Abstract 3533: Tolerance Induction Using Hematopoietic Stem and Progenitor Cells
Though short-term success in heart transplantation is high, long-term success is poor, with graft survival at 10 years averaging 60%. Tolerance induction would improve long-term graft survival. Hematopoietic cell transplantation (HCT) in the form of transplantation of bone marrow or mobilized peripheral blood has been long recognized as a means to induce lasting and robust tolerance for subsequently transplanted solid organs. Protocols resulting in high levels of donor-derived reconstitution and low-levels of reconstitution have been developed, each having benefits and drawbacks. Our laboratory focuses on protocols utilizing high levels of donor-derived reconstitution and has developed methods of reducing the morbidity and mortality previously associated with these protocols. Current efforts focus on improving immune competence in hosts. One novel approach that is currently being tested clinically to further improve outcome is the addition of unrelated, off-the-shelf, myeloid progenitors (MP) to the HCT. This has the potential to reduce infectious complications immediately post-transplant and clinical trials to evaluate these cells are underway. As this is a novel therapeutic approach however, it is unclear whether addition of third party MP would interfere with tolerance induction. To test this, BALB/c (H-2d) mice were irradiated and reconstituted with 4,000 AKR (H-2k) HSC or with 4,000 AKR HSC combined with 100,000 FVB (H-2q) MP. After two months the mice received skin grafts from these three strains or from an unrelated strain, C57BL/6 (H-2b). We found that BALB/c mice reconstituted with AKR HSC accepted BALB/c (2/2) and AKR skin grafts (6/6) and rejected FVB (0/6) and C57BL/6 (0/3) skin grafts. BALB/c mice reconstituted with AKR HSC and FVB MP accepted BALB/c (3/3) and AKR (3/3) skin grafts and rejected C57BL/6 (0/4) skin grafts. Surprisingly, all mice tested accepted FVB skin grafts (11/11), even with very low levels of FVB cells in circulation (p<0.0001 compared to no MP group, Fishers exact test). We conclude that addition of third party MP cells does not interfere with HCT-induced tolerance induction. Moreover, we find that the use of MP in this setting induces specific tolerance to MP, an observation we intend to explore in future studies.