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Y. Jin, S. K. Chauhan, D. R. Saban, R. Dana; Blockade of CCR7-Mediated Direct Allorecognition Pathway in High-Risk Corneal Transplantation. Invest. Ophthalmol. Vis. Sci. 2008;49(13):439.
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The role of CCR7 in mediating the migration of donor-derived antigen-presenting cells (APCs) to host draining lymph nodes (LN) in corneal transplantation has been established by our previous study. Here, we further investigate the relationship between CCR7-mediated donor APC trafficking and allo-reaction in high-risk (HR) corneal transplantation.
Corneal grafts from either CCR7-KO (CCR7-/-) or wild-type (WT) C57Bl/6 mouse group were transplanted onto the neovascularized corneal beds of the BALB/c recipient mice. Total T cells, CD4+CD25- effector T cells (Teffs) and CD4+CD25+ regulatory T cells (Tregs) were isolated from host draining lymph nodes at week 2 post-transplantation using an immunomagnetic sorter. The frequency of directly primed host T cells to corneal alloantigens was measured by the IFN-γ ELISPOT assay. Treg function was tested by in vitro suppression assay. Kaplan-Meier analysis was adopted to evaluate the survival ratio of the grafts from two groups.
There was no significant difference in the direct responses triggered between the recipients of CCR7-/- and WT grafts, reflected by a slight decrease in the frequency of IFN-γ-producing T cells in the CCR7-/- group. The frequency of IFN-γ-producing Teffs from CCR7-/- group was 2-fold decreased as compared to that in WT group. However, the inhibitory effects of Tregs from CCR7-/- group were lower than those from WT group, reflected by a 20% reduction in the suppression of IFN-γ-producing T cells in the ELISPOT assay and 30% less suppression of naïve T cells proliferation in anti-CD3 simulated suppression assay. There was no significant difference in the graft survival ratio between two groups.
Our data demonstrate that CCR7-mediated donor-derived APC trafficking is important for the induction of host Teff as well as Treg which regulate allo-reaction through two opposite directions: sensitization and tolerance. This may be the main reason for the lack of an effect of CCR7 blockade in HR allograft survival.
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