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J. Yamada, J. Hamuro, A. Fukushima, K. Terai, T. Ohteki, Y. Iwakura, S. Kinoshita; Corneal Allograft Rejection by IFN-Gamma-Independent Immune Reaction. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3724.
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© ARVO (1962-2015); The Authors (2016-present)
It has been widely accepted that Th1- and IFN-γ-mediated immune responses are indispensable for the rejection of MHC-matched corneal allografts in BALB/c mice hosts. The present study was designed to determine the role of IFN-γ in the corneal allograft rejection of C57BL/6 mice hosts that display high rejection rates.
BALB/c (MHC and minor H disparate) or 129 (MHC-matched) corneal grafts were placed in the eyes of wild-type C57BL/6 (WT), C57BL/6-IFN-γ-knockout (GKO), C57BL/6-IFN-γ-receptor-knockout (GRKO), or C57BL/6-IL-17-knockout (IL-17KO) mice. Graft fates were assessed clinically and histologically. At appropriate time intervals after allografting, RNA was isolated from cornea tissues and cervical lymph nodes. The cytokine mRNA levels of Th1 axis (IL-12p35, IFN-γ), Th17 type (IL-6, IL-23p19, IL-17A), and IL-12/IL-23p40 were analyzed by Real-Time PCR.
BALB/c allografts were rejected in GKO hosts (95%, MST=25.6 ± 2.2, n = 20), similar to WT hosts (100%, MST=18.7 ± 1.1, n = 20). 129 allografts were also rejected in GKO hosts (100%, MST=25.6 ± 1.4, n = 20), similar to WT (100%, MST=19.3 ± 1.1, n = 20) and GRKO hosts (100%, MST=21.7 ± 1.9, n = 10). Rejected BALB/c corneas of GKO hosts elicited intensive infiltration of eosinophils, CD11b+ macrophages and B220+ B cells, but few Gr-1+ CD11c- neutrophils. In contrast, rejected 129 corneas of GKO, as well as GRKO and WT hosts, elicited intensive infiltration of Gr-1+ CD11c- neutrophils and CD11b+ macrophages, but no eosinophils or B cells. Rejected BALB/c corneas in WT hosts showed features similar to the latter. At one week after 129 allografting, IL-12p35, IFN-γ, IL-6, IL-23p19, IL-17A, IL-17F, and IL-12p40 mRNA were up-regulated in WT hosts. In contrast, only IL-6, IL-23p19, IL-17A, and IL-17F up-regulation were observed in GKO hosts. It is of note that all 129 allografts were rejected also in IL-17KO hosts (100%, MST=22.4 ± 1.7, n = 10).
IFN-γ plays no critical role in the development of minor-specific allograft rejection in C57BL/6 mice. MHC matched corneal allografts are rejected by neutrophil infiltration in the absence of IFN-γ signaling. These results indicate the presence of alternative sophisticated rejection mechanisms not ascribed simply to Th1, Th2, or Th17.
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