Induction of bilateral transplantation tolerance to cellular and perfused allografts and xenografts with donor hematopoietic cells.

We have recently introduced a new approach for induction of transplantation tolerance to donor alloantigens using well-tolerated non-myeloablative conditioning across MHC and xenogeneic barriers in mice. Our regimen consists of no or very low doses of total lymphoid irradiation (TLI), previously shown to be tolerogenic because of profound yet non-myeloablative immunosuppression, followed by deletion of donor-reactive host lymphocytes activated in vivo with donor hematopoietic cells with a single dose of cyclophosphamide. Recipients of immunosuppressive regimen with lower intensity (e.g., no or one single dose of TLI) required a larger inoculum of donor bone marrow cells; the reverse was also true, both regimens resulting in stable mixed chimerism. A combination of low-dose TLI followed by depletion of donor-reactive host cells with cyclophosphamide resulted in consistent engraftment of even low numbers of T-cell-depleted donor-derived hematopoietic cells, known to be much more difficult to engraft, with consistent induction of permanent and donor-specific transplantation tolerance to donor skin allografts with signs of similar success across xenogeneic barriers.