| Title: |
Selective lymphodepletion underlies the efficacy of horse anti-thymocyte globulin-based immunosuppressive therapy in aplastic anemia |
| Authors: |
Emma S. Pool; Cilia R. Pothast; Shannah M. Gennesse; Esther H.M. van Egmond; Julia M. Giezen; Sabrina A.J. Veld; René E.M. Toes; Frits Koning; Constantijn J.M. Halkes; Mirjam H.M. Heemskerk; Dirk Jan A.R. Moes; Jennifer M-L. Tjon |
| Source: |
Haematologica, Vol 999, Iss 1 (2026) |
| Publisher Information: |
Ferrata Storti Foundation |
| Publication Year: |
2026 |
| Collection: |
Directory of Open Access Journals: DOAJ Articles |
| Subject Terms: |
Diseases of the blood and blood-forming organs; RC633-647.5 |
| Description: |
Horse-derived anti-thymocyte globulin (ATGAM) in combination with long-term ciclosporin is the first-line treatment for most immune-mediated aplastic anemia (AA) patients. The exact impact of this immunosuppressive therapy (IST) on hematological recovery and the immune landscape, however, remains poorly understood. We report a longitudinal analysis of the pharmacodynamic effects of ATGAM-based IST in a cohort of 44 AA patients. With flow cytometry we quantified plasma levels of lymphocyte-binding ATGAM, which is believed to mediate the therapeutic effect. Population pharmacokinetic modeling revealed substantial between-patient variability in ATGAM exposure, with higher exposure levels associating to earlier hematologic recovery. ATGAM bound all lymphoid lineages and profoundly depleted Tand NK-cells at high plasma concentrations. Strikingly, ATGAM did not deplete B-cells but instead induced an increase of CD27+ B-cells. Deep immunophenotyping on series of peripheral blood samples collected up to three years after start of IST demonstrated that ATGAM induced rapid depletion of T-cells, including KLRG1+ terminally differentiated CD8+ Tcells and Th17-like CCR6+CD4+ T-cells. Although naïve and pathogen-specific T-cells were also depleted, they recovered quickly, indicating preservation of protective immunity. Notably, CCR6++ B-cells, implicated in AA pathogenesis, escaped ATGAM depletion but reduced gradually over time along with residual potentially pathogenic T-cells, including the CCR6+CD4+ T-cells. This could explain the crucial contribution of long-term ciclosporin to successful IST. Collectively, our results identify ATGAM exposure as a factor influencing hematologic recovery, and indicate that the therapeutic effect of IST goes beyond total lymphodepletion but is rather the result of selective depletion and suppression of key lymphocyte subpopulations. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://haematologica.org/article/view/13129; https://doaj.org/toc/0390-6078; https://doaj.org/toc/1592-8721; https://doaj.org/article/331b188a61df4b2fb667bb6f66bd6958 |
| DOI: |
10.3324/haematol.2025.300002 |
| Availability: |
https://doi.org/10.3324/haematol.2025.300002; https://doaj.org/article/331b188a61df4b2fb667bb6f66bd6958 |
| Accession Number: |
edsbas.933F317B |
| Database: |
BASE |