Discovery of a female mouse with autoimmune, insulin dependent
diabetes mellitus (IDDM) in an incipient inbred line initially selected
for normoglycemia was surely a serendipitous event. The subsequent
selection for IDDM in the progeny of this female produced the current
Nonobese Diabetic (NOD) strain. Prior to development of the NOD
strain, the only animal model of autoimmune IDDM predictably developing
the disease at high frequency was the BioBreeding (BB) rat. The
advent of the NOD mouse provided researchers working in the field of
autoimmunity with the needed perspective to assess findings in BB rats
relative to what is known about pathogenic processes in humans. There
are common etiopathogenic features observed in all three genera, as exemplified
by involvement of susceptibility conferring major histocompatibility
complex (MHC) haplotypes at the genetic level and of
autoreactive T cells at the effector level. At the same time, there are sufficient
distinctions between the rat and mouse models to remind the
clinical investigator that rodents can only model various aspects of a
human disease syndrome, while at the same time exhibiting speciesunique
features. For example, resistance to development of severe ketoacidosis—despite
severe hyperglycemia—is a genus-specific feature
peculiar to the mouse model. Many generations of strict inbreeding have
produced unusual phenotypes in both rodent models that distinguish
them from each other, and probably from most humans destined to develop
IDDM. The diabetes-prone BB rat is severely T-lymphocytopenic
in peripheral lymphoid organs whereas the NOD mouse reflects the other
extreme: T-lymphoaccumulation. Yet both BB rats and NOD mice develop
a veritable “Pandora’s box” of organ-specific lymphocytic infiltrations,
showing that immunoregyulatory pathways are compromised in
both models, albeit in different ways. In-depth analysis of as many animal
models as possible enhances an investigator’s appreciation of the
etiologic complexity of IDDM in humans. Given the differences as well
as the similarities between IDDM development in BB rats and NOD
mice, a diabetes prophylactic treatment effective in both models becomes
a potential treatment to prevent IDDM in humans. The Diabetes Prevention
Trial using prophylactic insulin treatment discussed in chapter
6 is an illustration of how promising results obtained in several animal
models can be translated into human clinical trials.