PMID- 23823649
OWN - NLM
STAT- MEDLINE
DCOM- 20140721
LR  - 20220408
IS  - 1534-6080 (Electronic)
IS  - 0041-1337 (Linking)
VI  - 96
IP  - 3
DP  - 2013 Aug 15
TI  - Anti-donor HLA class I antibodies: pathways to endothelial cell activation and 
      cell-mediated allograft rejection.
PG  - 258-66
LID - 10.1097/TP.0b013e3182985504 [doi]
AB  - BACKGROUND: The development of donor-specific human leukocyte antigen (HLA) class 
      I antibodies after organ transplantation is associated with subsequent acute and 
      chronic rejection. The aim of this study was to examine the role of anti-HLA 
      class I antibody in modulating endothelium-leukocyte interaction. METHODS: Human 
      microvascular endothelial cells (HMEC-1) stimulated with HLA class I antibody 
      (W6/32) or allospecific antibodies from sensitized patients (n=6) were examined 
      for activation of transcription factor CREB by Western blotting. Up-regulation of 
      endothelial adhesion molecules and chemokines was measured by flow cytometry and 
      quantitative polymerase chain reaction, respectively. Leukocyte adhesion was 
      evaluated by chemotaxis and in vitro flow-based assays. RESULTS: Treatment of 
      HMEC-1 cells with HLA class I antibody resulted in the phosphorylation of CREB in 
      protein kinase A-dependent pathway. Furthermore, there was a significant increase 
      in the expression of cell surface VCAM-1 (Akt-dependent) and ICAM-1 in 
      Akt-dependent and extracellular signal-regulated kinase-dependent manner 
      (P<0.001). Additionally, exposure to W6/32 antibody induced significant 
      expression of interleukin-6, CXCL8, CXCL10, and CCL5. Knockdown of CREB produced 
      a reduction in W6/32-induced CXCL8 expression (P<0.001). Media from W6/32-treated 
      endothelial cells induced a significant monocyte chemotaxis (P<0.001) and 
      flow-based adhesion assay demonstrated an increase in monocyte adhesion to 
      endothelial cells compared with the control group (P<0.001). Importantly, 
      allospecific antibodies from sensitized patients also activated endothelial CREB 
      and significantly up-regulated VCAM-1, ICAM-1, and CXCL8. CONCLUSION: These 
      findings suggest that donor-specific HLA class I antibodies directly activate 
      endothelial cells leading to an increase in their potential to recruit and bind 
      recipient leukocytes, thereby increasing the potential for allograft 
      inflammation.
FAU - Naemi, Fatmah M A
AU  - Naemi FM
AD  - Applied Immunobiology and Transplantation Group, Institute of Cellular Medicine, 
      Medical School, University of Newcastle Upon Tyne, Newcastle Upon Tyne, UK.
FAU - Carter, Vaughan
AU  - Carter V
FAU - Kirby, John A
AU  - Kirby JA
FAU - Ali, Simi
AU  - Ali S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Transplantation
JT  - Transplantation
JID - 0132144
RN  - 0 (CREB1 protein, human)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (Cytokines)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Isoantibodies)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
SB  - IM
MH  - Cell Line
MH  - Chemotaxis, Leukocyte
MH  - Cyclic AMP Response Element-Binding Protein/metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/physiology
MH  - Cytokines/genetics
MH  - Endothelial Cells/*physiology
MH  - Extracellular Signal-Regulated MAP Kinases/physiology
MH  - Graft Rejection/*etiology
MH  - Histocompatibility Antigens Class I/*immunology
MH  - Humans
MH  - Isoantibodies/*physiology
MH  - Phosphatidylinositol 3-Kinases/physiology
MH  - Phosphorylation
MH  - Transplantation, Homologous
EDAT- 2013/07/05 06:00
MHDA- 2014/07/22 06:00
CRDT- 2013/07/05 06:00
PHST- 2013/07/05 06:00 [entrez]
PHST- 2013/07/05 06:00 [pubmed]
PHST- 2014/07/22 06:00 [medline]
AID - 10.1097/TP.0b013e3182985504 [doi]
PST - ppublish
SO  - Transplantation. 2013 Aug 15;96(3):258-66. doi: 10.1097/TP.0b013e3182985504.