Production of Donor T Cells Is Critical for Induction of Donor-Specific Tolerance and Maintenance of Chimerism

Abstract

Nonmyeloablative conditioning has significantly reduced the morbidity associated with bone marrow transplantation. The donor hemopoietic cell lineage(s) responsible for the induction and maintenance of tolerance in nonmyeloablatively conditioned recipients is not defined. In the present studies we evaluated which hemopoietic stem cell-derived components are critical to the induction of tolerance in a total body irradiation-based model. Recipient B10 mice were pretreated with mAbs and transplanted with allogeneic B10.BR bone marrow after conditioning with 100–300 cGy total body irradiation. The proportion of recipients engrafting increased in a dose-dependent fashion. All chimeric recipients exhibited multilineage donor cell production. However, induction of tolerance correlated strictly with early production of donor T cells. The chimeras without donor T cells rejected donor skin grafts and demonstrated strong antidonor reactivity in vitro, while possessing high levels of donor chimerism. These animals lost chimerism within 8 mo. Differentiation into T cells was aborted at a prethymic stage in recipients that did not produce donor T cells. Moreover, donor Ag-driven clonal deletion of recipient T cells occurred only in chimeras with donor T cells. These results demonstrate that donor T cell production is critical in the induction of transplantation tolerance and the maintenance of durable chimerism. In addition, donor T cell production directly correlates with the deletion of potentially alloreactive cells.

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

“…This result also suggested that DNTreg could be used in a broad range for treatment. Previous studies have demonstrated that early mixed chimerism may not always persist over the long term, particularly with regimens that involve a combination of immunosuppressive techniques [34,35]. Hence, tolerance in mixed chimerism must be more carefully assessed in the setting of transplantation, owing to the possibility that chimerism may be dissociated with tolerance [36][37][38].…”

Preconditioning of NOD mice with anti-CD8 mAb and costimulatory blockade enhances chimerism and tolerance and prevents diabetes, while depletion of αβ-TCR+ and CD4+ cells negates the effect

“…7 Strikingly, when NOD mice were preconditioned with anti-TCR␤ mAb, significantly impaired engraftment was observed. As for anti-CD4 mAb preconditioning, a higher TBI dose was required compared with TBI-only treated recipients ( Figure 2B).…”

“…Surprisingly, the elimination of recipient ␣␤-TCR ϩ T cells significantly impaired engraftment in NOD mice, in contrast with the enhanced engraftment observed after ␣␤-TCR ϩ mAb preconditioning in nonautoimmune mice. 7 Similarly, treatment of the NOD recipients with anti-CD4 mAb abrogated the engraftment-enhancing effect of anti-CD8 mAb treatment alone and actually increased the minimum TBI dose to above that for TBI alone. The combination of anti-CD152 and anti-CD154 mAb similarly abrogated the increased engraftment observed when either reagent was used alone.…”

“…The relative contribution of myelotoxic agents to preparing vacant niches versus controlling the host-versus-graft response is currently controversial. Recent data from nonmyeloablative conditioning models in nonautoimmune recipients suggest that the main role of myelotoxic agents is to control host-versus-graft alloreactivity rather than prepare vacant niches, 7,8 leading to the possibility of developing more benign antigen-driven conditioning strategies. For example, when total body irradiation (TBI) is used as the sole conditioning agent for allogeneic BMT in mice, a minimum of 700 cGy TBI is required.…”

“…10 The addition of both anti-CD8 and anti-T-cell receptor ␤ (TCR␤) mAb treatment to the conditioning approach decreases the TBI dose to as low as 300 cGy and eliminates the requirement for cyclophosphamide. 7 Blocking CD40-CD40L costimulation through anti-CD154 mAb decreases TBI dose to 400 cGy, 11 and the addition of cyclosporine A further decreases the TBI dose to 200 cGy. 12 Nonobese diabetic (NOD) mice share with humans with type 1 diabetes at least 20 genetic loci associated with diabetes.…”