High Doses of Myeloid Progenitor Cells Induce Tolerance in the Context of Autologous HSC Transplantation

Bone marrow transplantation has the potential to improve the outcome of many indications other than cancer, but this is hampered by the associated complications. Myeloid progenitor cells (MP), which produce a transient engraftment with myeloid cells, can be used as an adjuvant therapy which may help address some of the infectious complications of BMT, an approach that is being tested in clinical trials. The fact that MP can be cryopreserved and can be used effectively without being MHC matched to the host enables this approach. 

We have reported in preclinical models that we can use MP to induce specific and lasting tolerance for solid organ transplants. In our model, mice (typically BALB/c) are preconditioned and reconstituted with autologous or allogeneic hematopoietic stem cells (HSC) and allogeneic MP. MP-matched skin grafts are placed simultaneously and their fate is followed long-term. We have established that MP induce specific tolerance, MP-matched skin grafts are accepted, while grafts unmatched to the MP, HSC or host are rejected. MP from Rag2-/-IL2rg-/- mice that are incapable of producing B cells, T cells or NK cells, establish that only organ-graft matched myeloid cells are essential for this process. Tolerance can be induced by 100,000 MP in the context of allogeneic (third party) HSC transplantation. However, we have previously reported that the same number of MP only protects skin grafts in approximately 80% of the recipients that have been given autologous HSC (Transpl Immunol 31:112-118,2014).

Here we report that while tolerance induction by MP is more efficient when combined with allogeneic HSC, increasing the cell dose ensures the same outcome with autologous HSC. Injection of 40,000 or more Linneg/lo, Sca-1neg, c-Kit+ MP induces robust tolerance in recipients of allogeneic HSC. However, similar results can be obtained in the context of host-autologous HSC by using slightly higher cell doses (200,000 or more MP are needed to protect all skin grafts).

We conclude that organ matched MP can induce robust tolerance for simultaneously or subsequently placed solid organ transplants, without the need for long-term high level, multi-lineage engraftment. The specific properties of MP (they are clinically available, they can be cryopreserved, they can be used without matching and MP can be expanded ex vivo) makes these cells of particular interest. They offer a new approach to the use of BMT to help in improving solid organ transplantation.