Antigen-targeting to dendritic cells is required for engraftment of antigen-encoding bone marrow and long-term tolerance under non-myeloablative conditions (171.27)

Abstract

Transplantation of hematopoietic stem cells (HSC) or bone marrow (BM) engineered to encode antigens is a means of inducing antigen-specific tolerance that might be suitable for ‘turning off’ pathogenic effector and memory T-cell responses. However, transplantation into primed hosts under non-myeloablative conditions could lead to rejection of engineered HSC or BM. We hypothesized targeting antigen expression to mature APC would alleviate rejection of engineered HSC while still permitting expression in the ‘tolerogenic’ cells that arise after transplantation. Using non-myeloablative conditions, we compared engraftment and ‘tolerogenicity’ in naïve or immune hosts of BM encoding an antigen that was ubiquitously expressed, targeted to diverse APC, or targeted to DC. When antigen was expressed ubiquitously, engraftment failed (<1%) but targeting antigen to DC, permitted high levels of BM engraftment (≈40%). Unexpectedly, BM failed to engraft (<1%) when antigen was targeted using a MHC class II promoter. This was due low level MHC class II expression by HSC leading to antigen expression and subsequent immune rejection of engrafting HSC. Long-term tolerance of antigen-specific memory T cells occurred only when engraftment was facilitated by targeting antigen to DC. For clinical translation, careful selection for a promoter that optimally targets DC will be imperative to ensure engraftment of antigen-encoding cells and long-term tolerance.