In situ demonstration of T cell activation and elimination in the peripheral nervous system during experimental autoimmune neuritis in the Lewis rat

The mechanisms of activation and termination of autoimmune responses are poorly understood. We have studied the sites and mode of activation and elimination of T cells in actively induced experimental autoimmune neuritis (EAN) and in EAN adoptively transferred by P2-specific T cells (AT-EAN). The bromodeoxyuridine (BrdU) technique was employed to detect in situ proliferating cells in spleen and sciatic nerve. We assessed the nuclear morphology of infiltrating T cells using morphological criteria of apoptotic cell death. Apoptosis of lymphoid cells was also investigated using molecular labeling techniques. In AT-EAN, the number of BrdU-positive cells in splenic germinal centers peaked at day 2 after cell transfer [554 +/- 267 (mean +/- SEM) per mm(2); controls 98 +/- 35), 1 day before disease onset, and declined thereafter. BrdU incorporation in spleens from animals with active EAN peaked at day 11, around disease onset, but reached lower total values (165 +/- 29 per mm(2)). In neither model did we observe a significant proportion of BrdU-positive T cells in the peripheral nervous system. However, T cells exhibiting morphological signs of apoptosis were detected in the sciatic nerve immediately after disease onset. The number of these cells was highest on day 7 in AT-EAN (6.6 +/- 3.2 per mm(2)) and on day 17 in active EAN (11.2 +/- 2.2 per mm(2)), corresponding to the maximum of T cell infiltration in both animal models. T cell activation occurs systemically and not just in the autoimmune lesion. Infiltrating T cells are eliminated by apoptosis in situ, terminating the inflammatory process. Further insight into these mechanisms may help to develop new therapeutic strategies for autoimmune disorders of the peripheral nervous system.