Immune reconstitution patterns in allogeneic haematopoietic stem cell transplant recipients with human cytomegalovirus reactivation

Abstract

Allogeneic haematopoietic stem cell transplantation (HSCT) is a treatment with curative potential for a range of haematological malignancies and non‐malignant haematological disorders. Opportunistic infections are a major cause of transplant‐related morbidity and mortality in HSCT patients due to the profound immunodeficiency and immunosuppression associated with the procedure. Human cytomegalovirus (HCMV) reactivation is one of the most significant infectious complications following HSCT and frequently occurs in the first 100 days post‐transplant. This thesis aimed to investigate patterns of immune reconstitution associated with HCMV reactivation the first 100 days post‐HSCT. High parameter immune profiling technologies (mass cytometry and multiplex cytokine assays) were employed to characterise peripheral blood immune cell subset recovery and plasma cytokine profiles at key phases of HCMV reactivation (prior to detection, at the initial detection, at the peak and near resolution) in a cohort of allogeneic HSCT recipients. The data illustrate the emergence of distinct patterns of immune cell reconstitution and circulating cytokine signatures in patients who experienced HCMV reactivation, including elevated frequencies of activated T cell subsets and an inflammatory cytokine profile at the peak of reactivation. Mucosal associated invariant T (MAIT) cell levels at the initial detection of HCMV reactivation were significantly lower in patients who subsequently developed high‐level HCMV reactivation compared to those with low‐level HCMV reactivation. Faster effector memory CD4+ T cell recovery was also found to distinguish low‐level and high‐level reactivators. Together, this work provides comprehensive insight into immune reconstitution signatures linked with the evolution and magnitude of HCMV reactivation after allogeneic HSCT.