Mobilization of Host Stem Cells Enables Long Term Liver Transplant Acceptance in a Strongly Rejecting Rat Strain Combination

摘要

Careful examination of liver, kidney or heart transplants in human recipients has revealed small numbers of host bone marrow derived stem cells in the graft. If the limited recipient repopulation of a donor graft that is currently observed could be facilitated, it is possible that conversion to a predominantly host phenotype would permit long term graft function without immunosuppression. We proposed to “engineer” repopulation after transplant in a strain combination (DA to Lewis GFP+) which rejects liver grafts strongly, a model which more closely resembles the situation in humans. Treatment on days 0,1,2,3 and 7 after transplantation with low-dose (0.1mg/kg) tacrolimus (T) designed to blunt rejection combined with plerixafor (P) to mobilize host stem cells resulted in greater than 180 day graft survival with extensive albeit spotty conversion of a small (50%) DA graft to the recipient Lewis GFP+ genotype. Subsequent skin grafting revealed donor specific graft prolongation. T plus P treatment resulted in higher levels of Lin-Thy1+CD34+CD133+ stem cells and Foxp3+ regulatory T cells in the blood and liver at day 7. Thus, pharmacological mobilization of host stem cells sustains liver allografts by two mechanisms: repopulation of injured donor cells, and regulation of the immune response.