Modeling the interaction between donor-derived regulatory T cells and effector T cells early after allogeneic hematopoietic stem cell transplantation.

While allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative therapy against hematological malignancies, modulation of donor T cell alloreactivity is required to enhance the graft-versus-leukemia (GVL) effect and control graft-versus-host-disease (GVHD) after allo-HSCT. Donor-derived regulatory CD4CD25Foxp3 T cells (Tregs) play a central role in establishing of immune tolerance after allo-HSCT. They could be a key target to be modulated for increasing the GVL effect and control of GVHD. We constructed an ordinary differential equation model incorporating bidirectional interactions between Tregs and effector CD4 T cells (Teffs) as a mechanism for control of Treg cell concentration. The goal is to elucidate how the interaction between Tregs and Teffs is modulated in order to get insights into fine tuning of alloreactivity after allo-HSCT. The model was calibrated with respect to published Treg and Teff recovery data after allo-HSCT. The calibrated model exhibits perfect or near-perfect adaptation to stepwise perturbations between Treg and Teff interactions, as seen in Treg cell populations when patients with relapsed malignancy were treated with anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen 4). In addition, the model predicts observed shifts of Tregs and Teffs concentrations after co-stimulatory receptor IL-2R or TNFR2 blockade with allo-HSCT. The present results suggest simultaneous blockades of co-stimulatory and co-inhibitory receptors as a potential treatment for enhancing the GVL effect after allo-HSCT without developing GVHD.