Neurotoxicity induced by interleukin-2: involvement of infiltrating immune cells

Interleukin-2 (IL-2), a key regulator of immune functions, also has potent effects on neurons and glia. IL-2 modulates neural cell growth and survival and transmitter and hormone releases and is thought to mediate neuroimmune interactions. Investigating the neuroendocrine consequences of chronically elevated central nervous system (CNS) levels of IL-2, we recently observed marked neurotoxicity [Hanisch et al. (1994) Endocrinology 135:2465-2472]. In the present study, we characterize in detail the modifications in brain tissue architecture as they result in Sprague-Dawley rats from intracerebroventricular (i.c.v.) administration of low amounts of IL-2 (5 and 15 U/h, respectively, delivered by means of osmotic minipumps for up to 14 days). Histological inspection of the brains revealed massive cellular infiltrates in the ipsilateral hemisphere. The infiltrates were associated with pronounced angiogenesis and changes in the composition of the extracellular matrix. These anatomical changes apparently developed between day 7 and 14. They were specific for IL-2 and were not seen in animals treated, for example, with heat-inactivated IL-2 (controls). We further show that chronic central administration of IL-2 let to T and B lymphocyte invasion of the brain and an intracranial agglomeration of large numbers of MHC class II-positive cells. Immunocytochemistry revealed a widespread inundation of CNS tissue and a decoration of glial cells and neurons by endogenous antibodies. Tissue regions around the IL-2-induced infiltrates showed myelin destruction and neuronal cell loss. Chronically elevated CNS levels of IL-2 may, thus, not only interfere with neurotransmission and endocrine functions but also severely disturb tissue homeostasis. Therefore, the present findings could be relevant to brain injuries, CNS disorders, and clinical treatments associated with increased IL-2 levels or involving an immune component.