Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection

Hamada, Sarah; Dubois, Valérie; Koenig, Alice; Thaunat, Olivier

doi:10.1111/tan.14332

Cited by 21 publications

(10 citation statements)

References 84 publications

(108 reference statements)

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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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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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“…This is followed by further secretion of cytokines and chemokines by neutrophils, in order to recruit additional immune cells, such as NK cells and monocytes, which can differentiate into macrophages and dendritic cells (DCs) [53]. Recipient NK cells are suggested to undergo priming to full effectors upon IRI, which may have long-term consequences in later vulnerability to rejection episodes [54]. Presentation of alloantigens by antigen presenting cells will induce an adaptive immune response and T cell allorecognition, leading to prolonged inflammation.…”

Section: Immune Cellsmentioning

confidence: 99%

“…This, in turn, may increase the HLA expression on the cell surface and propagate antibody-mediated damage. In addition, NK cells seem to be capable of allorecognition by sensing the absence of self HLA class I molecules [54].…”

Section: Nk Cellsmentioning

confidence: 99%

Failing Heart Transplants and Rejection—A Cellular Perspective

Hurskainen

Ainasoja

Lemström

2021

JCDD

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The median survival of patients with heart transplants is relatively limited, implying one of the most relevant questions in the field—how to expand the lifespan of a heart allograft? Despite optimal transplantation conditions, we do not anticipate a rise in long-term patient survival in near future. In order to develop novel strategies for patient monitoring and specific therapies, it is critical to understand the underlying pathological mechanisms at cellular and molecular levels. These events are driven by innate immune response and allorecognition driven inflammation, which controls both tissue damage and repair in a spatiotemporal context. In addition to immune cells, also structural cells of the heart participate in this process. Novel single cell methods have opened new avenues for understanding the dynamics driving the events leading to allograft failure. Here, we review current knowledge on the cellular composition of a normal heart, and cellular mechanisms of ischemia-reperfusion injury (IRI), acute rejection and cardiac allograft vasculopathy (CAV) in the transplanted hearts. We highlight gaps in current knowledge and suggest future directions, in order to improve cellular and molecular understanding of failing heart allografts.

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“…Natural killer (NK) cells are well known to play a decisive role as a first line of defence against pathogens and tumour cells, contributing both to innate and adaptive immunity ( 1 ). More recent studies have also suggested that NK cells make an important contribution to the rejection of organ allografts ( 2 , 3 ). The extent of intra-graft NK cell infiltrates was shown to strongly predict graft survival and even to outperform conventional histologic rejection criteria ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome

et al. 2022

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Natural killer (NK) cells may contribute to antibody-mediated rejection (ABMR) of renal allografts. The role of distinct NK cell subsets in this specific context, such as NK cells expressing the activating receptor NKG2C, is unknown. Our aim was to investigate whether KLRC2 gene deletion variants which determine NKG2C expression affect the pathogenicity of donor-specific antibodies (DSA) and, if so, influence long-term graft survival. We genotyped the KLRC2wt/del variants for two distinct kidney transplant cohorts, (i) a cross-sectional cohort of 86 recipients who, on the basis of a positive post-transplant DSA result, all underwent allograft biopsies, and (ii) 1,860 recipients of a deceased donor renal allograft randomly selected from the Collaborative Transplant Study (CTS) database. In the DSA+ patient cohort, KLRC2wt/wt (80%) was associated with antibody-mediated rejection (ABMR; 65% versus 29% among KLRC2wt/del subjects; P=0.012), microvascular inflammation [MVI; median g+ptc score: 2 (interquartile range: 0-4) versus 0 (0-1), P=0.002], a molecular classifier of ABMR [0.41 (0.14-0.72) versus 0.10 (0.07-0.27), P=0.001], and elevated NK cell-related transcripts (P=0.017). In combined analyses of KLRC2 variants and a functional polymorphism in the Fc gamma receptor IIIA gene (FCGR3A-V/F158), ABMR rates and activity gradually increased with the number of risk genotypes. In DSA+ and CTS cohorts, however, the KLRC2wt/wt variant did not impact long-term death-censored graft survival, also when combined with the FCGR3A-V158 risk variant. KLRC2wt/wt may be associated with DSA-triggered MVI and ABMR-associated gene expression patterns, but the findings observed in a highly selected cohort of DSA+ patients did not translate into meaningful graft survival differences in a large multicenter kidney transplant cohort not selected for HLA sensitization.

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Allograft recognition by recipient's natural killer cells: Molecular mechanisms and role in transplant rejection

Cited by 21 publications

References 84 publications

Small Extracellular Vesicles in Transplant Rejection

Small Extracellular Vesicles in Transplant Rejection

Failing Heart Transplants and Rejection—A Cellular Perspective

Deletion of the Natural Killer Cell Receptor NKG2C Encoding KLR2C Gene and Kidney Transplant Outcome

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