Cellular Expression Requirements for Inhibition of Type 1 Diabetes by a Dominantly Protective Major Histocompatibility Complex Haplotype

Abstract

The H2^g7 (K^d, A^g7, E^null, and D^b) major histocompatibility complex (MHC) is the primary genetic contributor to type 1 diabetes in NOD mice. NOD stocks congenically expressing other MHC haplotypes such as H2^nb1 (K^b, A^nb1, E^k, and D^b) in a heterozygous state are type 1 diabetes resistant. Hematopoietically derived antigen-presenting cells (APCs) expressing H2^nb1 MHC molecules delete or inactivate autoreactive diabetogenic T-cells. Thus, provided a relatively benign preconditioning protocol is ultimately developed, hematopoietic chimerization by APCs expressing dominantly protective MHC molecules could conceivably provide a means for type 1 diabetes prevention in humans. Before hematopoietic chimerization can be considered for type 1 diabetes prevention, it must be determined what subtype(s) of APCs (B-cells, macrophages, and/or dendritic cells) expressing protective MHC molecules most efficiently inhibit disease, as well as the engraftment level they must achieve to accomplish this. These issues were addressed through analyses of NOD background bone marrow chimeras in which H2^nb1 molecules were selectively expressed on variable proportions of different APC subtypes. While a modest B-cell effect was observed, the strongest type 1 diabetes protection resulted from at least 50% of dendritic cells and macrophages expressing H2^nb1 molecules. At this engraftment level, H2^nb1-expressing dendritic cells and macrophages mediated virtually complete deletion of a highly pathogenic CD8 T-cell population.