Mixed chimerism and tolerance without whole body irradiation in a large animal model

Mixed hematopoietic chimerism may provide a treatment for patients with non malignant hematologic diseases, and may tolerize patients to organ allograf ts without requiring chronic immunosuppression. However, the toxicity of th e usual conditioning regimens has limited the clinical applicability of thi s approach. These regimens generally include some level of whole body irrad iation (WBI), which is thought to facilitate engraftment either by making r oom for donor hematopoietic stem cells or by providing sufficient host immu nosuppression to enable donor cells to engraft. Here, we have established m ixed chimerism across both minor and major histocompatibility barriers in s wine, by using high doses of peripheral blood stem cells in the absence of WBI. After mixed chimerism was established, swine leukocyte antigen-matched (SLA-matched) donor skin grafts were tolerated and maintained for a prolon ged period, whereas third-party SLA-matched skin was rejected promptly. Don or-matched kidney allografts were also accepted without additional immunosu ppression. Because of its low toxicity, this approach has potential for a w ide range of clinical applications. Our data may indicate that niches for e ngrafting stem cells are filled by mass action and that WBI, which serves t o empty some of these niches, can be omitted if the donor inoculum is suffi ciently large and if adequate host T-cell depletion is achieved before tran splant.