351: Early recovery of host T cells predicts primary graft rejection following non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation

Abstract

The incidence of graft rejection is increasing in association with an increased use of non-myeloablative conditioning regimen, alternative donors, and cord blood transplantation. We investigated a role of host T cells in graft rejection following non-myeloablative conditioning bone marrow transplantation (BMT) in an MHC mismatched B6D2F1 (H-2b/d) into B6 (H-2b) mouse model of BMT, where host T cells can be activated to kill donor cells. BMT following 6 Gy, 7Gy, and 10Gy total body irradiation (TBI) resulted in a primary graft rejection, secondary graft rejection, and engraftment of donor cells, respectively. Interestingly, expansion of host T cells is observed in the bone marrow and spleen 2 weeks after BMT, followed by a brisk increase in number of host T cells in peripheral blood one week later. CD8+ T cells isolated from bone marrow produced interferon-gamma and lysed donor cells. We then examined whether donor-derived dendritic cells (DCs) play a role in this rejection, using transgenic mice carrying diphtheria toxin receptor (DTR) under the control of the CD11c promoter, which allows selective ablation of CD11c+ DCs by injection of diphtheria toxin (DTx), as donors. In the recipients conditioned with 6Gy TBI, depletion of donor-derived DCs with DTx injection reduced the host T cell-expansion and leads to transient mixed chimerism in contrast to primary graft rejection in controls. We then tested whether such an early recovery of host T cells could be predictive of the graft rejection in 7 adult recipients of non-myeloablative cord blood transplantation. Three week post-transplant, an overshoot of host T cells was observed in 2 patients who experienced rejection, but in none of 5 patients with engraftment. These results suggest that residual host T cells are associated with graft rejection and an early recovery of host T cells may be predictive of graft rejection after non-myloablative allogeneic hematopoietic stem cell transplantation. The incidence of graft rejection is increasing in association with an increased use of non-myeloablative conditioning regimen, alternative donors, and cord blood transplantation. We investigated a role of host T cells in graft rejection following non-myeloablative conditioning bone marrow transplantation (BMT) in an MHC mismatched B6D2F1 (H-2b/d) into B6 (H-2b) mouse model of BMT, where host T cells can be activated to kill donor cells. BMT following 6 Gy, 7Gy, and 10Gy total body irradiation (TBI) resulted in a primary graft rejection, secondary graft rejection, and engraftment of donor cells, respectively. Interestingly, expansion of host T cells is observed in the bone marrow and spleen 2 weeks after BMT, followed by a brisk increase in number of host T cells in peripheral blood one week later. CD8+ T cells isolated from bone marrow produced interferon-gamma and lysed donor cells. We then examined whether donor-derived dendritic cells (DCs) play a role in this rejection, using transgenic mice carrying diphtheria toxin receptor (DTR) under the control of the CD11c promoter, which allows selective ablation of CD11c+ DCs by injection of diphtheria toxin (DTx), as donors. In the recipients conditioned with 6Gy TBI, depletion of donor-derived DCs with DTx injection reduced the host T cell-expansion and leads to transient mixed chimerism in contrast to primary graft rejection in controls. We then tested whether such an early recovery of host T cells could be predictive of the graft rejection in 7 adult recipients of non-myeloablative cord blood transplantation. Three week post-transplant, an overshoot of host T cells was observed in 2 patients who experienced rejection, but in none of 5 patients with engraftment. These results suggest that residual host T cells are associated with graft rejection and an early recovery of host T cells may be predictive of graft rejection after non-myloablative allogeneic hematopoietic stem cell transplantation.