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Invest Ophthalmol Vis Sci. 2014 Aug 21;55(9):5944-51. doi: 10.1167/iovs.14-14356.

The resolvin D1 analogue controls maturation of dendritic cells and suppresses alloimmunity in corneal transplantation.

Author information

1
Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States.
2
Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California, United States.
3
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States.

Abstract

PURPOSE:

To analyze the effect of a resolvin D1 (RvD1) analogue (RvD1a) on dendritic cell maturation, T-cell sensitization, and allograft rejection in corneal allotransplantation.

METHODS:

The receptor expression of RvD1 (ALX/FPR2) on bone marrow-derived dendritic cells (BMDC) was measured using quantitative real-time PCR. We determined BMDC maturation after treatment with RvD1a using ELISA to measure interleukin (IL)-12 protein expression and flow cytometry to assess the expression of CD40, major histocompatibility complex (MHC) II, CD80, and CD86. After corneal transplantation in BALB/c mice, we analyzed T-cell infiltration in the cornea and the draining lymph nodes using flow cytometry. The enzyme-linked immunospot (ELISPOT) assay was used to measure T-cell sensitization via the direct and indirect pathway. Angiogenesis and lymphangiogenesis in the cornea after transplantation were measured using immunohistochemistry. Graft opacity and survival were evaluated by slit lamp biomicroscopy.

RESULTS:

The receptor for RvD1, lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), was expressed at a significantly lower level on immature than mature dendritic cells (DCs), and RvD1a reduced DC expression of MHC II, CD40, and IL-12 following lipopolysaccharide (LPS) stimulation. Using a murine model of corneal transplantation, RvD1a-treated hosts exhibited significantly reduced allosensitization as demonstrated by decreased frequencies of interferon-gamma-secreting T cells in the draining lymph nodes, and reduced T-cell infiltration into the grafts. Graft survival was significantly enhanced and angiogenesis at the graft site was suppressed in RvD1a-treated hosts compared with vehicle-treated hosts.

CONCLUSIONS:

These results suggest that RvD1 inhibits DC maturation and reduces alloimmune sensitization following transplantation, thereby establishing a novel connection between resolvin D1 and the regulation of DC-mediated, antigen-specific immunity.

KEYWORDS:

dendritic cell; resolvin; transplant rejection

PMID:
25146982
PMCID:
PMC4172301
DOI:
10.1167/iovs.14-14356
[Indexed for MEDLINE]
Free PMC Article

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