Prevention of diabetes in the NOD mouse: implications for therapeutic intervention in human disease

MA Bowman, EH Leiter, MA Atkinson - Immunology today, 1994 - cell.com
MA Bowman, EH Leiter, MA Atkinson
Immunology today, 1994cell.com
The prevention of insulin-dependent diabetes (IDD/m humans remains an elusive goal,
despite the broad spectrum of therapeutic interventions that prevent the developmem of IDD
in the non-obese diabetic (NOD) mouse. Can an animal model in which spontaneous
autoimmune pathology is interrupted so easily ser,, e as an archetype for the design of
clinical trials aimed at the prevention of IDD in humans? In; IJis article, Mark~ ar,, Atkinson
review the intervention Bowman, Edward Leiter and AL strategies that prevent IDD in the …
The prevention of insulin-dependent diabetes (IDD/m humans remains an elusive goal, despite the broad spectrum of therapeutic interventions that prevent the developmem of IDD in the non-obese diabetic (NOD) mouse. Can an animal model in which spontaneous autoimmune pathology is interrupted so easily ser,, e as an archetype for the design of clinical trials aimed at the prevention of IDD in humans? In; IJis article, Mark~ ar,, Atkinson review the intervention Bowman, Edward Leiter and AL strategies that prevent IDD in the NOD mouse and indicate why these studies may well be relevant to the prevention of IDD in humans.
Many key featvres of human insulin-dependent diabetes (IDD) are reflected in the non-obese diabetic (NOD) mouse: the development of insulitis, whereby pancreatic islets of Langerhans are i: ffiltrated by lymphocytes that are selectively cytotc, xic to the insulinproducing [3 cells; the inheritance of particular major histocompatibility complex (MHC) class II alleles, representing the major component of genetic susceptibility; the transmission of IDD by hematopoietic cells in bone marrow; and the T-cell dependence of disease pathogenesis-s (Table I). The origin, genetics and immunological characteristics of the NOD; train, as well as the ability of environmental manipulations to effect the diabetqgenic processes in these mice, have recently bee~ reviewed 3'6';. For reason~ of brevity, the r:. ader is referred to these reviews foe" references to much of the information described below. There are relatively few characteristic differences between human and mouse disease. The presence of a high percentage of T cells (both CD4๗ and CD8 subsets) in NOD lymphoid tissues and peripheral blood distinguishes NOD mice from humans with IDD and from the severely T-lymphopenic diabetes-prone BB/Wor rat, which also spontaneot: s! y develops autoimmune IDD (Ref. 8). NOD mice do not display the severe diabetic ketoacidosis characteristic of untreated human patients with IDD, perhaps due to an enhanced ability of mice to metabolize blood ketones to lactate. In add:, tion, NOD mice exhibit a pronounced fen, ale gender bias for disease susceptlbility that is not observed in BB rats or in humans. While the specific reasons for this difference are unclear, female mice are known to be stronger immunological responders to exogenous stimuli than males and it ha~ been demonstrated that the lower incidence of IDD in NOD males is partially regulated by gonadal sex
cell.com