Abstract
Abstract Allogeneic mixed chimerim can prevent disease onset in Type 1 diabetes. While bone marrow (BM) allografts from MHC-mismatched donors can prevent disease in NOD mice, levels of mixed chimerism can be variable and unstable. Also, MHC-mismatched BM usually involve donor T cell depletion, increasing risk for graft-versus-host reactivity. Therefore, we tested the ability of MHC-matched donors to protect NOD mice from disease. Young female NOD mice were irradiated (2 x 450R) and grafted with the following BM donors: (1) Disease-prone NOD (H-2g7), (2) MHC-matched, disease-resistant C57Bl/6.H-2g7 (B6.H-2g7), (3) MHC-mismatched, disease-resistant C57Bl/6 (B6), or (4) Mixtures of disease-prone + disease-resistant BM. Importantly, donor BM was depleted of mature T and B cells. Recipients of only NOD BM recapitulated diabetes in 31/33 (94%) recipients by 30 weeks. Conversely, recipients of B6.H-2g7 BM alone did not develop diabetes (0/26). Mixed NOD + B6.H-2g7 BM grafts resulted in marked disease protection in 27/30 recipients (p <.001). However, recipients of mixed NOD + B6 BM grafts rejected the MHC-mismatched B6 donor and developed disease in 9/10 hosts (90%). Importantly, mixed NOD + B6.H-2g7 BM transplants resulted in remarkably stable, multi-lineage chimerism (>40-50% NOD) for ≥ 30 weeks. Thus, MHC-matched BM allografts permits dominant disease protection and stable macro-chimerism in NOD mice. Also, disease-prone MHC is not an intrinsic barrier to autoimmune regulation.
Published Version
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