Recent studies from our laboratory and by other investigators have shown that autoreactive CD4+ cells specific for peripheral nerve P2 protein have a powerful effect on blood-nerve barrier permeability. In this study we injected CD4+ T cells reactive to a nonneural antigen (ovalbumin) systemically and achieved their accumulation in the tibial nerve of Lewis rats by previous intraneural injection of ovalbumin. Selected rats were given systemic demyelinating antibody (antigalactocerebroside) to provide an indicator of changes in the permeability of the blood-nerve barrier, and the animals were monitored by sequential neurophysiological studies and histology. Circulating ovalbumin-specific T cells accumulated at sites of intraneural ovalbumin injection without inducing demyelination in control animals. In rats with circulating galactocerebroside antibodies, local conduction block and demyelination were seen in the region of T-cell accumulation. Electron microscopy demonstrated dissolution of some tight junctions between endothelial cells in areas of T-cell accumulation, and T cells traversing the endothelium between endothelial cells and through their cytoplasm. Endothelial cell damage was evident in these areas. This study demonstrates breakdown of the blood-nerve barrier by activated T cells, even of nonneural specificity, allowing the development of focal conduction block and demyelination in the presence of circulating antimyelin antibodies.

Experiments were conducted to investigate the effect of activated T cells on the blood-nerve barrier (BNB) in experimental allergic neuritis (EAN). T cells reactive to the P2 component of myelin (P2 T cells) and known to cause EAN were injected into the sciatic nerve of Lewis rats. Animals were then given daily intraperitoneal (i.p.) injections of serum with known demyelinating activity (rabbit EAN serum) or control serum. Serial nerve conduction studies across the injected segment were performed and nerves were removed at various stages for histology. Focal conduction block and perivascular demyelination were evidence in T cell injected nerves of animals treated with EAN serum. In animals treated with control serum no conduction block was seen and only perivascular infiltrates without demyelination were present. Similar results were obtained with T cells reactive to non-neural antigens, although the effect was less marked. Systemically administered rabbit immunoglobulin (Ig) was demonstrated within the endoneurium of P2 T cell injected nerves by immunofluorescence and the endoneurial blood vessels showed increased permeability to circulating horseradish peroxidase (HRP). These findings demonstrate that activated T cells cause focal breakdown of the BNB, allowing circulating antimyelin antibody to enter the endoneurium with consequent focal demyelination. P2 reactive EAN producing T cells do not cause significant demyelination when injected intraneurally (i.n.) in the absence of circulating antimyelin antibody. Intraneural injection of tumour necrosis factor alpha (TNF-alpha) yielded similar results, causing conduction block and perivascular demyelination in the presence of circulating antimyelin antibody but not in control serum treated animals.

No abstract

Previous studies have shown that activated T cells can successfully cross endothelial barriers and will accumulate in tissue which contains their specific antigen. Myelin specific T cells (e.g. myelin basic protein specific) are recognized to play an important role in the induction of experimental autoimmune demyelinating disease of the CNS and have been shown to induce blood-brain barrier breakdown effectively. In this study we injected T cells reactive to a non-neural antigen (ovalbumin) systemically into Lewis rats and caused them to accumulate in the thoracic dorsal column by a prior injection of ovalbumin. Selected rats were given systemic demyelinating antibody, antimyelin oligodendrocyte antibody (anti-MOG antibody), to provide evidence of permeability changes to the blood-brain barrier. These animals were compared with control rats given systemic anti-P0 monoclonal antibody and to other rats given a direct micro-injection (3 microliters) of anti-MOG antibody into the thoracic dorsal column. All animals were monitored by serial neurophysiological studies and by histological examination. Direct anti-MOG antibody injection produced a focal block in conduction at the injection site and a large circumscribed area of primary demyelination with axonal preservation within the dorsal column. An even more profound conduction block and more extensive plaque-like region of demyelination were seen in animals given antigen, activated T cells and systemic antibody. However, animals given antigen and T cells without relevant antibody did not show conduction impairment or demyelination, except when very large numbers of T cells were given; such rats developed severe irreversible axonal damage. This study demonstrates the blood-brain barrier is disrupted by activated T cells of non-neural specificity and allows large plaque-like regions of demyelination to form in the presence of circulating antimyelin antibody. The relevance of this finding to multiple sclerosis is discussed.