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Jerry Y. Niederkorn, Khrishen Cunnusamy, Peter W. Chen; Inhibition Of Interferon- Promotes Survival Of MHC-mismatched Corneal Allografts But Exacerbates Rejection Of MHC Plus Minor Histocompatibility Antigen-mismatched Corneal Allografts. Invest. Ophthalmol. Vis. Sci. 2012;53(14):4128.
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To determine the effect of interferon-γ (IFN-γ) on corneal allograft survival.
Fully allogeneic (MHC + multiple minor histocompatibility loci-mismatched) corneal allografts (C57BL/6; H-2b) or MHC-mismatched, minor histocompatibility matched (BALB.B; H-2b) corneal allografts were transplanted to BALB/c (H-2d) recipients that were treated with either anti-IFN-γ antibody or isotype control antibody. CD4+ T cells were isolated from grafted mice and cytokine production was evaluated by ELISA. CD4+CD25+ T regulatory cells (Tregs) were isolated from grafted mice and transferred to athymic nude mice prior to applying corneal allografts. A local adoptive transfer (LAT) assay was used to detect T reg-mediated suppression of delayed-type hypersensitivity (DTH) responses to donor alloantigens.
Depletion of IFN-γ abolished immune privilege of fully allogeneic corneal allografts resulting in rejection in 90% of the hosts (N = 50; P = 0.008). By contrast, anti-IFN-γ enhanced immune privilege of MHC-matched allografts, resulting in 70% graft survival compared to 20% survival in controls (N = 20; P= 0.004). However, the cytokine profiles of both groups of anti-IFN-γ-treated mice were skewed to a Th2 phenotype (production of IL-4, IL-5, and IL-13 and reduced IFN-γ). Anti-IFN-γ antibody-treated hosts grafted with MHC-mismatched corneal allografts developed T regs that inhibited DTH responses and enhanced graft survival. By contrast, anti-IFN-γ treatment abolished immune privilege and exacerbated rejection of fully allogeneic corneal grafts.
IFN-γ exerts profoundly different effects on the immune response to MHC-mismatched versus fully allogeneic corneal allografts. T regs that suppress the immune rejection of MHC-mismatched grafts are inhibited by IFN-γ while blockade of IFN-γ promotes Treg development and enhances graft survival. By contrast, IFN-γ promotes the survival of 50% of the fully allogeneic corneal grafts, while blockade of IFN-γ abolishes immune privilege and culminates in graft rejection in 90% of the hosts.
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