Date: Tuesday, June 14, 2016
Session Time: 4:30pm-6:00pm
Presentation Time: 5:18pm-5:30pm
Location: Room 309
This study examines the basic mechanisms by which high levels of circulating HLA class II donor-specific-antibodies can contribute to microvasculature damage in chronic antibody mediated rejection of solid organ allografts.
In a microvascular endothelial cell model, conditions for the cell surface expression of HLA-DR alone or HLA-DR and -DQ were optimized. These cells were stimulated using both monoclonal (anti-HLA-DR or –DQ antibodies) and luminex-analyzed polyclonal antibodies isolated from alloimmunized patients. The resulting signal transduction was assessed by immunoblotting, whilst functional outcomes were evaluated by co-culture of the differently activated endothelial cells with allogeneic peripheral blood mononuclear cells and the analysis of the expansion of selective CD4+-T cell sub-populations by intracellular cytokine staining.
The time-course of cell surface expression of HLA-DR differed with that of HLA-DQ in microvascular endothelial cells, and optimal expression of HLA-DQ required a combination of IFNγ and TNFα, whereas IFNγ alone was sufficient for optimal HLA-DR expression. Addition of either anti-HLA-DR or -DQ antibodies (monoclonal or polyclonal) rapidly activated Akt phosphorylation, and furthermore anti-DQ antibodies induced S6RP phosphorylation. Anti-HLA-DR antibody-mediated pre-activation of endothelial cells increased Th17 and decreased FoxP3hiTreg generation (Lion et al Am J Transplant 2015). Anti-HLA-DQ antibodies also selectively modified the expansion of Th17 and Treg subpopulations, but in contrast to anti-HLA-DR antibodies, the expansion of the Th17 subset was reduced, not increased.
These data indicate that whilst both anti-HLA-DR and –DQ antibodies are associated with allograft damage, they may have differential mechanisms of damage implicating the pro-inflammatory allogeneic CD4+-T cell response. Such effects have the potential to be compounded in the presence of both antibodies.
CITATION INFORMATION: Mooney N, Cross A, Lion J, Haziot A, Glotz D. Differential Regulation of the Microvascular Endothelial Cell Mediated Allogeneic CD4+ T Cell Response by Anti-HLA-DR and -DQ Alloantibodies in an Inflammatory Context. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Mooney N, Cross A, Lion J, Haziot A, Glotz D. Differential Regulation of the Microvascular Endothelial Cell Mediated Allogeneic CD4+ T Cell Response by Anti-HLA-DR and -DQ Alloantibodies in an Inflammatory Context. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/differential-regulation-of-the-microvascular-endothelial-cell-mediated-allogeneic-cd4-t-cell-response-by-anti-hla-dr-and-dq-alloantibodies-in-an-inflammatory-context/. Accessed February 25, 2021.
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