Rapid Tolerance Induction for Solid Organ Transplantation by Myeloid Progenitor Cells

Purpose Donor specific hematopoietic cell transplantation (HCT) has long been recognized for its potential to induce tolerance for subsequent organ transplantation. To date, however, HCT tolerance induction regimens have either been inconsistent or have been associated with high levels of morbidity. We have recently published that tolerance can be consistently induced with a population of cells, called Myeloid Progenitor Cells (MP), that should reduce complications. MP can induce tolerance without the need for long-term high-level engraftment. Importantly, MP are clinically available, and are currently in clinical trials (to prevent infectious complications in bone marrow transplantation). We hypothesized that tolerance induction in this model does not require administration of the MP two-months before the organ transplantation, that it can be reliably induced with simultaneous cell transplantation and organ transplantation, and that it does not require donor lymphoid cells. Methods and Materials BALB/c mice were lethally irradiated and reconstituted with 4,000 FVB HSC and 100,000 B10;B6-Rag2-/-Il2rg-/- MP. MP-matched (or mismatched) skin grafts were placed on the same day and their fate followed for more than 6 months. Results When mice were reconstituted with B10;B6-Rag2-/-Il2rg-/- cells, donor specific tolerance was induced. B10;B6-Rag2-/-Il2rg-/- mice lack the Rag-2 recombinase and the common gamma chain of the interleukin-2 receptor, and consequently are incapable of producing functional B, T or NK cells. 15/16 mice that were reconstituted with B10;B6-Rag2-/-Il2rg-/- MP (and 4,000 FVB HSC) and 10/10 mice that were reconstituted with B10;B6-Rag2-/-Il2rg-/- bone marrow accepted their MP-matched skin grafts (placed at the day of HCT) for up to 200 days. Six third party grafts (AKR) were all rejected. Conclusions These observations significantly increase the potential clinical applicability of this approach in the organ transplant setting as it enables tolerance induction in the context of deceased donor grafts without the need for graft-matched lymphoid cells.