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HLA Class II Molecules Partner with TLR4 to Stimulate Endothelial Cell Activation and Proliferation.

Y.-P. Jin, E. Reed.

Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA

Meeting: 2017 American Transplant Congress

Abstract number: B30

Keywords: Endothelial activation, HLA antibodies, MHC class II, Rejection

Session Information

Session Name: Poster Session B: Allorecognition and T Cell Biology

Session Type: Poster Session

Date: Sunday, April 30, 2017

Session Time: 6:00pm-7:00pm

 Presentation Time: 6:00pm-7:00pm

Location: Hall D1

Background: Transplant recipients developing donor specific HLA antibodies (DSA) are at a higher risk for acute and chronic antibody-mediated rejection (AMR). DSA contribute to the process of AMR by binding to the HLA molecules expressed on endothelial cells (EC) and triggering signal transduction pathways leading to EC activation. Ligation of HLA-I with Ab on EC and smooth muscle cells has been shown to contribute to the process of transplant vasculopathy (TV). However, the mechanism(s) underlying how HLA-II Ab contribute to chronic rejection remain unknown. The HLA-II molecule lacks a signaling motif in its short cytoplasmic tail. We therefore postulated that HLA-II associates with TLR4 to transduce signals leading to EC activation and proliferation.

Methods: HLA-II molecule expression in primary human aortic EC was induced using recombinant adenovirus pAd/PL-DEST encoding CIITA (Ad-CIITA) an HLA-II transactivator, or pretreated with TNF-α/IFN-γ. HLA-II expression was determined by flow cytometry. Ad-CIITA infected or cytokine-treated EC were stimulated with anti-HLA-II Ab and protein:protein complex formation was measured by co-immunoprecipitation, protein expression and phosphorylation detected by Western Blot, and EC proliferation was measured by BrdU incorporation.

Results: Infection of EC with Ad-CIITA or pretreatment of EC with TNF-α and IFN-γ induced a marked and consistent increase in HLA-II antigen expression and CIITA protein presentation. Ligation of HLA II on EC with HLA-II Ab triggered molecular association between HLA II and TLR4 and this physical interaction was necessary for HLA II induced EC proliferation. Ligation of HLA-II antigens on EC stimulated phosphorylation of proteins in the mTOR pathway known to regulate protein synthesis and cell proliferation including Akt, mTOR, S6K, S6RP, MEK, and ERK. Knockdown of TLR4 in EC abrogated the ability of HLA II to stimulate phosphorylation of these kinases as well as cell proliferation.

Conclusion: These results indicate a mutual dependency between HLA II and TLR4 to stimulate the proliferation of endothelial cells, which may be important in promoting transplant vasculopathy. Our results provide novel mechanisms of HLA-II Ab-mediated alteration in EC and suggest that disrupting HLA II: TLR4 interactions may provide a novel therapeutic approach to prevent TV.

CITATION INFORMATION: Jin Y.-P, Reed E. HLA Class II Molecules Partner with TLR4 to Stimulate Endothelial Cell Activation and Proliferation. Am J Transplant. 2017;17 (suppl 3).

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To cite this abstract in AMA style:

Jin Y-P, Reed E. HLA Class II Molecules Partner with TLR4 to Stimulate Endothelial Cell Activation and Proliferation. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/hla-class-ii-molecules-partner-with-tlr4-to-stimulate-endothelial-cell-activation-and-proliferation/. Accessed May 8, 2025.

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