Urinary metabolites give new clues to kidney transplant tolerance

International audienceNo abstract availabl

The Role of the Endothelium during Antibody-Mediated Rejection: From Victim to Accomplice

Antibody-mediated rejection (AMR) of solid organ transplants is characterized by the activation and injury of the allograft endothelium. Histological and transcriptomic studies have associated microvascular inflammation and endothelial lesions with the severity of rejection and poor graft outcomes. The allograft endothelium forms the physical barrier between the donor organ and the recipient; this position directly exposes the endothelium to alloimmune responses. However, endothelial cells are not just victims and can actively participate in the pathogenesis of rejection. In healthy tissues, the endothelium plays a major role in vascular and immune homeostasis. Organ transplantation, however, subjects the endothelium to an environment of inflammation, alloreactive lymphocytes, donor-specific antibodies, and potentially complement activation. As a result, endothelial cells become activated and have modified interactions with the cellular effectors of allograft damage: lymphocytes, natural killer, and myeloid cells. Activated endothelial cells participate in leukocyte adhesion and recruitment, lymphocyte activation and differentiation, as well as the secretion of cytokines and chemokines. Ultimately, highly activated endothelial cells promote pro-inflammatory alloresponses and become accomplices to AMR

Neutrophils cause a “NET” increase in skin allograft allogenicity

International audienceWhile current immunosuppressive treatments efficiently prevent early rejection of organ transplants such as kidney, they have little or no effect in skin transplantation.Initial trauma and tissue injury resulting from the application of a skin allograft to a wound is associated with a potent inflammatory process and the initiation of both an innate and an adaptive immune response. The current study of Wong et al1 reveals the importance of neutrophils and neutrophil extracellular traps (NETs) in skin al-lograft rejection both in a mouse model and in allografts from pa-tients with burns.NETs are large, extracellular structures composed of a mixture of cytosolic and granule proteins assembled on a platform of de-condensed chromatin. Formation of NET requires the activation of peptidylarginine deiminase 4 (PAD4) that citrullinates arginine residues on histones leading to chromatin decondensation before NET release (reviewed in 2). The mechanism of NET clearance is not entirely understood, although activation of the plasma nuclease DNAse1 rapidly degrades NET-associated DNA.3The current report reveals that cleavage of ultralarge von Willebrand Factor (vWF) in recipients, by a vWF specific recombi-nant protease (ADAMTS13), increased skin allograft survival across a full MHC mismatch in mice. Neutrophils were recruited and NETs were bound by vWF, and ADAMTS13 treatment both reduced the number of neutrophils and abrogated NETs in allografts. In PAD4-deficient mice, ADAMTS13 treatment did not further improve al-lograft survival, leading to the suggestion that both were targeting the same pathway. Studies in tissue from patients with severe burns reiterated the observation of enrichment of neutrophils and NETs in skin allografts.The authors suggest that preventing the formation of NETs could be a useful strategy to prolong skin allograft survival and that tar-geting the PAD4 pathway could also be helpful. They point out that PAD4 inhibition would potentially have other beneficial anti-inflam-matory effects by reducing pro-inflammatory cytokine production.Although the mechanism of ADAMTS13 reduction of neutrophils and NETs in skin allografts was not elucidated, it was proposed to depend on destruction of the site of neutrophil recruitment and NET adhesion within the graft. The pathway to NET potentiation of the alloimmune response remains unclear, although NET-mediated acti-vation of intragraft antigen-presenting cells (eg, Langerhans cells or endothelial cells) may be envisaged. Previous studies have reported histone-mediated endothelial cell activation, and a link between NETs and endothelial damage has been proposed in an autoimmune vasculitis.4 The cytotoxicity of NETs for endothelial cells has also been reported, and this may potentiate intragraft inflammation.The importance of this article is not only due to the observation that large aggregates of DNA or NETS contribute to the alloimmune re-sponse but also due to the identification of new and plausible therapeu-tic targets to prevent allogenic skin-graft rejection. This would represent a major advance in the practice of skin grafts in nonoptimal conditions, particularly in situations where the possibility of carrying out an autolo-gous skin graft is unavailable. It is unfortunately the case that many such situations arise outside specialized skin transplantation centers.Finally, a recent study of metoprolol, a selective β1-adrenergic receptor antagonist, reported the ability of this drug to directly in-hibit the capacity of neutrophils to infiltrate tissues in vivo in a model of peritonitis.5 This, too, could be considered as a future means of denying NETs access to the allograft

Organisation dynamique des molécules du complexe majeur d'histocompatibilité de classe II dans les radeaux lipidiques (implications dans la signalisation et la présentation antigénique)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Rôle de la cellule endothéliale dans la réponse immune en transplantation d'organe

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Cytokines in Liver Transplantation

International audienc

The Role of the Endothelium during Antibody-Mediated Rejection: From Victim to Accomplice

International audienc

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 (ECs). 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, EC 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 and preactivation of the EC by HLA-DR antibody binding promoted a proinflammatory Th17 response. However, whether or not immunosuppressors alter EC immunogenicity has not been examined. In alloimmunized patients with AMR, cyclosporine A (CsA) and mycophenolic acid (MPA) are often combined with intravenous immunoglobulins (IVIgs). This study reports changes in the microvascular EC 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. Interleukin 6 secretion was reduced by all three immunomodulators. Preincubation of ECs 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 ECs 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 ECs. Results of experiments associating IVIg with either CsA or MPA underlined the differences observed using individual immunosuppressors. Paradoxically, CsA or MPA may increase EC 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