Validation of Early Increase in Complement Activation Marker sC5b-9 as a Predictive Biomarker for the Development of Thrombotic Microangiopathy After Stem Cell Transplantation

Mező, Blanka; Horváth, Orsolya; Sinkovits, György; Veszeli, Nóra; Kriván, Gergely; Prohászka, Zoltán

doi:10.3389/fmed.2020.569291

Cited by 14 publications

(10 citation statements)

References 25 publications

(32 reference statements)

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“…Soluble MAC (sMAC) is an immune activation complex that is formed from MAC assembly precursors released into plasma and scavenged by blood-based chaperones. While in healthy individuals sMAC exists in trace amounts, these levels are dramatically elevated during an immune response, providing a biomarker for infectious and autoimmune disease 7 , 8 , transplant 9 , 10 , and trauma 11 . sMAC, also known as sC5b9, is composed of the complement proteins C5b, C6, C7, C8, and C9 together with the extracellular regulatory proteins, clusterin, and vitronectin 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

Structural basis of soluble membrane attack complex packaging for clearance

et al. 2021

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Unregulated complement activation causes inflammatory and immunological pathologies with consequences for human disease. To prevent bystander damage during an immune response, extracellular chaperones (clusterin and vitronectin) capture and clear soluble precursors to the membrane attack complex (sMAC). However, how these chaperones block further polymerization of MAC and prevent the complex from binding target membranes remains unclear. Here, we address that question by combining cryo electron microscopy (cryoEM) and cross-linking mass spectrometry (XL-MS) to solve the structure of sMAC. Together our data reveal how clusterin recognizes and inhibits polymerizing complement proteins by binding a negatively charged surface of sMAC. Furthermore, we show that the pore-forming C9 protein is trapped in an intermediate conformation whereby only one of its two transmembrane β-hairpins has unfurled. This structure provides molecular details for immune pore formation and helps explain a complement control mechanism that has potential implications for how cell clearance pathways mediate immune homeostasis.

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Section: Introductionmentioning

confidence: 99%

Structural basis of soluble membrane attack complex packaging for clearance

et al. 2021

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“…Transplant-associated TMA is multifactorial, and the risk factors include therapy used in conditioning regimens, human leukocyte antigen mismatch, graft-versus-host disease (GVHD), and viral infections, exposure to calcineurin inhibitors s, although its pathophysiology is poorly understood. One report showed that patients with transplantationassociated TMA were only identified during or after cyclosporine immunosuppression [27]; whereas another report showed that the use of cyclosporine /tacrolimus-based GVHD prophylaxis was not a risk factor for transplant-associated-TMA in pediatric patients with hematopoietic stem cell transplantation [28].…”

Section: Discussionmentioning

confidence: 99%

Current Status of Adverse Event Profile of Cyclosporine in Kidney, Stem Cell, and Heart Transplantations Using the Japanese Pharmacovigilance Database

Niinomi¹,

Oyama²,

Inada³

et al. 2022

Cureus

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Background: Cyclosporine is widely used to prevent allograft rejection after transplantation. The purpose of this study was to clarify the adverse events profiles associated with cyclosporine in transplant patients using a spontaneous reporting system database.Methods: Retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database, with the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event.Results: The database comprised 3,327, 958, and 956 reports associated with cyclosporine in the kidney, stem cell, and heart transplant patients, respectively. Infectious and renal disorders were commonly detected in these transplant patients. The signal scores of cyclosporine for toxic nephropathy were noteworthy in the kidney (ROR: 15.1, 95% CI: 11-20.8) and stem cell (ROR, 216; 95% CI, 29.3-1593) transplantation. Cyclosporine in heart transplantation was strongly associated with gastric cancer (ROR, 39.4; 95% CI, 16.7-93.2), but not kidney or stem cell transplantation.Conclusion: It was suggested that there is a diversity in the strength of the association between cyclosporine and adverse events in the kidney, stem cell, and heart transplantation. Our results may provide useful information for treatment with cyclosporine, although further research with more data is needed.

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“…The concentration of soluble products derived from complement activation (C5b-9, C3a) may be measured in plasma. It could help in predicting the diagnosis and severity of TA-TMA [164,[172][173][174].…”

Section: Transplant-associated Thrombotic Microangiopathy (Ta-tma)mentioning

confidence: 99%

Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology

Milone

Bellofiore

Leotta

et al. 2022

JCM

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Endothelial dysfunction (ED) is frequently encountered in transplant medicine. ED is an argument of high complexity, and its understanding requires a wide spectrum of knowledge based on many fields of basic sciences such as molecular biology, immunology, and pathology. After hematopoietic stem cell transplantation (HSCT), ED participates in the pathogenesis of various complications such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), graft-versus-host disease (GVHD), transplant-associated thrombotic microangiopathy (TA-TMA), idiopathic pneumonia syndrome (IPS), capillary leak syndrome (CLS), and engraftment syndrome (ES). In the first part of the present manuscript, we briefly review some biological aspects of factors involved in ED: adhesion molecules, cytokines, Toll-like receptors, complement, angiopoietin-1, angiopoietin-2, thrombomodulin, high-mobility group B-1 protein, nitric oxide, glycocalyx, coagulation cascade. In the second part, we review the abnormalities of these factors found in the ED complications associated with HSCT. In the third part, a review of agents used in the treatment of ED after HSCT is presented.

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Validation of Early Increase in Complement Activation Marker sC5b-9 as a Predictive Biomarker for the Development of Thrombotic Microangiopathy After Stem Cell Transplantation

Cited by 14 publications

References 25 publications

Structural basis of soluble membrane attack complex packaging for clearance

Structural basis of soluble membrane attack complex packaging for clearance

Current Status of Adverse Event Profile of Cyclosporine in Kidney, Stem Cell, and Heart Transplantations Using the Japanese Pharmacovigilance Database

Endothelial Dysfunction after Hematopoietic Stem Cell Transplantation: A Review Based on Physiopathology

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