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Anti-Donor HLA Class I Antibodies: Pathways to Endothelial Cell Activation and Cell-Mediated Allograft Rejection

Lookup NU author(s): Fatmah Naemi, Emeritus Professor John Kirby, Professor Simi Ali

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Abstract

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.

Publication metadata

Author(s): Naemi FMA, Carter V, Kirby JA, Ali S

Publication type: Article

Publication status: Published

Journal: Transplantation

Year: 2013

Volume: 96

Issue: 3

Pages: 258-266

Print publication date: 15/08/2013

ISSN (print): 0041-1337

ISSN (electronic): 1534-6080

Publisher: Lippincott Williams & Wilkins

URL: http://dx.doi.org/10.1097/TP.0b013e3182985504

DOI: 10.1097/TP.0b013e3182985504

PubMed id: 23823649

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