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J. Yamada, J. Hamuro, S. Kinoshita; Regulating Intracellular Thiol Redox Status Mediates the Survival of MHC Semi–Allogeneic Limbal Transplantation in Mice . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4742.
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Purpose:Both major histocompatibility complex (MHC) and minor histocompatibility antigen (minor H) are the target alloantigens in corneal limbal transplant rejection, unlike in penetrating keratoplasty (PKP) rejection. The strategy of suppressing Th1–type response can mediate allograft survival of minor H incompatible donors, but thus far not of MHC + minor H incompatible donors, in either limbal transplant or PKP. We have previously demonstrated in a PKP model that MHC semi–allogeneic donors exhibited graft survival similar to that of minor H only incompatible donors under oxidative macrophage (OMp) induction (reduced intracellular glutathione content). We therefore wished to investigate semi–allogeneic limbal transplant survival and allogeneic MHC–specific immune response under OMp induction. Methods:N,N’–diacetyl–L–cystine dimethylester (NM2) was used to reduce intracellular glutathione content and to induce OMp (Th2 type immune circumstance). For mixed lymphocyte reaction (MLR), BALB/c (H2d) responder splenocytes were cultured with irradiated C57BL10 (H2b, MHC and minor H–incompatible) or CBF1 (H2b/d, semi–allogeneic) stimulator splenocytes co–cultured with NM2 (10 µg/ml or none). For transplant survival, NM2 was injected subconjunctivally (8 µg or saline only) into both donor and recipient mice on days 1, 4 and 7 prior to transplantation. After epithelial removal, C57BL10 or CBF1 corneal limbal allografts were placed on BALB/c recipients. (N = 11 in each group) Results:The proliferation response in MLR was suppressed by NM2 in stimulation of both C57BL10 (11446 ± 492 to 6281 ± 994) and CBF1 (5480 ± 630 to 2678 ± 437). After transplantation of C57BL10 (with and without NM2) and CBF1 (without NM2), corneal epithelium was rejected within 8 days. In contrast, CBF1 allografts with NM2 could mediate significant epithelium survival (64% survival for more than 60 days, p<0.0001). Conclusions:Both MHC semi–matching and NM2 treatment can suppress MHC–specific immune response. Cumulative suppression may enhance allogeneic corneal epithelium survival. Partial MHC matching and the strategy of suppressing Th1–type response presumably yield clinical benefit in limbal transplantation.
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