IMMUNOLOGICAL-TOLERANCE TO A PANCREATIC ANTIGEN AS A RESULT OF LOCAL EXPRESSION OF TNF-ALPHA BY ISLET BETA-CELLS

Recent experiments have suggested that tumor necrosis factor alpha (TN F alpha) can down-regulate islet-specific T cells and prevent the deve lopment of autoimmune diabetes. Here we demonstrate that transgenic mi ce expressing both TNF alpha and the Leishmania major LACK antigen in the pancreas (RIP-TNF alpha/RIP-LACK) exhibit an impaired ability to m ount a CD4(+) T cell response against LACK. In addition, peripheral CD 4(+) T cells from TCR transgenic mice (TCR-LACK/RIP-TNF alpha/RIP-LACK ) produced reduced interleukin-2 but elevated levels of T helper 2 cyt okines in response to LACK peptide in vitro. Taken together, our data suggest that TNF alpha may act in vivo to modulate a potentially damag ing self-reactive T cell response by inducing tolerance to pancreatic antigens.