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Title: Investigation into the development of thymopoiesis, mechanism of action and assessment of quality of life in a cohort of paediatric patients with acute graft-versus-host disease treated with extracorporeal photopheresis
Author: Flinn, Aisling Mary
ISNI:       0000 0004 7961 0185
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2018
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Abstract:
The primary immunological aim following allogeneic haematopoietic stem cell transplantation (HSCT) is to achieve complete, sustained immune reconstitution and requires a functioning thymus for naïve T-lymphocyte neogenesis. Acute graft-versus-host disease (aGVHD) remains a major obstacle and targets the thymus, with damage to the thymic microenvironment impairing thymopoiesis, further compounded by corticosteroid treatment. Extracorporeal photopheresis (ECP) is an alternative therapy for aGVHD, possibly acting in an immunomodulatory fashion, although the true in vivo effects are not established. 21 paediatric patients were recruited; 8 ECP patients, 6 patients with no aGVHD (control group 1) and 7 patients with aGVHD not requiring ECP (control group 2). Thymic recovery was quantitatively measured by enumeration of CD3+CD4+CD45RA+CD31+ naïve T-lymphocytes by flow cytometry and TRECs using PCR, and qualitatively by TCR DNA spectratyping. Investigations of mechanisms of action of ECP included examination of dendritic cell (DC) subset patterns and regulatory T-lymphocytes (Tregs) using flow cytometry, and Th1 and Th2 cytokine profiles using ELISA. Quality of life was assessed using the PedsQL Generic Core Scales at the beginning and end of ECP treatment, and at 4 months post-HSCT for the control groups. Four patients completed ECP therapy and demonstrated qualitative and quantitative improvement in thymic output. Faster thymic recovery was evident in those who started ECP earlier. Two patients remain on prolonged ECP treatment but with negligible thymic output, suggesting irreversible thymic damage. Comparison with the control groups demonstrated superior thymic recovery in the ECP group compared to control group 2. An increase in cDC and pDC populations was observed with a decline in the cDC/pDC ratio. There was reduced DC co-stimulatory marker expression in the responding ECP patients. Variable patterns in Tregs, and a decline in Th1 and incline in Th2 cytokines in the responding ECP patients with treatment progression were seen. QOL of life was lowest in the ECP group pre ECP, and post ECP there was an improvement in QOL parent-proxy scores. These data demonstrate that ECP facilitates thymopoiesis in some, but not all, patients. Early initiation may promote faster thymic recovery. Patients with aGVHD not treated ii with ECP appeared to have slower thymic recovery. Exploration of the mechanisms supported promotion of a tolerogenic environment in responding patients. Although additional data are needed, ECP appears to promote immune tolerance and, by reducing aGVHD and immunosuppression, facilitates thymic recovery and complete immune reconstitution post-HSCT.
Supervisor: Not available Sponsor: Bubble Foundation ; Mallinckrodt Pharmaceuticals
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.773777  DOI: Not available
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