Antibody-induced vascular inflammation skews infiltrating macrophages to a novel remodeling phenotype in a model of transplant rejection

Wei, Xuedong; Valenzuela, Nicole M.; Rossetti, Maura; Sosa, Rebecca A.; Nevarez‐Mejia, Jessica; Fishbein, Gregory A.; Mulder, Arend; Dhar, Jayeeta; Keslar, Karen; Baldwin, William M.; Fairchild, Robert L.; Hou, Jianquan; Reed, Elaine F.

doi:10.1111/ajt.15934

Cited by 15 publications

(24 citation statements)

References 67 publications

(138 reference statements)

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“…Although older studies did demonstrate that HLA class I antibodies can directly trigger cytokine secretion from endothelial cells (15,63), our data are in accordance with the study of Wei et al, where HLA class I antibodies did not induce cytokine production directly from endothelial cells derived from aortic rings, but cell-cell contact of monocytes with antibodyactivated endothelial cells was required for cytokine production (57). The observation that this is also true for glomerular endothelial cells used in our experiments, which are more relevant for kidney microvascular injury, is novel.…”

Section: Discussionsupporting

confidence: 93%

“…In a previous study by Wei et al. ( 57 ) studying monocytes and DSA-mediated injury of endothelial cells, using F(ab′)2 alone induced only upregulation of the antigens on the endothelial cells, leading to increased tethering and adhesion of monocytes. Only in the presence of the Fc region was the extra signal for activation of the monocytes provided, inducing cytokine secretion, suggesting that FcyR-mediated signaling is essential for the cytokine production in DSA-mediated injury.…”

Section: Discussionmentioning

confidence: 91%

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Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings

Loon¹,

Lamarthée²,

Barba³

et al. 2022

Front. Immunol.

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Despite the critical role of cytokines in allograft rejection, the relation of peripheral blood cytokine profiles to clinical kidney transplant rejection has not been fully elucidated. We assessed 28 cytokines through multiplex assay in 293 blood samples from kidney transplant recipients at time of graft dysfunction. Unsupervised hierarchical clustering identified a subset of patients with increased pro-inflammatory cytokine levels. This patient subset was hallmarked by a high prevalence (75%) of donor-specific anti-human leukocyte antigen antibodies (HLA-DSA) and histological rejection (70%) and had worse graft survival compared to the group with low cytokine levels (HLA-DSA in 1.7% and rejection in 33.7%). Thirty percent of patients with high pro-inflammatory cytokine levels and HLA-DSA did not have histological rejection. Exploring the cellular origin of these cytokines, we found a corresponding expression in endothelial cells, monocytes, and natural killer cells in single-cell RNASeq data from kidney transplant biopsies. Finally, we confirmed secretion of these cytokines in HLA-DSA-mediated cross talk between endothelial cells, NK cells, and monocytes. In conclusion, blood pro-inflammatory cytokines are increased in kidney transplant patients with HLA-DSA, even in the absence of histology of rejection. These observations challenge the concept that histology is the gold standard for identification of ongoing allo-immune activation after transplantation.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 91%

Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings

Loon¹,

Lamarthée²,

Barba³

et al. 2022

Front. Immunol.

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“…The result found that ABO and HLA incompatibilities could increase the probability of infection-medicated rejection and influence the overall survival both for patient and graft [ 31 ]. Moreover, HLA donor-specific antibodies could induce inflammation, vessel injury and AMR by binding to vascular endothelial cells of the allograft [ 34 ]. As three important members in HLA class I heavy chain paralogues, HLA-A, HLA-C and HLA-G were found to be potentially regulated by miR-23b-3p in this study.…”

Section: Resultsmentioning

confidence: 99%

Multi-omics network characterization reveals novel microRNA biomarkers and mechanisms for diagnosis and subtyping of kidney transplant rejection

Lin

Wang

et al. 2021

J Transl Med

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Background Kidney transplantation is an optimal method for treatment of end-stage kidney failure. However, kidney transplant rejection (KTR) is commonly observed to have negative effects on allograft function. MicroRNAs (miRNAs) are small non-coding RNAs with regulatory role in KTR genesis, the identification of miRNA biomarkers for accurate diagnosis and subtyping of KTR is therefore of clinical significance for active intervention and personalized therapy. Methods In this study, an integrative bioinformatics model was developed based on multi-omics network characterization for miRNA biomarker discovery in KTR. Compared with existed methods, the topological importance of miRNA targets was prioritized based on cross-level miRNA-mRNA and protein–protein interaction network analyses. The biomarker potential of identified miRNAs was computationally validated and explored by receiver-operating characteristic (ROC) evaluation and integrated “miRNA-gene-pathway” pathogenic survey. Results Three miRNAs, i.e., miR-145-5p, miR-155-5p, and miR-23b-3p, were screened as putative biomarkers for KTR monitoring. Among them, miR-155-5p was a previously reported signature in KTR, whereas the remaining two were novel candidates both for KTR diagnosis and subtyping. The ROC analysis convinced the power of identified miRNAs as single and combined biomarkers for KTR prediction in kidney tissue and blood samples. Functional analyses, including the latent crosstalk among HLA-related genes, immune signaling pathways and identified miRNAs, provided new insights of these miRNAs in KTR pathogenesis. Conclusions A network-based bioinformatics approach was proposed and applied to identify candidate miRNA biomarkers for KTR study. Biological and clinical validations are further needed for translational applications of the findings.

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“…In vitro studies of cocultured monocytes with HLA class I antibody-activated endothelial cells demonstrated secretion of proinflammatory cytokines. 196,197 This cytokine production can orchestrate the recruitment and activation of deleterious immune cells that perpetuate the rejection process by eliciting direct graft injury or secreting even more cytokines. Among these, CXC chemokine ligand 10 is produced by both endothelial cells and monocytes, and its increase is well associated with ABMR, recruiting both innate CXC chemokine receptor 3 þ NK cells and adaptive CXC chemokine receptor 3 þ T cells.…”

Section: Crosstalk Of Allorecognition Pathways In Kidney Transplantationmentioning

confidence: 99%

Allorecognition and the spectrum of kidney transplant rejection

Callemeyn

Lamarthée

Koenig

et al. 2022

Kidney International

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Antibody-induced vascular inflammation skews infiltrating macrophages to a novel remodeling phenotype in a model of transplant rejection

Abstract: I F(ab′) 2), macrophages differentiated by endothelium activated with HLA IgG F(ab′) 2 fragment; M(HLA IgG), macrophages differentiated by endothelium activated with intact HLA IgG; TV, transplant vasculopathy.

Cited by 15 publications

References 67 publications

Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings

Circulating Donor-Specific Anti-HLA Antibodies Associate With Immune Activation Independent of Kidney Transplant Histopathological Findings

Multi-omics network characterization reveals novel microRNA biomarkers and mechanisms for diagnosis and subtyping of kidney transplant rejection

Allorecognition and the spectrum of kidney transplant rejection

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