Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall C & D
*Purpose: Human microvascular endothelial cell expression of HLA class II antigens is strongly increased, both in vitro and in vivo, under inflammatory conditions. HLA class II antibody binding to endothelial cells enhances IL-6 secretion and thereby increases the ability of the endothelial cell to activate and to differentiate pro-inflammatory Th17 CD4+ lymphocytes mediated by an IL-6 dependent activation of Stat-3 (Taflin PNAS 2011, Lion Am J Trans. 2016). The Interleukin-6-specific antibody, Clazakizumab, was studied to determine it’s ability to act upon HLA II expressing endothelial cells.
*Methods: Endothelial cells were pre-incubated with Clazakizumab prior to and during co-culture with PBMC from non-related individuals. Additionally, binding of HLA-specific antibodies to endothelial cells results in complement activation and leads to C5b-C9 deposition. This was tested in the presence of Clazakizumab. CD4+ T cell sub-populations were identified by intracellular cytokine staining and C5b-C9 was detected by multicolour flow cytometry.
*Results: This study reports that pre-incubation of endothelial cells with Clazakizumab decreased IL-6 secretion by human endothelial cells. Clazakizumab also reduced levels of the chemoattractant CCL2 in endothelial cell co-cultures with allogeneic PBMC.. Moreover the endothelial cell mediated expansion of pro-inflammatory Th17 and Th1 populations was decreased. Deposition of C5b-C9 was determined after HLA-antibody binding to endothelial cells and was significantly reduced when Clazakizumab was present.
*Conclusions: Together these data support the idea that Clazakizumab acts directly on endothelial cells. The combined outcomes of limited CCL2 production, of reduced pro-inflammatory CD4+-T differenciation and of decreased formation of the C5b-C9 complex, may result in an overall protective effect on the allograft endothelium in the context of chronic humoral rejection associated with HLA-specific alloantibodies.
To cite this abstract in AMA style:Lion J, Poussin K, Chong E, Glotz D, Mooney NA. Clazakizumab Acts on Endothelial Cells to Limit Antibody Mediated Damage [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/clazakizumab-acts-on-endothelial-cells-to-limit-antibody-mediated-damage/. Accessed July 13, 2020.
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