title: Loss of myeloid related protein-8/14 exacerbates cardiac allograft rejection.
abstract: BACKGROUND
  The calcium-binding proteins myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) form MRP-8/14 heterodimers (S100A8/A9, calprotectin) that regulate myeloid cell function and inflammatory responses and serve as early serum markers for monitoring acute allograft rejection. Despite functioning as a proinflammatory mediator, the pathophysiological role of MRP-8/14 complexes in cardiovascular disease is incompletely defined. This study investigated the role of MRP-8/14 in cardiac allograft rejection using MRP-14(-/-) mice that lack MRP-8/14 complexes.
  
  
  RESULTS
  We examined parenchymal rejection after major histocompatibility complex class II allomismatched cardiac transplantation (bm12 donor heart and B6 recipients) in wild-type (WT) and MRP-14(-/-) recipients. Allograft survival averaged 5.9±2.9 weeks (n=10) in MRP-14(-/-) recipients compared with >12 weeks (n=15; P<0.0001) in WT recipients. Two weeks after transplantation, allografts in MRP-14(-/-) recipients had significantly higher parenchymal rejection scores (2.8±0.8; n=8) than did WT recipients (0.8±0.8; n=12; P<0.0001). Compared with WT recipients, allografts in MRP-14(-/-) recipients had significantly increased T-cell and macrophage infiltration and increased mRNA levels of interferon-γ and interferon-γ-associated chemokines (CXCL9, CXCL10, and CXCL11), interleukin-6, and interleukin-17 with significantly higher levels of Th17 cells. MRP-14(-/-) recipients also had significantly more lymphocytes in the adjacent para-aortic lymph nodes than did WT recipients (cells per lymph node: 23.7±0.7×10(5) for MRP-14(-/-) versus 6.0±0.2×10(5) for WT; P<0.0001). The dendritic cells (DCs) of the MRP-14(-/-) recipients of bm12 hearts expressed significantly higher levels of the costimulatory molecules CD80 and CD86 than did those of WT recipients 2 weeks after transplantation. Mixed leukocyte reactions with allo-endothelial cell-primed MRP-14(-/-) DCs resulted in significantly higher antigen-presenting function than reactions using WT DCs. Ovalbumin-primed MRP-14(-/-) DCs augmented proliferation of OT-II (ovalbumin-specific T cell receptor transgenic) CD4(+) T cells with increased interleukin-2 and interferon-γ production. Cardiac allografts of B6 major histocompatibility complex class II(-/-) hosts and of B6 WT hosts receiving MRP-14(-/-) DCs had significantly augmented inflammatory cell infiltration and accelerated allograft rejection compared with WT DCs from transferred recipient allografts. Bone marrow-derived MRP-14(-/-) DCs infected with MRP-8 and MRP-14 retroviral vectors showed significantly decreased CD80 and CD86 expression compared with controls, indicating that MRP-8/14 regulates B7-costimulatory molecule expression.
  
  
  CONCLUSIONS
  Our results indicate that MRP-14 regulates B7 molecule expression and reduces antigen presentation by DCs and subsequent T-cell priming. The absence of MRP-14 markedly increased T-cell activation and exacerbated allograft rejection, indicating a previously unrecognized role for MRP-14 in immune cell biology.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB7, Boston, MA 02115, USA. ksmz@rics.bwh.harvard.edu
authors.forename: Koichi
authors.initials: K
authors.lastname: Shimizu
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.forename: Viviane Z
authors.initials: VZ
authors.lastname: Rocha
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Folco
authors.forename: Rica
authors.initials: R
authors.lastname: Shubiki
authors.forename: Nir
authors.initials: N
authors.lastname: Grabie
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Jang
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Lichtman
authors.forename: Ayako
authors.initials: A
authors.lastname: Shimizu
authors.forename: Nancy
authors.initials: N
authors.lastname: Hogg
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Simon
authors.forename: Richard N
authors.initials: RN
authors.lastname: Mitchell
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
mesh_terms: D000818:Animals; D060887:B7 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D040501:Calgranulin A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D040502:Calgranulin B / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006084:Graft Rejection / Q000378:metabolism*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D006648:Histocompatibility / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D039841:Leukocyte L1 Antigen Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018168:Receptors, Retinoic Acid / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014184:Transplantation, Homologous; D000097768:Retinoic Acid Receptor gamma; D000098815:T-bet Transcription Factor
chemical_list: D060887:B7 Antigens; D040501:Calgranulin A; D040502:Calgranulin B; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D039841:Leukocyte L1 Antigen Complex; D018168:Receptors, Retinoic Acid; D020825:T-Box Domain Proteins; D000097768:Retinoic Acid Receptor gamma; D000098815:T-bet Transcription Factor; C086145:S100a8 protein, mouse