Induction of Mixed Chimerism With MHC-Mismatched but Not Matched Bone Marrow Transplants Results in Thymic Deletion of Host-Type Autoreactive T-Cells in NOD Mice

Abstract

OBJECTIVE Induction of mixed or complete chimerism via hematopoietic cell transplantation (HCT) from nonautoimmune donors could prevent or reverse type 1 diabetes (T1D). In clinical settings, HLA-matched HCT is preferred to facilitate engraftment and reduce the risk for graft versus host disease (GVHD). Yet autoimmune T1D susceptibility is associated with certain HLA types. Therefore, we tested whether induction of mixed chimerism with major histocompatibility complex (MHC)-matched donors could reverse autoimmunity in the NOD mouse model of T1D. RESEARCH DESIGN AND METHODS Prediabetic wild-type or transgenic BDC2.5 NOD mice were conditioned with a radiation-free GVHD preventative anti-CD3/CD8 conditioning regimen and transplanted with bone marrow (BM) from MHC-matched or mismatched donors to induce mixed or complete chimerism. T1D development and thymic deletion of host-type autoreactive T-cells in the chimeric recipients were evaluated. RESULTS Induction of mixed chimerism with MHC-matched nonautoimmune donor BM transplants did not prevent T1D in wild-type NOD mice, although induction of complete chimerism did prevent the disease. However, induction of either mixed or complete chimerism with MHC-mismatched BM transplants prevented T1D in such mice. Furthermore, induction of mixed chimerism in transgenic BDC2.5-NOD mice with MHC-matched or -mismatched MHC II−/− BM transplants failed to induce thymic deletion of de novo developed host-type autoreactive T-cells, whereas induction of mixed chimerism with mismatched BM transplants did. CONCLUSIONS Induction of mixed chimerism with MHC-mismatched, but not matched, donor BM transplants re-establishes thymic deletion of host-type autoreactive T-cells and prevents T1D, with donor antigen-presenting cell expression of mismatched MHC II molecules being required.