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

Lebraud, Emilie; Eloudzeri, Maëva; Rabant, Marion; Lamarthée, Baptiste; Anglicheau, Dany

doi:10.3389/fimmu.2022.864730

Cited by 17 publications

(16 citation statements)

References 176 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This dichotomization in the clinically used Banff classification is challenged by accumulating insights in the heterogeneity of rejection and the alloreactive potential of the innate immune system 3,6 . For example, the frequent observation of histological features of ABMR in absence of donor-specific antibodies (DSA) is puzzling 7 and can potentially be explained by antibody-independent mechanisms [8][9][10][11] . Second, therapeutic strategies directed at canonical pathways have shown mixed results.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection

Lamarthée

Callemeyn

Herck

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the interactions of the alloreactive inflammatory infiltrate. Here we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies and generated cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A+ NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A+ NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxic activity is a central mechanism of NK cell mediated graft injury. To unravel the spatial distribution of immune cells in the allograft, multiplexed immunohistochemistry using 38 markers was applied on 18 independent biopsy slides. In antibody-mediated rejection, FcγRIII+ NK and FcγRIII+ nonclassical monocytes specifically infiltrated the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and indicate several potential therapeutic targets to improve allograft longevity.

show abstract

Section: Introductionmentioning

confidence: 99%

Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection

Lamarthée

Callemeyn

Herck

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Currently, studies on macrophage polarization in the field of transplantation mainly focus on ischemia-reperfusion injury, and research on rejection, especially ABMR, is still lacking ( Zhang et al, 2018 ; Ye et al, 2020 ). More importantly, recent studies have pointed out that monocytes and macrophages could be considered as secondary effectors and capable of direct allorecognition, indicating the potential therapeutic target for ABMR treatment ( Callemeyn et al, 2022 ; Lebraud et al, 2022 ). The concrete molecular mechanism needs to be studied further.…”

Section: Discussionmentioning

confidence: 99%

Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4

et al. 2022

View full text Add to dashboard Cite

Background: This study aimed to explore the effect and mechanism of iguratimod (IGT) on M1 macrophage polarization and antibody-mediated rejection (ABMR) after renal transplant.Methods: Bioinformatics analysis was performed using three public databases derived from the GEO database. Sprague–Dawley (SD) rats were pre-sensitized with donors of Wistar rats in skin transplantation and a rat renal transplant ABMR model was established from the donors to skin pre-sensitized recipients. Subsequently, IGT was treated on the ABMR model. Routine staining and immunofluorescence (IF) staining were performed to observe the pathological changes in each group and flow cytometry was performed to detect the changes of DSA titers in peripheral blood. In addition, bone-marrow-derived macrophage (BMDM) was extracted and interfered with IGT to explore the effect of IGT in vivo. PCR, IF staining, and Western blot were used to detect the expression of related genes and proteins.Results: Bioinformatics analysis revealed that several immune cells were significantly infiltrated in the ABMR allograft, while M1 macrophage was noticed with the most significance. Results of IF staining and PCR proved the findings of the bioinformatics analysis. Based on this, IGT was observed to significantly attenuate the degree of peritubular capillary vasculitis and arteriolitis in the rat renal transplant ABMR model, whereas it decreases the expression of C4d and reduces the titer of DSA. Results in vitro suggested that M1 macrophage-related transcripts and proteins were significantly reduced by the treatment of IGT in a dose- and time-dependent manner. Furthermore, IGT intervention could remarkably decrease the expression of KLF4.Conclusion: Polarization of M1 macrophages may aggravate ABMR after renal transplant by promoting DSA-mediated endothelial cell injury, and IGT may attenuate the pathogenesis of ABMR by targeting KLF4.

show abstract

“…For example, immune cells like granulocytes could induce injury to the graft endothelium via ADCC ( 36 , 37 ). The kidney biopsy from the patient described here showed infiltration of granulocytes.…”

Section: Discussionmentioning

confidence: 99%

“…We refer to the recently published review by Lebraud et al. for a detailed discussion on the mechanisms of microvascular damage to the allograft in the absence of HLA antibodies ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Renal Endothelial Cytotoxicity Assay to Diagnose and Monitor Renal Transplant Recipients for Anti-Endothelial Antibodies

Lammerts

Born²,

Huberts-Kregel³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

Tissue-specific nonhuman leukocyte antigen (HLA) antigens can play crucial roles in allograft immunity and have been shown to trigger humoral responses leading to rejection of HLA-matched kidney allografts. Interest in the role of endothelial-specific antigens has grown over the past years, and several case reports have been described in which antibodies reacting with endothelial cells (ECs) are associated with rejection. Such antibodies escape the detection in conventional crossmatch tests as they do not react with lymphocytes. However, due to the heterogeneity of endothelial cells from different vascular beds, it remains difficult to draw organ-specific conclusions from studies describing endothelial crossmatch assays. We present a case of a 69-year-old male patient whose kidney allograft was rejected as hyperacute, despite the absence of pretransplant HLA-specific antibodies. To place findings from previous studies in a kidney-related context, we performed crossmatch assays with primary renal endothelial cells. The patient’s serum was reactive with primary renal ECs, demonstrated by antibody binding and complement-dependent cytotoxicity. Antibodies from this patient did not react with lymphocytes nor were HLA donor-specific antibodies (DSAs) found. Two years later, the patient successfully received a second kidney transplant after treatment with rituximab and plasmapheresis before and after transplantation. We demonstrated that the removal of antibodies against non-HLA EC-specific molecules can be monitored using a primary renal EC crossmatch test, possibly contributing to a successful transplantation outcome.

show abstract

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

Cited by 17 publications

References 176 publications

Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection

Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection

Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4

Renal Endothelial Cytotoxicity Assay to Diagnose and Monitor Renal Transplant Recipients for Anti-Endothelial Antibodies

Contact Info

Product

Resources

About