Abstract 14692: Loss of Myeloid Related Protein (MRP)-8/14 Augments B7 molecule Expression and Exacerbates Cardiac Allograft Rejection
MRP-8/14 complexes regulate myeloid cell function and inflammatory responses, and serve as serum markers for allograft rejection. Despite functioning as putative pro-inflammatory mediator, the pathophysiological role of MRP-8/14 in cardiovascular disease remains unknown. This study investigates the role of MRP-14 in cardiac allograft rejection using MRP-14-deficient mice (MRP14−/−).
Methods and Results: In major histocompatibility complex class II (MHC II) allomismatched cardiac transplantation, allograft survival averaged 5.9±2.9 weeks (n=10) in MRP14−/− recipients compared to > 12 weeks (n = 15, p<0.0001) in wild-type (WT) recipients. At 2 week post-transplantation, allografts in MRP14−/− recipients had significantly higher parenchymal rejection scores (2.8±0.8, n=8) than WT recipients (0.8±0.8, n=12, p <0.0001). MRP14−/− recipients had significantly increased allograft accumulation of T cells, Th-17 cells, and macrophages and levels of mRNAs encoding IL-6, IL-10, IL-17, IFN-γ, IP-10, Mig, and I-TAC compared to WT recipients. The MRP14−/− recipients also had significantly more lymphocytes in adjacent lymph nodes than WT recipients (cell number per lymph nodes: 23.7±0.7 × 105 for MRP14−/− vs. 6.0±0.2 × 105 for WT, p < 0.0001). The dendritic cells (DC) of the MRP14−/− recipient allografts expressed significantly higher levels of the co-stimulatory molecules CD80 and CD86 than those of WT recipients two weeks after transplantation. Mixed leukocyte reactions using allo-EC-primed MRP14−/− DC resulted in significantly higher antigen-presenting function than WT DC. Cardiac allografts of B6 MHC II−/− host adoptively receiving MRP-14−/− DC significantly augmented inflammatory cell infiltration compared to WT DC transferred recipient allografts. Bone marrow-derived MRP14−/− DC infected with MRP-8/14-retroviral vector showed significantly decreased CD80 and CD86 expression compared to controls, indicating that MRP-8/14 regulates B7-costimulatory molecule expression.
Conclusions: The results indicate that MRP-14 regulates B7 molecule expression and reduces DC antigen presentation and subsequent T cell priming. The absence of MRP-14 markedly increased T cell activation and exacerbated allograft rejection.
- © 2010 by American Heart Association, Inc.