ACCELERATED BETA-CELL DESTRUCTION IN ADOPTIVELY TRANSFERRED AUTOIMMUNE DIABETES CORRELATES WITH AN INCREASED EXPRESSION OF THE GENES-CODINGFOR TNF-ALPHA AND GRANZYME-A IN THE INTRA-ISLET INFILTRATES

Autoimmune destruction of beta-cells in nonobese diabetic (NOD) mice i s greatly accelerated by adoptive cotransfer of syngeneic CD4(+) and C D8(+) T-cells from diabetic animals into newborn NOD mice. We followed , by in situ hybridization, the appearance of mRNA of the tumor necros is factor (TNF)-alpha gene and, as a marker for activated cytotoxic T- cells, of the serine protease granzyme A gene in the cellular infiltra tes generated by cell transfer at birth, Cells expressing the genes fo r granzyme A or TNF-alpha were seen in considerable numbers already on day 14, after adoptive transfer. These numbers gradually increased in the intra-islet infiltrates from day 14 through day 30 after adoptive transfer. Compared with our previous findings in NOD mice developing spontaneous insulin-dependent diabetes mellitus (IDDM) (Held W, MacDon ald HR, Weissman IL, Hess MW, Mueller C: Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoi mmune diabetes. Proc Natl Acad Sci USA 87:2239-2243, 1990), frequencie s of cells with TNF-alpha and granzyme A mRNA were 2-and 12-fold highe r, respectively, in transferred IDDM (trIDDM). TNF-alpha mRNA positive cells were predominantly found in the CD4(+) T-cell subset of the pan creas-infiltrating cells, whereas granzyme A mRNA positive cells were mainly observed in the CD4(-) T-cell subset. The effects of the observ ed enhanced TNF expression upon the pathogenesis of trIDDM are as yet unknown. One may speculate, however, that a local production of TNF-al pha exerts direct cytotoxicity upon beta-cells and promotes lymphocyte traffic to the pancreatic islets, thus resulting in an increased freq uency of antigen-specific cytotoxic cells (mainly CD8(+) T-cells) with in the islets of Langerhans. The burst of activated granzyme A gene-ex pressing cells at the onset of diabetes further suggests that enhanced cell-mediated cytotoxicity may significantly contribute to the accele rated loss of beta-cells.