Bridging Mice to Men: Using HLA Transgenic Mice to Enhance the Future Prediction and Prevention of Autoimmune Type 1 Diabetes in Humans.

Similar to the vast majority of cases in humans, the development of type 1 diabetes (T1D) in the NOD mouse model is due to T-cell mediated autoimmune destruction of insulin producing pancreatic ß cells. Particular major histocompatibility complex (MHC) haplotypes (designated HLA in humans; and H2 in mice) provide the primary genetic risk factor for T1D development. It has long been appreciated that within the MHC, particular unusual class II genes contribute to the development of T1D in both humans and NOD mice by allowing for the development and functional activation of ß cell autoreactive CD4 T cells. However, studies in NOD mice have revealed that through interactions with other background susceptibility genes, the quite common class I variants (K(d), D(b)) characterizing this strain's H2 (g7) MHC haplotype aberrantly acquire an ability to support the development of ß cell autoreactive CD8 T cell responses also essential to T1D development. Similarly, recent studies indicate that in the proper genetic context some quite common HLA class I variants also aberrantly contribute to T1D development in humans. This review focuses on how "humanized" HLA transgenic NOD mice can be created and used to identify class I dependent ß cell autoreactive CD8 T cell populations of clinical relevance to T1D development. There is also discussion on how HLA transgenic NOD mice can be used to develop protocols that may ultimately be useful for the prevention of T1D in humans by attenuating autoreactive CD8 T cell responses against pancreatic ß cells.

Bridging mice to men: using HLA transgenic mice to enhance the future prediction and prevention of autoimmune type 1 diabetes in humans.

Similar to the vast majority of cases in humans, the development of type 1 diabetes (T1D) in the NOD mouse model is due to T-cell mediated autoimmune destruction of insulin-producing pancreatic beta cells. Particular major histocompatibility complex (MHC) haplotypes (designated HLA in humans and H2 in mice) provide the primary genetic risk factor for T1D development. It has long been appreciated that within the MHC, particular unusual class II genes contribute to the development of T1D in both humans and NOD mice by allowing for the development and functional activation of beta-cell autoreactive CD4 T cells. However, studies in NOD mice have revealed that through interactions with other background susceptibility genes, the quite common class I variants (K(d), D(b)) characterizing this strain's H2 ( g7 ) MHC haplotype aberrantly acquire an ability to support the development of beta cell autoreactive CD8 T-cell responses also essential to T1D development. Similarly, recent studies indicate that in the proper genetic context some quite common HLA class I variants also aberrantly contribute to T1D development in humans. This chapter will focus on how "humanized" HLA transgenic NOD mice can be created and used to identify class I-dependent beta cell autoreactive CD8 T-cell populations of clinical relevance to T1D development. There is also discussion on how HLA transgenic NOD mice can be used to develop protocols that may ultimately be useful for the prevention of T1D in humans by attenuating autoreactive CD8 T-cell responses against pancreatic beta cells.

"Blue heart": characterization of a mifepristone-dependent system for conditional gene expression in genetically modified animals.

A detailed characterization of a cardiac muscle-specific, ligand-regulated gene expression system was performed in transgenic mice using the inducing ligand mifepristone (MFP). Several lines of double transgenic mice were created that expressed a bacterial lacZ reporter gene in the heart, under the control of a MFP-activated transcription factor constitutively expressed in cardiac muscle. The transgenic mice, which were administered MFP at a dose of 1 micromol/l in the drinking water, responded to the ligand within 24 h. Induction of beta-galactosidase enzyme activity in the heart continued for up to 21 days and resulted in an average 17-fold increase in enzyme activity. The highest individual animal response measured was a 94-fold increase in enzyme activity. The EC(50) for MFP induction of beta-galactosidase activity in the heart was 0.7 micromol/l when MFP was administered in the drinking water. Pharmacokinetic analysis of MFP dosing in wild-type FVB/N mice showed that absorption was very rapid (T(max) 1-10 min), bioavailability was modest ( approximately 10%) and the t(1/2) of MFP in mouse plasma was determined to be approximately 5 h. Thus, the system functions effectively in transgenic mouse heart where induction of gene expression is sensitive and can be accomplished by a simple and broadly applicable drinking water protocol.

Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS).

Transgenic overexpression of Cu(+2)/Zn(+2) superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (SOD1(G93A)) in a Sprague-Dawley rat results in ALS-like motor neuron disease. Motor neuron disease in these rats depended on high levels of mutant SOD1 expression, increasing from 8-fold over endogenous SOD1 in the spinal cord of young presymptomatic rats to 16-fold in end-stage animals. Disease onset in these rats was early, approximately 115 days, and disease progression was very rapid thereafter with affected rats reaching end stage on average within 11 days. Pathological abnormalities included vacuoles initially in the lumbar spinal cord and subsequently in more cervical areas, along with inclusion bodies that stained for SOD1, Hsp70, neurofilaments, and ubiquitin. Vacuolization and gliosis were evident before clinical onset of disease and before motor neuron death in the spinal cord and brainstem. Focal loss of the EAAT2 glutamate transporter in the ventral horn of the spinal cord coincided with gliosis, but appeared before motor neuron/axon degeneration. At end-stage disease, gliosis increased and EAAT2 loss in the ventral horn exceeded 90%, suggesting a role for this protein in the events leading to cell death in ALS. These transgenic rats provide a valuable resource to pursue experimentation and therapeutic development, currently difficult or impossible to perform with existing ALS transgenic mice.