically. B10.D2 grafted recipients were evaluated for donor-specific delayed-type hypersensitivity (DTH) and their splenocytes were examined for donor-specific cytokine production (IFN-γ, IL-4, IL-10) in vitro at 1 and 2 weeks postoperatively. In other experiments, 20 million splenocytes from (NACOMe)2-treated recipients that had clear B10.D2 allografts for 2 weeks were adoptively transferred to naive BALB/c mice; B10.D2 corneal grafts were then placed in the neovascularized eyes of these BALB/c mice. Results: 66.7 % of B10.D2 grafts survived indefinitely in (NACOMe)2-treated mice (n = 15), whereas none survived in the control mice (0%, n = 10, p < 0.0001). However, (NACOMe)2-treatment did not enhance C57BL/10 graft survival in comparison with control (n = 10 each). At two weeks after B10.D2 grafting, the control mice acquired donor-specific DTH, their splenocytes showing Th1 type response in vitro. However, (NACOMe)2-treated mice did not acquire DH (p < 0.01); their splenocytes showed various types of response, such as Th1 (n = 2), Th0 (n = 3), and Th2-like (n = 1). Moreover, adoptive transfer of splenocytes from (NACOMe)2-treated mice did not promote corneal allograft survival. Conclusion: OMp induction promotes minor H only incompatible, but not total disparate, corneal graft survival, which promotion may depend on suppression of innate immunity and abolition of indirect pathway allorecognition.
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