Endothelial Cell Amplification of Regulatory T Cells Is Differentially Modified by Immunosuppressors and Intravenous Immunoglobulin

Immunosuppressive treatment is a prerequisite for both organ transplantation and tolerance of the allograft. However, long-term immunosuppression has been associated with a higher incidence of malignancies and infections. Immunosuppressors mainly target circulating immune cells and little is known of their “off-target” effects, such as their impact on endothelial cells. In chronic antibody mediated rejection (AMR), the allograft endothelium is a target of damage, histologically detected as transplant glomerulopathy, and which correlates with poor graft survival. Under inflammatory conditions, endothelial cell expression of HLA class II antigens can lead to CD4+-T lymphocyte alloactivation and selective expansion of pro-inflammatory Th17 and pro-tolerance Treg subsets. This response can be modified an preactivation of the endothelial cell by HLA-DR antibody binding promoted a pro-inflammatory Th17 response. However, whether or not immunosuppressors alter endothelial cell immunogenicity has not been examined. In alloimmunized patients with AMR, Cyclosporine A (CsA) and Mycophenolate acid (MPA) are often combined with Intravenous Immunoglobulins (IVIg). This study reports changes in the microvascular endothelial cell phenotype and function after treatment with CsA, MPA or IVIg. Both CsA and MPA decreased HLA-DR and increased CD54 expression, whereas IVIg increased HLA-DR expression. IL-6 secretion was reduced by all three immunomodulators. Preincubation of endothelial cells with CsA or MPA limited, while IVIg amplified, Treg expansion. Because CsA, MPA and IVIg are known for their ability to act upon leukocytes, we confirmed that endothelial cells maintained their immunoregulatory role when allogeneic leukocytes were pretreated with CsA, MPA or IVIg. The results reveal that individual immunosuppressors, used in the induction and maintenance of renal allograft tolerance, had direct and distinct effects on endothelial cells. Results of experiments associating IVIg with either CsA or MPA underlined the differences observed using individual immunosuppressors. Paradoxically, CsA or MPA may increase endothelial cell mediated inflammatory responses and long-term exposure may contribute to limitation of allograft tolerance. In contrast, IVIg interaction with the endothelium may mediate some of its immunosuppressive effects through promotion of Treg expansion, contributing to the maintenance of allograft tolerance.