Faculty Collaboration Database

Cellular expression requirements for inhibition of type 1 diabetes by a dominantly protective major histocompatibility complex haplotype. Diabetes 2007 Feb;56(2):424-30

Date

01/30/2007

Pubmed ID

17259387

DOI

10.2337/db06-1303

Scopus ID

2-s2.0-33847028326 (requires institutional sign-in at Scopus site)   11 Citations

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.

Author List

Chen YG, Silveira PA, Osborne MA, Chapman HD, Serreze DV

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antigen-Presenting Cells
B-Lymphocytes
Bone Marrow
CD8 Antigens
Chimera
Dendritic Cells
Diabetes Mellitus, Type 1
Disease Models, Animal
Disease Susceptibility
Female
Haplotypes
Immunity, Innate
Insulin-Secreting Cells
Macrophages
Major Histocompatibility Complex
Mice
Mice, Inbred NOD