Selective lymphodepletion underlies the efficacy of horse anti-thymocyte globulin-based immunosuppressive therapy in aplastic anemia

Résumé fourni par la source

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 hematologic 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. We used flow cytometry to quantify 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 with earlier hematologic recovery. ATGAM bound all lymphoid lineages and profoundly depleted T and natural killer cells at high plasma concentrations. Strikingly, ATGAM did not deplete B cells but instead induced an increase in 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+ T cells 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.

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