Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

Co-senior authors.Mixedhematopoieticchimerismisapowerfulmeansofgenerating donor-specific tolerance, allowing long-term graft acceptance without lifelong dependenceon immunosuppressive drugs. To avoid the need forwhole body irradiation and associated side effects, weutilizedaradiation-freeminimalconditioningregimetoinducelong-termtoleranceacrossmajorhistocompati-bility barriers. We found that low-dose busulfan, incombination with host T cell depletion and short-termsirolimus-based immunosuppression, facilitated effi-cientdonorengraftment.Tolerancewasachievedwhenmice were transplanted with whole or T cell–depletedbone marrow, or purified progenitor cells. Toleranceinduction was associated with an expansion in regula-tory T cells and was not abrogated in the absence of athymus, suggesting a dominant or compensatoryperipheral mode of tolerance. Importantly, we wereable to generate durable chimerism and tolerance todonorskingraftsinbothyoungandagedmice,despiteage-related thymic atrophy and immune senescence.Clinically, this is especially relevant as the majority oftransplantrecipients areolderpatients whoseimmunerecoverymightbedangerouslyslowandwouldbenefitfrom radiation-free minimal conditioning regimes thatallow efficient donor engraftment without fully ablat-ing the recipient immune system.Abbreviations:BMT,bonemarrowtransplantation;Bu,busulfan; LSK, Lineage Sca-1