DIFFERENTIAL SUSCEPTIBILITY OF HUMAN CNS-DERIVED CELL-POPULATIONS TO TNF-DEPENDENT AND INDEPENDENT IMMUNE-MEDIATED INJURY

We examined whether oligodendrocytes, neurons, and astroglia derived f rom the human central nervous system differ in susceptibility to injur y mediated by tumor necrosis factor (TNF)-alpha and by activated CD4() T cells acting via a TNF-independent mechanism, Injury was assessed either as cell membrane-directed (lysis), measured by (51)chromium (Cr ) or lactate dehydrogenase (LDH) release, or nucleus-directed (apoptos is), measured by morphologic features based on propidium iodide (PI) s taining and by DNA fragmentation measured by a terminal transferase (T dT)-mediated dUTP biotin nick end labeling technique (TUNEL). TNF did not induce Cr-51 or LDH release in any cell targets, but did induce nu clear (66 +/- 2% of cells) and DNA (68 +/- 2% of cells) fragmentation selectively in the oligodendrocytes over 96 hr, At this time, there wa s no significant loss of oligodendrocyte cell number, Nuclear injury c ould be induced in neurons by serum deprivation and in malignant astro cytes by the combination of TNF and low serum, CD4(+) T cells activate d with phytohemagglutin (pha) or anti-CD3 plus interleukin-2 induced s ignificant Cr-51 and LDH release in all target cells tested; only pha- activated CD4(+) T-cell cocultures showed reduced target cell numbers, Significant nuclear fragmentation was observed only for glioma cells (22 +/- 1% of cells), Differences in susceptibility to different immun e effector mechanisms and in the nature of the injury response to the same effector mediator among human CNS-derived neural cells will need to be considered in design of therapeutic strategies aimed at protecti ng or limiting target cell injury consequent to disease or trauma.