Page 101 - 2021_05-Haematologica-web

Cell Therapy & Immunotherapy
Endothelial injury, F-actin and vitamin D binding protein after hematopoietic stem cell transplant and association with clinical outcomes
Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1321-1329
Nathan Luebbering,1,2 Sheyar Abdullah,1,2 Dana Lounder,1,2 Adam Lane,1,2 Nikhil Dole,1,2 Jeremy Rubinstein,1,2 Martin Hewison,2 Nicholas Gloude,1,2 Sonata Jodele,1,2 Kitty MR Perentesis,1,2 Kelly Lake,1,2 Bridget Litts,1,2 Alexandra Duell,1,2 Christopher E. Dandoy1,2 and Stella M. Davies1,2
1Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children’s Hospital Medical Center Cincinatti, OH, USA; 2Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA and 3School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
ABSTRACT
Endothelial injury after hematopoietic stem cell transplant is an important initiating factor for early transplant toxicities of throm- botic microangiopathy and acute graft versus host disease. We hypothesized that release of the angiopathic molecule filamentous actin (F-actin) from hematopoietic cells lysed during conditioning prior to stem cell transplant would be associated with clinical outcomes. We detected F-actin in the blood of 52% of stem cell transplant recipients in the first 14 days after transplant, and children with detectable F-actin had a significantly elevated risk of thrombotic microangiopathy (P=0.03) and non-relapse mortality (P=0.04). F-actin is cleared from the circula- tion by vitamin D binding protein (VDBP) so we expected that higher levels of VDBP would improve outcomes. In a cohort of 190 children receiving an allogeneic transplant, risk of thrombotic microangiopathy was reduced in those with serum concentrations of VDBP above the median at day 30 (10% vs. 31%, P=0.01), and graft versus host disease and non-relapse mortality were reduced in those with levels above the median at day 100 (3% vs. 18%, P=0.04 and 0% vs. 15%, P=0.002). Western blot analyses demonstrated actin-VDBP complexes in the blood, which cleared by day 21-28. Our data support modulation of cytokine secretion and macrophage phenotype by VDBP later after transplant. Taken together, our data identify an association between F- actin, a mediator of endothelial damage, and VDBP, an actin scavenger, as modifiers of risk of clinical consequences of endothelial injury.
Introduction
Chemotherapy and radiation are used in very high doses to purposely eradicate an entire organ, the hematopoietic system, in situ, inside a human body prior to hematopoietic stem cell transplant (HSCT). This is a bold endeavour which results in significant toxicity, most notably in the first 4 weeks after transplant, when mor- bidity and mortality are high. Biomarker data support the hypothesis that early events, in the first 14 days after transplant, set the scene for later adverse events such as transplant-associated thrombotic microangiopathy (TA-TMA) and graft versus host disease (GvHD) which occur 21-60 days after HSCT.1 Endothelial injury seems to be a key event in the initiation of TA-TMA and GvHD, and contributes significantly to organ injury and death.2-11 We set out to identify possible mecha- nisms of endothelial injury, and to identify potential factors that ameliorate injury and modify the individual risk of TA-TMA and GvHD.
Cell lysis leads to the release of toxic intracellular molecules into the circulation, including filamentous actin (F-actin) and nucleotides such as ATP, that are usually
Correspondence:
STELLA M. DAVIES
stella.davies@cchmc.org
Received: July 25, 2019. Accepted: March 19, 2020. Pre-published: April 2, 2020.
https://doi.org/10.3324/haematol.2019.233478
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2021; 106(5)
1321
ARTICLE