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 (NMZ) reduces the intracellular glutathione content (icGSH) in antigen-presenting cells (APCs) and down-regulates Th1 responses. Therefore, we subconjunctivally (scj) injected NMZ 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 NMZ (P < 0.0001). MHC+minor H-disparate C57BL/10 allograft survival was prolonged only by scj injection of NM, (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 NMZ and 50% of the B6C3F1 grafts survived indefinitely only after scl NM, injection; no control grafts survived (MST= 18.9 +/- 1.1, P < 0.0001). Conclusions. The local application of NM, 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.