Bone marrow expressing a diabetes resistance MHC class II allele: diabetes deviation by chronic immune stimulation.
The major histocompatibility complex (MHC) of the type 1 diabetes-prone NOD mouse lacks a functional class II H2-Ea gene such that antigen presenting cells (APCs) are I-E null. Transgenic expression of Ea in NOD mice both restores I-E expression and confers complete protection from diabetes progression. Non-myeloablative neonatal transplantation of bone marrow cells from such I-E+ transgenic donors into NOD recipients resulted in low-level but long-term haematopoietic stem cell (HSC) engraftment. Despite low levels of I-E antigen expression in blood (averaging 0.4-3.8% of total MHC class II-positive population), chimeric recipients were protected from overt diabetes, although not insulitis development. Adoptive transfer of diabetes into immunodeficient NOD-Rag recipients that received chimeric splenocytes from primary recipients confirmed the presence of an autoreactive T cell repertoire. The demonstration that purified T cells from these weak chimeras were not tolerant to irradiated transgenic I-E+ splenocytes indicated that I-E+ donor cells provide a constant, low-level immune stimulation capable of up-regulating nominally deficient immunoregulatory networks. This study raises the possibility that cord blood HSCs from infants with high risk HLA haplotypes and a family history of type 1 diabetes might be re-introduced without myoablative treatments following transfection with a single HLA class II allele associated with diabetes resistance.
Reifsnyder
Peter
P
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Schott
William
W
Pomerleau
Darcy
D
Lessard
Mark D
MD
Soper
Brian W
BW
Leiter
Edward H
EH
D000483:Alleles; D000818:Animals; D016026:Bone Marrow Transplantation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D012737:Sex Factors
D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen