Endogenous Stem Cell Mobilization Via CXCR4 Antagonism Allows for Drug Free Kidney Transplantation in a Large Animal Preclinical Model.

Abstract

Organ Transplantation is lifesaving therapy but requires immunosuppresion (IS) with resultant morbidity. Current IS strategies focus on inhibition of T cell activation and seek to avoid donor-recipient engagement. Marrow derived endogenous stem cells have been shown to participate in organ regeneration and recovery in injury scenarios and also demonstrate immunomodulatory properties. However a role for endogenous stem cells post transplant has not been described, though recent small animal data is suggestive. Here we show that pharmacologic mobilization of endogenous stem cells immediately post kidney transplant leads to host repopulation of the graft and donor specific immunologic unresponsiveness allowing for subsequent immunosuppressive-free long term graft and recipient survival. We found in a series of maximally mismatched SLA defined miniature swine renal transplants indefinite survival and relatively normal graft histology after animals had received a short course of stem cell mobilization with the CXCR4 antagonist plerixafor and low dose tacrolimus. This ten-day treatment was repeated at 1 and 2 months after transplant, after which no further treatment was given. Three animals displayed long term normal graft function, minimal inflammatory changes on biopsy, and donor immunologic unresponsiveness, in contrast to control animals which expired of rejection and renal insufficiency relatively rapidly. To determine kidney allograft replacement by host-derived cells, Y-chromosome (Sry) expression in genomic DNA of graft biopsies was analyzed by qPCR in sex-mismatched transplants and revealed 50% of genomic DNA from kidney biopsies to be of host genotype at 6 months post transplantation indicating host repopulation of the graft. Our results demonstrate that mobilization of endogenous stem cells in the post transplant setting allows for graft repopulation and immunoregulation in the absence of further immunosuppression. We anticipate that endogenous stem cell mobilization via CXCR4 antagonism may represent a novel post transplant strategy which would avoid the morbidities of current conventional IS.