[PDF][PDF] The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD

TL Delovitch, B Singh - Immunity, 1997 - cell.com
TL Delovitch, B Singh
Immunity, 1997cell.com
Who is more contemptible than he who scorns knowledge of himself?—John of Salisbury
bodies; and the autoreactive T cell dependence of IDDM pathogenesis and the ability to
intervene with disease This statement reflects our concern about the factors, progression by
modulation of T cell function (Bach, 1994; Bowman et al., 1994; Tisch and McDevitt, 1996).
both internaland external, that control our lives. Unfortunately, there are times when our
immune system, which Considerable evidence suggests that IDDM in NOD mice is mediated …
Who is more contemptible than he who scorns knowledge of himself?—John of Salisbury bodies; and the autoreactive T cell dependence of IDDM pathogenesis and the ability to intervene with disease This statement reflects our concern about the factors, progression by modulation of T cell function (Bach, 1994; Bowman et al., 1994; Tisch and McDevitt, 1996). both internaland external, that control our lives. Unfortunately, there are times when our immune system, which Considerable evidence suggests that IDDM in NOD mice is mediated by T cells. IDDM is prevented by neonormally protects us from adverse infections and diseases, scorns our body and mounts an autoaggressive natal thymectomy, by immunosuppressive agents that targetTcells, andbyanti-CD4andanti-CD8monoclonal attack against it, resulting in autoimmune disease. Among the many severely debilitating autoimmune dis- antibody treatments. Furthermore, IDDM can be adoptively transferred to neonatal NOD mice and immunodeeases are multiple sclerosis, rheumatoid arthritis, and insulin-dependent diabetes mellitus (IDDM), or type 1 ficient NOD. SCID (severe combined immunodeficiency) mice by T cells from spontaneously diabetic adult NOD diabetes. What are the factors, both genetic and environmental (diet and infection) that mediate the onset of mice. IDDM pathogenesis in NOD mice is heralded by the these diseases? How do we identify these factors? And how can we control these factors in order to prevent the infiltration—first by dendritic cells and macrophages and then by T cells (CD4 and CD8) and B cells—of the onset of autoimmune diseases? Studies of autoimmune diseases in representative animal models have proven perivascular duct and peri-islet regions of the pancreatic islets of Langerhans (peri-insulitis) beginning at 3–4 to be very informative. This review focuses on the use of one such animal weeks of age. This stage is followed by the slow, progressive, and selective T cell–mediated destruction of model, the nonobese diabetic (NOD) mouse, which spontaneously develops IDDM. The NOD mouse has insulin-producing islet cells by 4–6 months of age. Whereas a nondestructive peri-insulitis is observed in become the most extensively studied model of spontaneous organ-specific autoimmune disease. Excellent re- all female and male NOD mice, NOD females develop a more invasive and destructive insulitis and incur a higher views exist on the origin, genetics, immunological characteristics, and influence of environmental factors on incidence (80%–90%) of IDDM than males (10%–40%). This pronounced female gender bias is not observed in IDDM in NOD mice (Kikutani and Makino, 1992; Leiter and Serreze, 1992). Importantly, experiments conducted humans. A consensus view of the factors eliciting IDDM in the with NOD mice in recent years have begun to provide clues about how we may modulate and regulate the NOD mouse is that dysregulation of the immune response is a principal factor: an excess of islet antigen–immune response in order to protect against IDDM in humans (Bowman et al., 1994; Bach and Mathis, 1997). specific T helper type 1 (Th1) cells arise, perhaps as a consequence of a deficiency in regulatory or suppressor The central questions that we address in this review are: What are the immunological mechanism (s) that in- T cells. duce this T cell–mediated autoimmune disease? Is there a single mechanism that elicits IDDM or are there multi-
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