Induction of allogeneic mixed chimerism by immature dendritic cells and bone marrow transplantation leads to prolonged tolerance to major histocompatibility complex disparate allografts

Abstract

Mixed chimerism has been shown to lead to prolonged major histocompatibility complex (MHC) disparate allograft survival and immune-specific tolerance; however, traditional conditioning regimes often involve myeloablation, which may pose a significant safety risk. In this study we examined the use of donor C57BL/6 (H-2(b)) immature dendritic cells (imDCs) to tolerize the BALB/c (H-2(d)) recipient to bone marrow transplantation (BMT), allowing the induction of mixed chimerism without immunosuppression or myeloablation. We showed that successful mismatched bone marrow engraftment can be achieved using imDCs given up to 3 days prior to BMT and that mixed chimerism can be established and detected in excess of 100 days post-BMT without evidence of graft-versus-host disease. Furthermore, we showed that imDCs can suppress lymphocyte proliferation in response to mismatched MHC stimulation, leading to increased expression of interleukin (IL)-4 and IL-10 and decreased expression of IL-2 and interferon-gamma (IFN-gamma). The induction of stable chimeras through pre-conditioning of mice with donor imDCs followed by BMT led to tolerance, allowing the long-term survival (> 110 days) of mismatched cardiac allografts and the prolonged survival of mismatched skin allografts without the need for immunosuppression or myeloablation. Transplantation with third-party C3H allografts were rapidly rejected in this model, suggesting that immune-specific tolerance was achieved. The induction of immune-specific tolerance without the need for immunosuppression or myeloablation represents a significant advance in transplant immunology and may provide clinicians with a plausible alternative in combating organ rejection following transplantation.