Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes.

Abstract

SummaryMice bearing a tumor necrosis factor (TNF) ot transgene controlled by an insulin promoter developed an increasingly severe lymphocytic insulitis, apparently resulting from the induction of endothelial changes with features similar to those observed in other places of intense lymphocytic traffic. This was accompanied by dissociation of the endocrine tissue (without marked decrease in its total mass), islet fibrosis, and the development of intraislet ductules containing, by places, cells in their walls, suggesting a regenerative capacity. Islet disorganization and fibrosis did not result from lymphocytic infiltration, since they were also observed in SCID mice bearing the transgene. Diabetes never developed, even though a number of potentially inducing conditions were used, including the prolonged perfusion of interferon 3' and the permanent expression of a nontolerogenic viral protein on/3 cells (obtained by using mice bearing two transgenes). It is concluded that (a) a slow process of TNF release in pancreatic islets induces insulitis, and may be instrumental in the insulitis resulting from local cell-mediated immune reactions, but (b) that insulitis per se is not diabetogenic, lymphocyte stimulation by cells other than B cells being necessary to trigger extensive B cell damage. This provides an explanation for the discrepancy between the occurrence of insulitis and that of clinical disease in autoimmune diabetes.

TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

“…Systemic administration or overexpression of TNF in islet b cells in neonatal C57BL/6 mice leads to massive insulitis and accelerates diabetes in NOD mice (11)(12)(13)(14)(15)(16)(17)(18). Consistent with this finding, anti-TNF Ab prevents diabetes progression when given to neonatal NOD mice (15).…”

Kinetics of TNF-alpha and IFN-gamma mRNA expression in islets and spleen of NOD mice

“…The levels of TNF-a gene expression progressively increased with age, with overexpression being observed at the 28th week. In some cases, TNF-a expression did not correlate with the progression of diabetes, suggesting that TNF-a can be more important for the development and maintenance of insulitis than diabetes (39,40).…”

Regulation of autoimmune diabetes by non‐islet‐specific T cells — a role for the glucocorticoid‐induced TNF receptor

“…However, conclusions from these results are severely hampered with the observations that IL-4-deficient (IL-4 -/-) NOD mice developed diabetes with the same kinetics and incidence as wild-type NOD mice [47] and that BDC Th2 T cells caused diabetes [48]. IL-10 as well as TNF- § accelerated or inhibited diabetes depending on the experimental conditions [49][50][51][52][53][54][55][56][57][58][59].…”