Repeated daily injections of the adrenergic blocking agent guanethidine in high doses (SO mg/kg) to either newborn or adult rats produces a permanent sympathectomy which is thought to involve an immune-mediated mechanism. Ultrastructural examination of the acute phase of guanethidine-induced neuronal degeneration in the superior cervical ganglion demonstrated a prominent lymphocytic infiltrate in the ganglionic parenchyma and perivascular spaces. Within the satelliting cell sheath there were lymphocytes with delicate processes in intimate contact with abnormal or degenerating principal sympathetic neurons. The lymphocytic infiltrate and early evidence of neuronal degeneration developed within three days of onset of treatment and reached a maximum on the 7th day. Immunocytochemical studies of the ganglion demonstrated that the mononuclear infiltrate was composed primarily of CD-8 positive, OX-19 negative lymphocytes, which may represent a natural killer (NK) or NK-like effector cell, as well as scattered monocytes and macrophages. Guanethidine showed little effect on the prevertebral (superior mesenteric and celiac) sympathetic ganglia compared to the paravertebral (superior cervical) chain ganglia of the same animals. Considerable rat strain selectivity was noted with Lewis and Sprague-Dawley strains showing a greater degree of neuronal destruction than Fischer 344 rats. Neonatal thymectomy failed to prevent neuronal degeneration and the lymphocytic infiltrate. These features of immune neuronal killing are not typical of a characterized antibody or T-lymphocyte mediated effector mechanism, but may represent a selective NK cell or NK-like cell mediated pathogenetic pathway. Guanethidine- induced neuronal destruction appears to be a unique type of drug-induced, cell-mediated, autoimmune attack on sympathetic neurons and may provide insight into autoimmune disorders and possibly into diseases characterized by selective neuronal degeneration
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