NK cells in antibody‐mediated rejection – Key effector cells in microvascular graft damage

O'Neill, Megan A.; Hidalgo, Luis

doi:10.1111/iji.12532

Cited by 12 publications

(5 citation statements)

References 66 publications

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“…Besides the complement system, alternative immunopathogenic pathways could be involved in aABMR, accounting for aABMR in the absence of C5b-9 in biopsies. A broad body of evidence emphasizes complement-independent mechanisms in ABMR pathogenesis, possibly mediated via Natural Killer cells ( 47 – 51 ). Others emphasized that DSA-binding could directly cause complement-independent endothelial cell activation ( 52 – 55 ).…”

Section: Discussionmentioning

confidence: 99%

Weak Expression of Terminal Complement in Active Antibody-Mediated Rejection of the Kidney

et al. 2022

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BackgroundThe role of the complement system in antibody-mediated rejection (ABMR) is insufficiently understood. We aimed to investigate the role of local and systemic complement activation in active (aABMR). We quantified complement activation markers, C3, C3d, and C5b-9 in plasma of aABMR, and acute T-cell mediated rejection (aTCMR), and non-rejection kidney transplant recipients. Intra-renal complement markers were analyzed as C4d, C3d, C5b-9, and CD59 deposition. We examined in vitro complement activation and CD59 expression on renal endothelial cells upon incubation with human leukocyte antigen antibodies.MethodsWe included 50 kidney transplant recipients, who we histopathologically classified as aABMR (n=17), aTCMR (n=18), and non-rejection patients (n=15).ResultsComplement activation in plasma did not differ across groups. C3d and C4d deposition were discriminative for aABMR diagnosis. Particularly, C3d deposition was stronger in glomerular (P<0,01), and peritubular capillaries (P<0,05) comparing aABMR to aTCMR rejection and non-rejection biopsies. In contrast to C3d, C5b-9 was only mildly expressed across all groups. For C5b-9, no significant difference between aABMR and non-rejection biopsies regarding peritubular and glomerular C5b-9 deposition was evident. We replicated these findings in vitro using renal endothelial cells and found complement pathway activation with C4d and C3d, but without terminal C5b-9 deposition. Complement regulator CD59 was variably present in biopsies and constitutively expressed on renal endothelial cells in vitro.ConclusionOur results indicate that terminal complement might only play a minor role in late aABMR, possibly indicating the need to re-evaluate the applicability of terminal complement inhibitors as treatment for aABMR.

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Section: Discussionmentioning

confidence: 99%

Weak Expression of Terminal Complement in Active Antibody-Mediated Rejection of the Kidney

et al. 2022

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“…This education is necessary to prevent NK cells from becoming autoreactive and depleting their cytotoxic granules, as is the case when malignant or virally infected cells downregulate surface HLA class I expression. In the case of transplantation, if donor endothelial cells express an HLA I allotype that is unable to interact with a KIR receptor expressed by the recipient’s NK cells, these recipient NK cells would be likely to attack through the missing self mechanism ( 157 ) ( Figure 1 ).…”

Section: Antibody-independent MVImentioning

confidence: 99%

Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms

et al. 2022

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Antibody-mediated rejection (ABMR) is associated with poor transplant outcomes and was identified as a leading cause of graft failure after kidney transplantation. Although the hallmark histological features of ABMR (ABMRh), i.e., microvascular inflammation (MVI), usually correlate with the presence of anti-human leukocyte antigen donor-specific antibodies (HLA-DSAs), it is increasingly recognized that kidney transplant recipients can develop ABMRh in the absence of HLA-DSAs. In fact, 40-60% of patients with overt MVI have no circulating HLA-DSAs, suggesting that other mechanisms could be involved. In this review, we provide an update on the current understanding of the different pathogenic processes underpinning MVI. These processes include both antibody-independent and antibody-dependent mechanisms of endothelial injury and ensuing MVI. Specific emphasis is placed on non-HLA antibodies, for which we discuss the ontogeny, putative targets, and mechanisms underlying endothelial toxicity in connection with their clinical impact. A better understanding of these emerging mechanisms of allograft injury and all the effector cells involved in these processes may provide important insights that pave the way for innovative diagnostic tools and highly tailored therapeutic strategies.

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“…The current transplant immunology dogma states that the innate immunity is not powerful enough to effectively reject an allograft on its own. However, growing evidence suggests a key role of NK cells in the pathogenesis of immune-mediated graft damage in kidney transplantation [ 76 , 77 , 78 ]. The dominating immune mechanisms associated with graft rejection are mediated by adaptive immune response elements.…”

Section: Sev In Solid Organ Transplantationmentioning

confidence: 99%

Small Extracellular Vesicles in Transplant Rejection

Gołębiewska

Wardowska

Pietrowska

et al. 2021

Cells

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Small extracellular vesicles (sEV), which are released to body fluids (e.g., serum, urine) by all types of human cells, may stimulate or inhibit the innate and adaptive immune response through multiple mechanisms. Exosomes or sEV have on their surface many key receptors of immune response, including major histocompatibility complex (MHC) components, identical to their cellular origin. They also exhibit an ability to carry antigen and target leukocytes either via interaction with cell surface receptors or intracellular delivery of inflammatory mediators, receptors, enzymes, mRNAs, and noncoding RNAs. By the transfer of donor MHC antigens to recipient antigen presenting cells sEV may also contribute to T cell allorecognition and alloresponse. Here, we review the influence of sEV on the development of rejection or tolerance in the setting of solid organ and tissue allotransplantation. We also summarize and discuss potential applications of plasma and urinary sEV as biomarkers in the context of transplantation. We focus on the attempts to use sEV as a noninvasive approach to detecting allograft rejection. Preliminary studies show that both sEV total levels and a set of specific molecules included in their cargo may be an evidence of ongoing allograft rejection.

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NK cells in antibody‐mediated rejection – Key effector cells in microvascular graft damage

Cited by 12 publications

References 66 publications

Weak Expression of Terminal Complement in Active Antibody-Mediated Rejection of the Kidney

Weak Expression of Terminal Complement in Active Antibody-Mediated Rejection of the Kidney

Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms

Small Extracellular Vesicles in Transplant Rejection

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