Promotion of corneal allograft survival by the induction of oxidative macrophages.
OBJECTIVE
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-2(d)) mice to induce Mps with a low intracellular glutathione content (icGSH). Corneal grafts from C57BL/10 (H-2(b)), B10.D2 (H-2(d)), and DBA/2 (H-2(d)) 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.
Yamada
Jun
J
Department of Ophthalmology, Meiji University of Oriental Medicine, Kyoto, Japan. jyamada@ophth.kpu-m.ac.jp
Maruyama
Kazuichi
K
Sano
Yoichiro
Y
Kinoshita
Shigeru
S
Murata
Yukie
Y
Hamuro
Junji
J
D019264:Adoptive Transfer; D000818:Animals; D002455:Cell Division; D003315:Cornea / Q000502:physiology*; D016039:Corneal Transplantation / Q000502:physiology*; D003553:Cystine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005978:Glutathione / Q000378:metabolism; D006085:Graft Survival / Q000502:physiology*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010084:Oxidation-Reduction; D018417:Th1 Cells / Q000502:physiology; D014184:Transplantation, Homologous
D016207:Cytokines; D003553:Cystine; D005978:Glutathione; C034582:cystine dimethyl ester