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 XXXX .

@entity19 @entity5168 @entity8200 @entity1723 @entity2132 @entity792
OBJECTIVE: Induction of mixed or complete chimerism via hematopoietic cell transplantation (HCT) from nonautoimmune donors could prevent or reverse @entity1723 ( @entity1723 ). In clinical settings, HLA-matched HCT is preferred to facilitate engraftment and reduce the risk for @entity2132 ( @entity2132 ). Yet autoimmune @entity1723 susceptibility is associated with certain HLA types. Therefore, we tested whether induction of mixed chimerism with major histocompatibility complex (MHC)-matched donors could reverse @entity792 in the NOD @entity19 model of @entity1723 . RESEARCH DESIGN AND METHODS: Prediabetic wild-type or transgenic BDC2.5 NOD @entity19 were conditioned with a radiation-free @entity2132 preventative anti- @entity5168 /CD8 conditioning regimen and transplanted with bone marrow (BM) from MHC-matched or mismatched donors to induce mixed or complete chimerism. @entity1723 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 @entity1723 in wild-type NOD @entity19 , although induction of complete chimerism did prevent the disease. However, induction of either mixed or complete chimerism with MHC-mismatched BM transplants prevented @entity1723 in such @entity19 . Furthermore, induction of mixed chimerism in transgenic BDC2.5-NOD @entity19 with MHC-matched or -mismatched @entity8200 (-/-) 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 @entity1723 , with donor antigen-presenting cell expression of mismatched @entity8200 molecules being required.
