"Humanized" HLA transgenic NOD mice to identify pancreatic beta cell autoantigens of potential clinical relevance to type 1 diabetes.
The mechanistic basis by which the H2(g7) major histocompatibility complex (MHC) provides the primary risk factor for the development of T cell-mediated autoimmune type 1 diabetes (T1D) in non-obese diabetic (NOD) mice involves contributions not only from the unusual A(g7) class II molecule, but also from the more common K(d) and/or D(b) class I variants it encodes. Similarly, transgenic studies in NOD mice have confirmed the possibility first suggested in association studies that in the proper genetic context the common human HLA-A2.1 class I variant can mediate diabetogenic CD8 T cell responses. T1D continues to develop in a further refined NOD stock that expresses human HLA-A2.1, but no murine class I molecules (designated NOD.beta2m-.HHD). Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an important antigenic target of diabetogenic CD8 cells in standard NOD mice. Three IGRP-derived peptides have also been identified that are presented by human HLA-A2.1 molecules to diabetogenic CD8 T cells in NOD.beta2m-.HHD mice. At least one of these IGRP peptides (265-273) can also be the target of autoreactive CD8 T cells in HLA-A2.1-expressing human T1D patients. Studies are currently under way to determine whether HLA-A2.1-restricted IGRP peptides can be used in a tolerance-inducing protocol that inhibits T1D development in NOD. beta2m-.HHD mice. If so, this knowledge could ultimately lead to the development of a similar T1D prevention protocol in humans.
Serreze
David V
DV
The Jackson Laboratory, Bar Harbor, ME 04609, USA. dave.serreze@jax.org
Marron
Michele P
MP
Dilorenzo
Teresa P
TP
D000818:Animals; D001324:Autoantigens / Q000302:isolation & purification* / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy; D006680:HLA Antigens / Q000235:genetics*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic
D001324:Autoantigens; D006680:HLA Antigens; D015789:HLA-A2 Antigen