Allogeneic haematopoietic cell transplants as dynamical systems: influence of early-term immune milieu on long-term T-cell recovery.

Abstract

Immune recovery following haematopoietic cell transplantation (HCT) functions as a dynamical system. Reducing the duration of intense immune suppression and augmenting antigen presentation has the potential to optimise T-cell reconstitution, potentially influencing long-term outcomes. Based on donor-derived T-cell recovery, 26 patients were adaptively randomised between mycophenolate mofetil (MMF) administered for 30-day post-transplant with filgrastim for cytokine support (MMF30 arm, N = 11), or MMF given for 15 days with sargramostim (MMF15 arm, N = 15). All patients underwent in vivo T-cell depletion with 5.1 mg kg-1 antithymocyte globulin (administered over 3 days, Day -9 through to Day -7) and received reduced intensity 450 cGy total body irradiation (3 fractions on Day -1 and Day 0). Patients underwent HLA-matched related and unrelated donor haematopoietic cell transplantation (HCT). Clinical outcomes were equivalent between the two groups. The MMF15 arm demonstrated superior T-cell, as well as T-cell subset recovery and a trend towards superior T-cell receptor (TCR) diversity in thefirst month with this difference persisting through the first year. T-cell repertoire recovery was more rapid and sustained, as well as more diverse in the MMF15 arm. The long-term superior immune recovery in the MMF15 arm, administered GMCSF, is consistent with a disproportionate impact of early interventions in HCT. Modifying the 'immune-milieu' following allogeneic HCT is feasible and may influence long-term T-cell recovery.